IN this presentation, Dr. Cady reviews several of the handful of functional, integrative medicine techniques required for a holistic and comprehensive management of psychiatric issues. MTHFR, hormone balance, diagnosis and treating intestinal dysbiosis, need for trace elements, and hormones (including thyroid, testosterone and estradiol) are reviewed.

3. The Moral Imperative of
Integrative Medicine
Louis B. Cady, MD, FAPA
CEO, Founder – Cady Wellness Institute
Presented for the 11th annual IMMH Conference, August 20, 2020

4. I, Louis Cady, have the following current and
historical conflicts to declare….
• Speaker honoraria previously received from:
• Immunolaboratories, Great Plains Diagnostic Labs, LABRIX,
National Procedures Institute
• Speaker’s bureaus (active) for:
• Takeda/Lundbeck
• Historical data – speaker’s bureau for Allergan (Aventis), Arbor,
Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly, Glaxo-Smith
Kline, Janssen, McNeil, NEOS, Pfizer-Roerig, Sanofi~aventis,
Searle, Sepracor, Shionogi, Shire, Sunovion, Takeda, Vaya
Pharma, Wyeth-Ayerst
• Distributor – Pharmanex supplements & Biophotonic scanner

5. “The beginning of wisdom is the
definition of terms.” Socrates
• Moral [mores (L) = HABITS]:
– “a person’s standards of behavior or beliefs concerning
what is and is not acceptable for them to do.”
• Imperative:
– “of vital importance; crucial.” “An essential or urgent
thing.”
• Integrative:
– “serving or intending to unify separate things.”
• Medicine:
– “the science or practice of the diagnosis, treatment,
and prevention of disease.”

6. Orientation
“Tell me the facts and I’ll learn.
Tell me the truth and I’ll believe.
But tell me a story and it will live
in my heart forever.”
- Native American Proverb

7. The first story…
• 12 year old 7th grader. Intake Nov 15, 2019.
• “Worried about food being contaminated and that he
is going to have a heart attack.”
• “Worried about the lead in his pencils hurting him.”
• Things “getting stuck in his head – “like tunes,
sports, good stuff.”
• Holding saliva in his mouth constantly.
• Admits to “getting bored some times.”
• Math teacher comments about “careless errors.”
• Already started on Escitalopram 10 mg by
pediatrician Oct 26. Increased to 20 mg Nov. 4.

8. On exam:
• From intake: “Alert, pleasant, remarkably poised,
self-confident, mature and communicative. He is a
straight talking, ‘put it all out on the table’ kind of kid.
He is extremely refreshing. He clearly wants to get
better.”
• Childhood depression inventory relevant positives:
– “I worry that bad things will happen to me.”
– “Many bad things are my fault.”
– “I cannot make up my mind about things.”
– “There are some bad things about my looks.”
– “I have to push myself all the time to do my
schoolwork.”
– “I worry about aches and pains many times.”
– “I can never be as good as other kids.”

9. DSM5 review
Anxiety
• Constant worry
• Repetitive, senseless
thoughts
• Fearful feelings
• Keyed up/on edge
• Trouble concentrating
Depression:
• Sad/depressed/down in
the dumps
• Lack of/loss of interest in
things
• Decrease in appetite
and weight (due to
obsessionality)
• Trouble concentrating
• Frequent thoughts of
death. Of suicide he
says, “oh, no. I don’t
want to do that.”
Miscellaneous
•Feeling life is not worth
living
•Fear of dying
•Frequent crying or
weeping

10. Questions
• Diagnoses:
– Psychotic disorder?
– AD(H)D?
– Mixed depression/anxiety?
– Other?
• What to do?
– (already on max adult dose of escitalopram)
• Add antipsychotic?
• Add concomitant antidepressant?
• Add ADD medication?
• Refer for even more intense psychotherapy?
• How long do you think it will take to get him better?

11. The differential dx and treatment plan:
• Differential/case management ideas:
– OCD
– Mixed depression/anxiety
– Features of mild ADHD
– Doubt psychotic disorder
– Potential MTHFR polymorphism as a fundamental weakness
– Possible cytochrome p450 2D6 hypermetabolic genotype
(“SSRI pathway”)
• Tx:
– Leave escitalopram alone
– L-methylfolate 800 ug – ½ q am x 3-5 d, then 1 q am
– 5-HTP 50 mg + P5P supplement before bedtime.
– Haloperidol 0.1 mg – ½ or 1 before bedtime, or ½ - 1 twice
daily ONLY AS NEEDED FOR SEVERE OCD SYMPTOMS.
DO NOT FILL FOR ONE WEEK UNLESS NEEDED.
• LABS – cheek swab for pharmacogenomic testing
• FOLLOW UP – one month.

12. The follow up – Dec 13, 2019
Only 2 symptoms remained:
- “a tiny bit” of constant worry
- Increase in appetite (which was
HEALTHY)
Current Rx :
• Escitalopram 20 mg
• L-methylfolate – 800 ug daily
• 5HTP with P5P before bedtime.
• NO HALOPERIDOL WAS USED.

13. STATUS – 12/13/2019
• Fully resolved OCD + mixed
depression/anxiety
• MTHFR polymorphism – “homozygous at
the A1298C gene”
• Poor SLC6A4 – might not even need
escitalopram in the future.
• Plan is taper the escitalopram as able
and see back in four months.

14. RELEVANT LABS & status
GENE
SLC6A4 (SERT) S/S SSRI’s don’t work well
MTHFR
- C677T
- A1298C
C/C
C/C
Perfect. This is the major gene.
Worst POSSIBLE genotype at minor gene
= needs L-MF (This minor gene is
OMITTED by one of the major purveyors of
this type of test.)
COMT Val/met The best genotype “right down the middle.”
Cyp 2D6 2/4 NORMAL SSRI metabolizer (escitalopram)
Cyp 2B6 1/1 Bupropion would work if ever needed.
OPRM1 – a
“lagniappe”
G/G Worst POSSIBLE genotype – opioids will
not work for pain (if ever needed). This
gene is also omitted by one of the major
players in gene testing.

16. Stahl SM. L-methylfolate: a vitamin for your monoamines. J
Clin Psychiatry. 2009 Sep;69(9):1352-3
Strategy: test for “MTHFR genotype.”
References:
www.genomind.com www.genesight.com

17. Foundational matters:
• “The neo-Kraepeliain revolution in psychiatric diagnosis.” Eur
Arch Psychiatry Clin Neurosci. 1995;245 (4-6) 196-201.
– Take home point: don’t just consider the SYMPTOMS
• “We know from extensive research that early-life stress,
adversity, and especially trauma present prominent risks for the
later development of psychopathology.”
– Kalin, NH. Am J Psychiatry 177:1; January 2020.
– Cf also: Walker, P. Complex PTSD: From Surviving to
Thriving. © 2013
• Take home point: remember the possibility of trauma
and brain changes from early childhood ages on.

18. “If you just know the names of
the terms you absolutely know
nothing, and nothing about it.”
- Richard P. Feynman, Ph.D.

19. “If you can only read one article
in your entire career at Mayo on
psychotherapy, read this one.”
- John Graf, MD
Greben, S.
Can Psychiatr. Assoc
Journ. Vol 22 (1977):
371-380
“On Being
Therapeutic”

20. Greben’s “Seven Habits”
• Empathy & concern
• Warmth
• Interaction
• Ability to arouse hope
• Expectation of improvement
• “Not to despair”
• Reliability & Friendliness
*Requires clinical depth and breadth of knowledge
*
“On Being Therapeutic” - Stanley Greben, MD [Canadian Psychiatric
Association Journal. Vol. 22(1977) 371-380].

21. Commence Treatment!!
Childhood trauma – abuse, neglect
• THYROID
PROBLEMS?
Trace
elements?
• Adrenal and
sex
hormones?
• GI issues?
• Excess screen
time (video
games,
“dopamine
resistance”?)
NT’s – 5HT, NE, DA. Membrane
stabilization. Antipsychotics.
RX:
• Conventional meds –
antidep, ADHD Rx, mood
stabilizers.
• GI meds/supplements
• Supplements, foundational
nutritionals (eg. L-MF).
• Diet modification
Pharmacogenomics
Workup:
• Conventional labs
• For fatigue – adrenal, sex
hormone, and thyroid
testing
• Integrative labs (select &
draw as needed):
• IgG panel
• OAT
• Heavy metals
• Mold panel
Out of energy?

22. Organization of this presentation
• Illustration of need for optimum range of focus in
diagnosis & treatment of ALL psychiatric disorders
• CAVEATS:
• Can’t cover every nutritional intervention, hormone, or
diagnosis in detail
• Some of the fine points will clarify for you over the next
three days. 
• The purpose is to expose you to the concepts.
• Further study will be required to master this material.

23. Example: Integrative Treatment of
Schizophrenia
• (Psychodynamic:
– do not neglect psychotherapy!)
•Biological ≡ Holistic
– Biological – “of or relating to biology or to life
and living processes.”
• [Merriam-Webster]
–This is the very essence of
INTEGRATIVE medicine.

24. Case presentation
• Alan – presents on Feb 16, 2007,
diagnosed with depression vs. psychosis.
– Previous treatment at Pfeiffer Treatment Center
• He appeared notably fatigued and grossly
over-sedated.
• Morose and depressed. Lucid. Intelligent.

25. Past history
• “Ever since I can remember, I’ve always had
the same feelings about things – how people
treat each other and stuff like that.” “My
feelings just kept getting worse and worse the
more I was picked on. That was the only
thing that was wrong, people just calling you
names and stuff.”
• Alan became suicidal in middle school – 8th
grade year. “I just thought everyone was
making fun of me, so why should I go on?”

26. • Treated with fluoxetine in the past for depression
• Stopped being able to do homework as a
sophomore in high school
• “I was just really resentful of my parents a lot
during the past few months [at that time] – I just
started yelling at them in front of the therapist guy.”
• Partially stabilized by previous MD on aripiprazole
(20 mg), olanzapine (20 mg) and sertraline (50mg).
• Per Mom – “It was hard for him to be out and be
around a lot of people.”

27. 2007 - 2009
• More explosive outbursts. Lamotrigine
(200 mg) added topiramate continued
• “I know that I’m acting ridiculous – like a
schizophrenic, but I feel good, and I’m
talking more to everybody, and I’m trying
to get my point across, and I don’t feel as
evil as I used to.”

28. 2007- June 30, 2009
• He comments that he feels
his “mouth is going faster
than his thoughts.”
• Mom reports that
“traveling out here (to
appointment) wears on
him.” “He does better
when he’s quiet and in the
house.”
• RX:
– Olanzapine 30 mg at
9 pm
– Aripiprazole 20 mg
a.m.
– Topiramate 100 mg
HS
– Lamotrigine 200 mg
in a.m.
– Duloxetine – 120 day
– Modafinil – 100 mg
daily
– 5HTP 100 mg in the a.m.
TEGRATIVE MEDICINE TESTING
finally ordered!

29. Integrative (“functional”) medical testing
done
• Micronutrient analysis (functional
intracellular analysis) – deficiencies in:
– Vitamins A & D, zinc, Oleic acid, antioxidant
capacity
• IgG food allergy testing 7/22/2009
– 12 total sensitivities
• 2+ to eggs, cow’s milk, wheat, brewer’s yeast
• 1+ to cheese, mung bean, oat, pork, pumpkin,
sesame, tuna & baker’s yeast.

30. Patient “Alan”

31. SCHIZOPHRENIA AND
GLUTEN

32. “ Gluten sensitivity
schizophrenia”
search as of July
19, 2020
filter: date

33. “ Gluten sensitivity
schizophrenia”
search as of July
19, 2020
filter: relevance

34. • “1/3rd of people with schizophrenia have elevated IgG
antibodies to Gliadin & increased inflammation.”
• Glutamate ionotropic receptor (NMDA type) has similar
protein structure to gliadin – representing a potential
target for cross-reactivity.
• “Mimicry through the process of cross-reactivity
between and gliadin and the glutamate ionotropic
receptor might disrupt the functions of the glutamate
system and relate to illness pathophysiology.”

35. Differential antibody responses to gliadin-derived
indigestible peptides in patients with schizophrenia
• Evaluation: IgG and IgA antibodies against
indigestible gliadin-derived peptide antigens by
ELISA
• 169 patients with schizophrenia; 236 controls.
• RESULTS:
–Patients with schizophrenia had
increased levels of plasma IgG
against the gamma-gliadin-derived
fragment (AAQ6C) compared to
control subjects.
– No difference against NATIVE gliadins between patient
McLean RT et al. Translational Psychiatry. 2017 May 9;7(5):e1121.

36. Gliadin – a definition
“GLIADIN is the alcohol soluble fraction
of gluten and is the primary antigen
leading to an inflammatory reaction in the
small intestine, characterized by chronic
inflammatory infiltrate and villous
atrophy.”
From Chapter 17 – Molecular Basis of Diseases of Immunity. Beenhouwer,
DO. Molecular Pathology, © 2009, pages 291-304.
(https://www.sciencedirect.com/science/article/pii/B9780123744197000172)

37. Another recent schizophrenic patient for comparison

38. Last four months January 21, 2010
• On IgG diet. “He has been doing well on it.”
• At Christmas, however, he “went off of it.” Had cookies
everywhere – couldn’t keep him out of the wheat.
Following that gluten feast he exploded on New Year’s
eve.
• After the outburst, Alan specifically wanted to go back on
the diet program. “He seems really good [now].”

39. April 15, 2013
Low dose Lithium orotate started

41. Repeat testing 13 months later – May 21, 2014
(after lithium orotate)

42. “Lithium schizophrenia” search 7/19/2020 1,279 results

43. Conclusion:
“Lithium may attenuate olanzapine-induced
oxidative & inflammatory responses that
result from metabolic side effects associated
with olanzapine.”

44. Putative role of trace element
deficiencies in mental disorders
Diagnosis Relevant elements
Depression: Zn,Cr, Se, Fe, Co, I
PMDD, binge eating Cr
Schizophrenia Zn, Se, (and, per other articles, Li.)
Cognitive deterioration/
dementia
B, Zn, Fe, Mn, Co (Se)
Autism Zn, Mn, Cu, Co
Attention deficit disorder Fe (check FERRITIN and Fe)
Excess quantity (overexposure, genetic error) can also lead
to mental disturbances.
Janka Z. Ideggyogy Sz. 2019 Nov 30;72(11-12):367-379.

45. November 18, 2012
Mild elevation – probiotic
started

47. 4 of 5 papers in the literature
“schizophrenia candida”
• 1. Clozapine found to inhibit yeast budding to
hyphal transition. This and other antifungals might
have therapeutic activity in the future.
– Midkif J et al. Small molecule inhibitors of the Candida albicans
budded-to-hyphal transition act through multiple signaling pathways.
PLoS One. 2011;6(9):e25395.
• 2. Cyclic dipeptides from food and intestinal yeast cyclic
dipeptides may play a role in causing psychiatric disorders
such as schizophrenia. From cancer research, cyclic
dipeptides such as cyclo (proline-phenylalanine) have been
found to activate the pathways of apoptosis and to cause
programmed cell death.
– Semon BA. Dietary cyclic dipeptides, apoptosis and psychiatric disorders: a
hypothesis. Med Hypotheses. 2014 Jun;82(6):740-3.

48. 3. Odds ratio of schizophrenia with candida
albicans seropositivity
• Case control differences investigated regarding candida
albicans.
• 947 individuals studied
– 261 with schizophrenia (139 of which had 1st episode
schizophrenia
– 270 with bipolar disorder
– 277 non-psychiatric controls
• C. albicans seropositivity conferred increased
odds for a schizophrenia diagnosis (OR 2.04-
9.53, P⩽0.0001).
– Severance EG et al. Candida albicans exposures, sex specificity and cognitive deficits
in schizophrenia and bipolar disorder. NPJ Schizophr. 2016; 2: 16018.
• Published online 2016 May 4.
– Full article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898895/

49. 4. Probiotic normalization of Candida albicans in
schizophrenia: A randomized, placebo-controlled, longitudinal
pilot study.
• Longitudinal, double-blind, placebo-controlled pilot
investigation of 56 outpatients with schizophrenia.
Studied impact of probiotic treatments on yeast
antibody levels, and between levels of antibodies
and abdominal discomfort/ psychiatric symptoms.
• “Results from this pilot study hint at an
association of C. albicans seropositivity with
worse positive psychiatric symptoms, which
was confirmed in a larger cohort of 384 males with
schizophrenia.”
Severance EG et al. Brain Behav Immun. 2017 May;62:41-45.

50. How to order the labs (Lab Corp, Quest):
• Candida antibodies:
– IgG, IgA, Ig M with QUANTITATIVE TITERS
• Gluten:
– Anti-gliadin antibodies - IgG, IgA, IgM with
quantitative titers
– Tissue trans-glutaminase
• Integrative – Organic Acid Test

52. Off-target effects of psychoactive drugs
revealed by genome-wide assays in yeast
Drug effect
81 compounds “inhibited wild-type yeast growth”
Fluoxetine “interfered with establishment of cell polarity
Cyproheptadine Targeted essential genes with chromatine-remodeling
roles
Paroxetine Interfered with RNA metabolism genes
Clozapine
Haloperidol
Pimozide
All had “off target” effects in
yeast
Ericson E et al. PLoS Genet. 2008 Aug 8;4(8):e1000151. doi:
10.1371/journal.pgen.1000151.on

53. A mashup from the literature…
• “MTHFR deficiency schizophrenia” – 8
citations
• “Vitamin D deficiency schizophrenia” – 138
• “B12 deficiency schizophrenia” – 45
• “B-vitamin deficiency schizophrenia – 80
• “PUFA deficiency schizophrenia” – 17
PubMed Search – July 20, 2020

54. Alan – updates
• March 26, 2019:
– “We go out every day. We’re going to restaurants now, and we are
going anywhere without hesitation.”
– “Each day I have more energy and less anxiety. When I’m out and
about in the cars – it doesn’t bother me any more….. It’s like a
whole new experience.”
– RX:
• Clozapine (300 mg bedtime), vortioxetine, Vitamin D3. L-methylfolate in a.m. ,
Coenzyme Q10,
• Medical Rx per his primary care MD
• Still on IgG diet.
• October 21, 2019
– “Every day we’re getting out and doing things.”
– Back on e-bay selling guitar stuff.
– Went to the Fall Festival twice, including watching the parade.
– No affective symptoms. Not paranoid. Good energy.

55. Alan, January 27, 2020
• Medications:
– Clozapine & vortioxetine. Atenolol from LMD.
– L-MF 1mg q a.m. Coenzyme Q10
• “The only thing that bothers me is being on
computers and stuff like that.” “But I can do
the job at Salvation Army. The paranoia is
kind of gone. As I keep getting better, I’m
not paranoid.”
• “Those paranoid thought are just erased.
Those thoughts just seem to be gone.”
• Medications:
– Clozapine & vortioxetine. Atenolol from LMD.
– L-MF 1mg q a.m. Coenzyme Q10
• “The only thing that bothers me is being on
computers and stuff like that.” “But I can do
the job at Salvation Army. The paranoia is
kind of gone. As I keep getting better, I’m
not paranoid.”
• “Those paranoid thought are just erased.
Those thoughts just seem to be gone.”

56. Key concept
“ADRENALS
BEFORE
THYROID.”

58. DHEA(S) – The Critical Hormone Most
Conventional Doctors Never Check
• Produced in the adrenal cortex
– Humans and primates are unique in secreting large amounts –
“the most abundant steroid hormone in the human body.”
(Maninger et al. Front. Neuroendocrinol. 2009 Jan; 30(1):65-91.)
• Immune system booster, Insulin regulator
• Energy increase* – remarkable
• Boosts growth hormone
– 20% in men; 30% in women in one study
• [Yen, Morales Khorram – one year double-blind placebo controlled crossover
experiment – with 100mg DHEA]
• Antidepressant effects

59. DHEA- more references
• “DHEA produced in the spinal cord
exerts a regulatory effect on
nociception in neuropathic rats. In this
short review, we discuss recent studies
concerning crucial signaling cascades and
molecular mechanisms involved in pain generation
as well as the potential link between DHEA activity
and nociception.”
– Huang K et al. Potential of dehydroepiandrosterone in
modulating osteoarthritis-related pain.

60. DHEA appears remarkably effective
for reducing chronic fatigue
• CFS patients frequently associate their disease
onset with a period of high physical &/or
emotional stress
• Of initially screened patients with CF
– 76% (116/of 153) were 35-55 yoa
– 89% (103/116) of all those screened had
decreased production of DHEA
• Supplementation with DHEA to CFS patients led
to multiple benefits…
Himmel PB, Seligman TMN. A pilot study employing
Dehydroepiandrosterone (DHEA) in the treatment of chronic fatigue
syndrome. J Clin Rheumatol. 1999 Apr;5(2):56-9,

61. Here were the benefits:
• Significant reduction in symptoms of CFS
• Pain: improved by 18%
• Fatigue – decreased by 21%
• ADL’s – improved by 8.5%
• Helplessness – decreased by 11%
• Anxiety – decreased by 35% (!! p<0.01)
• Thinking – improved by 22%
• Memory – improved by 17%
• Sexual problems – improved by 22%
Himmel PB, Seligman TMN. A pilot study employing
Dehydroepiandrosterone (DHEA) in the treatment of chronic
fatigue syndrome. J Clin Rheumatol. 1999 Apr;5(2):56-9,

62. Anabolic Hormone Profiles in Elite Military
Men: Robust Associations with Age, Stress
and Fatigue
• Lower DHEA and testosterone concentration associated
with higher fatigue
• Quartile segmentation:
– Those with the lowest quartile of testosterone in evening had
highest level of fatigue of the four groups
• “This study…showed that anabolic hormone profiles…
are also valuable predictors of stress & fatigue in elite
military men.”
Taylor MK et al. Steroids. 2017 Aug;124:18-22.

63. THYROID AND DEPRESSION

64. • 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)

65.  Depressed mood 100%
 Reduced energy: 97%3
 Fatigue or loss of energy: 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.

66. The Glamorous Grandmother – Post
Tune-up: DHEA, Thyroid, Testosterone,
Progesterone
9/28/2011 (Permission granted to use photos & data) 01/26/2012

67. 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 to T3 requires Se and Zinc!
T4
And these are the factors that
improve cellular sensitivity to
thyroid hormones:
• Vitamin A
• Exercise
• Zinc
Adapted by Louis B. Cady, MD (2018) from Institute For Functional Medicine graphic, 2011
Factors that Affect Thyroid Function
THYROID
GLAND
T3
Nucleus
mitochondria
Rev
T3

69. What You Can Do with an Integrated
Approach in 15 Months
RX: dairy free diet (+IgG test); D3 5000 IU/d; porcine thyroid, Testosterone
cypionate 100 mg IM q wk., MVI, Zinc, DHEA 50 mg SR, CoQ10 400mg
(photo shot 15
months after tx)
(permission granted to use photos & data)

70. The Case of the Mismanaged Executive –
Summary
• 42 year old male ADHD CEO, Background in psychology,
Now EXTREMELY stressed
• “So tired I feel like I’m dying.” “Depressed.”
• Lab findings – Low testosterone, despite multiple pumps
daily of low potency FDA-approved “Big Pharma”
transdermal testosterone gel managed by endocrinologist
• Low thyroid, Low DHEA
• RX: Testosterone cypionate IM – 60 mg twice weekly. DHEA
– 50 mg SR. Porcine thyroid – ½ grain
• Clinical status: Total resolution of symptoms in 3- 4 weeks,
No antidepressant used

71. TESTOSTERONE THERAPY: HAS
OVER USE UNDERMINED USE?
www.thelancet.com/diabetes-endocrinology. Vol
6, March 2018
DTC’S in US until 2014: “low T”, imagery of cars and
speedboats, “suggesting that youthful vigour is
achievable with testosterone products.”
“The issue of the cardiovascular safety of testosterone
therapy is of particular relevance in this context,
although the evidence from both trials and
observational studies in conflicting and inconclusive.”
“In the large population of healthier off-label users, the
possibility of an increased risk of cardiovascular
events is a major cause for concern.”
“Inappropriate and overuse of testosterone therapy remains
widespread.”

72. Testosterone Treatment and Mortality in
Men with Low Testosterone Levels
• Observational MORTALITY study: T-treated men
vs. non-tx.
– 1,031 male veterans, > 40 yoa
– Low TT (</= 250 mg/dl), no hx of prostate CA
– Assessed Jan 2001 – Dec 2002; followed through
2005.
• The results:
– 10.3% mortality in testosterone tx’ed men
– 20.7% in un-tx’ed men (P<0.0001)
Shores MM, Smith NL, Forsberg CW, et al. Testosterone treatment and mortality in men with low
testosterone levels. J Clin Endocrinol Metab. 2012;97:2050–8.

73. “In an observational cohort of men
with low testosterone levels,
testosterone treatment was
associated with decreased
mortality compared with no
testosterone treatment.”
Shores MM, Smith NL, Forsberg CW, et al. Testosterone treatment and mortality in men with low
testosterone levels. J Clin Endocrinol Metab. 2012;97:2050–8.
CONCLUSIONS

74. Another Literature Review
• Men with low T have higher all cause mortality, mainly
due to increase in CV disease
– Shores MM et al. Arch Intern Med. 2006;166:1660-5.
– Khaw KT et al. Circulation. 2007;116:2694-7091
– Haring R et al. Low serum testosterone levels are associated with
increased risk of mortality in a population cohort of men aged 20 – 790 (!!)
Heart J. 2010;31:1494-501
• T Rx assoc with inc LBM, fat reduction, inc in muscle
strength
– Svartberg J et al. In J Impo Res. 2008;20:378-87.
– Page ST et al. J Clin Endocrinol Metab. 2005;90:1502-10.
– Sih R et al. J Clin Endocrinol. Metab. 19978; 82:1661-7.
– Srinivas-Shankar U et al. J Clin Endocrinol. 2010;95:639-50. (NB –
randomized, double-blind, placebo controlled study.)

75. Long-term T Treatment…
•Reduction in fat mass, increase in
muscle strength with significant
changes in FUNCTIONAL ABILITY in
older men.
• Svartber J et al. Int J Impot Res. 2008;20:378-87.
• Page ST et al. J Clin Endocrinol Metab. 2005;90:1502-10
• Sih R et al. J Clinc Endocrinol Metab. 1997;82:166-7.
• Srinivas-Shankar U et al. (randomized double blind, placebo
controlled study in elder men) J Clin Endocrinol Metab.
2010;95:639-50.

76. Long-term T Treatment…
• Reduces body fat mass, regional fat
distribution and waist circumference in
hypogonadal men w/ and w/o obesity.
• Page ST et al. J Clin Endocrinol Metab. 2005;90:1502-10.
• Does not increase risk of voiding symptoms
but may increase prostate size to that of
eugonadal men.
• McVary KT et al. J Urol. 2011; 185:1793-803.
• Behre HM et al. Clin Endocrinol (Oxf). 1994;40:341-9.

77. T vs. Mood in Men
• Study: 278 men, >45yo, followed 2 years
• Compared to eugonadal patients,
hypogonadal men w/TT <200ng/dL had
– 4-fold increase risk of depression
– Significantly shorter time to depression
diagnosis
• Depression risk inversely related to TT
w/statistical significance <280ng/dL
Shores MM, Arch Gen Psychiatry. 61(2004):162-7

78. T vs. Mood in Men (June 2019)
• “Recent publications support the finding
that testosterone replacement
therapy in men with
low testosterone may
improve depression, and that
androgen deprivation therapy
in men with prostate cancer may
contribute to depression.”
Need KT. Androgens and depression: a review and update. Curr Opin Endocrinology
Diabetes Obes. 2019 Jun;26(3):175-179.

79. T vs. Cognitive Function
• 400 independently living men, 40-80yo
– 100 in each age decade
– MMSE 21-30, average 28
– TT: 208-1141ng/dL; Bio-avail T 78-470ng/dL
• HIGHER T = better cognitive performance in OLDEST
AGE category
• Men in lowest quintile of T = worse than men in
highest quintile of T
• Highest Bio-available T more significant than TT, age,
intelligence level, mood, smoking, and alcohol.
Muller M, et al. Neurology. 2005 Mar;64(5): 866-71. [NB – more recent studies show no
correlation.]

80. 9 Unanimous Resolutions
1. TD [testosterone deficiency] is well
established, clinically significant, and
affects male sexuality.
2. S/Sxs of TD occur as a result of low levels
of T and may benefit from treatment
regardless of whether there is an identified
underlying etiology.
3. TD is a global health concern.
4. T therapy for men is effective, rational, and
evidence-based.
Morgentaler A et al. Mayo Clinic Proceedings. 2016 Jul;91(7):881-96.

81. 9 Unanimous Resolutions
5. There is no T threshold that reliably
distinguishes those who will reliably
respond to tx from those who will not.
6. There is no scientific basis for any age-
specific recommendations against the use
of T therapy in men
7. The evidence does not support
increased risks of cardiac event with T
therapy.
Morgentaler A et al. Mayo Clinic Proceedings. 2016 Jul;91(7):881-96.

82. 9 Unanimous Resolutions
8. The evidence does not support increased
risk of prostate cancer with T therapy.
9. The evidence supports a major research
initiative to explore possible benefits of T
therapy for cardiometabolic disease,
including diabetes.
“These resolutions may be considered points
of agreement by a broad range of experts
based on the best available science."
Morgentaler A et al. – Mayo Clinic Proceedings. 2016 Jul;91(7):881-96.

83. Testosterone in women
• (Transdermal) testosterone
improves:
– Sexual desire, arousal, orgasm frequency,
and sexual satisfaction in premenopausal
and post-menopausal women.
– Also associated with favorable effects on body
composition, bone, cardiovascular fxn, and
COGNITION
Davis SR. Androgen therapy in women, beyond libido. Climacteric. 2013 Aug;16 Suppl
1:18-24. doi: 10.3109/13697137.2013.801736. Epub 2013 May 27.

84. Testosterone Enhances Estradiol’s Effect on
Postmenopausal Bone Density and Sexuality
• Study of effects of E2 and T implants on BMD and
sexuality
– 2 year, single-blind, randomized trial
• N= 34
• 50 mg of E2, or 50 mg of E2 + 50 mg T
• Cyclic oral “progestins” used in cases of intact uterus
• Results:
– DEXA scans improved in both groups
– BMD increased more rapidly in T treated group at all
sites
– All sexual parameters improved in both groups
Davis DR. Maturitas. 1995 Apr;21(3):277-36.

85. One destigmatizing notion:
Estrogen as MAOI
• Estrogen & Testosterone (!) decrease
MAO
– Luin, VN. Effect of gonadal steroids on activities of MAO
and choline acetylase in rat brain. Brain Res. 1975;86:273-306
• Platelet MAO levels inversely
correlated to estradiol levels
– Klaiber EL et al. Psychoneuroendocrinology.
1997 Oct;22(7):549-58.
• Estrogen decreases MAO-A & MAO-B
– Holschneider DP et al. Life Sci. 1998;63(3):155-60

87. Estrogen: Good For Your Brain
• Estradiol influences performances of learning and
memory tasks as well as increase working memory
– Sub-point – women are living three decades longer;
hence they are spending more time hypoestrogenic
• Pompilli A et al. Estrogens and memory in physiological and
neuropathological conditions. Psychoneuroendocrinology. 2012 Sept;
37 (9):1379-96
• Estradiol = protective against schizophrenia.
• Kulkarni J, et al. Hormones and Schizophrenia. Curr Opin Psychiatry.
2012 Mar;25(2):89-95

88. Testosterone: The “sexist” bias against women
(e.g., “your loss of sex drive is just natural for
your age.”)
• Fall in the circulating testosterone and the adrenal
preandrogens most closely parallel increasing age.
• Accelerated decrease occurs in the years preceding
menopause (like estrogen).
• Their loss affects: libido, vasomotor symptoms (hot
flashes), mood, well-being, bone structure, and muscle
mass.
– Burd, Bachmann. Androgen replacement in menopause. Curr Womens
Health Rep. 2001 Dec; 1(3):202-5.

90. Joey: Seen for intake in my office –
9/5/2012
• Alert. Serious. Intent on toys.
Played with them loudly. Not
speaking in complete
sentences. Phonated
repetitively.
• Huddled down and pulled his
lunch box in front of him when
I asked him a question.
• Obsessive play with toys.
“Push push push.”
Extensive laboratory testing ordered. Armour restarted.

91. December 5, 2012 follow-up
• RX:
– Porcine thyroid 1 ½ grains (with
PERFECT labs); Nystatin; high dose
MVI with B-complex; GSH precursors,
Cod liver oil, B6, Vit C, probiotics, 1
mg ionic Lithium.
– On food antigen diet.
• Family now able to go to church and
sit in pew. Went to MGM’s 95th
birthday party.
• Mental Status Examination:
– Alert, pleasant, happy, engaging.
Talking more. Gait improved. Speech
much more intelligible. Played happily
and cooperatively with Dad.

92. The REST of the Story - Joey
9/15/20139/5/2012

93. “Make no little plans
…they have no magic to stir men's blood and
probably themselves will not be
realized. Make big plans; aim high in
hope and work, remembering that a noble,
logical diagram once recorded will never die, but
long after we are gone be a living thing,
asserting itself with ever-growing insistency.”
Daniel Burnham (1846-1912)
World famous Chicago architect and the
single reason that Chicago was named the
site of the Columbian Exposition (World’s
Fair) in 1893.

94. Commence Treatment!!
Childhood trauma – abuse, neglect
• THYROID
PROBLEMS?
Trace
elements?
• Adrenal and
sex
hormones?
• GI issues?
• Excess screen
time (video
games,
“dopamine
resistance”?)
NT’s – 5HT, NE, DA. Membrane
stabilization. Antipsychotics.
RX:
• Conventional meds –
antidep, ADHD Rx, mood
stabilizers.
• GI meds/supplements
• Supplements, foundational
nutritionals (eg. L-MF).
• Diet modification
Pharmacogenomics
Workup:
• Conventional labs
• For fatigue – adrenal, sex
hormone, and thyroid
testing
• Integrative labs (select &
draw as needed):
• IgG panel
• OAT
• Heavy metals
• Mold panel

95. Palace of Fine Arts – 1893. Daniel Burnham, architect
(Now part of the Museum of Science and Industry)

96. Louis B. Cady, MD
Cady Wellness Institute
4727 Rosebud Lane – Suite F
Newburgh, IN 47630 USA
Office (812) 429-0772
www.cadywellness.com
info@cadywellness.com
www.facebook.com/cadywellness
Twitter: @LouisCadyMD
www.cadywellness.com
See all of the slides, including ones I
had to trim out, at:
www.slideshare.net/lcadymd