For Smitty
FIELD MANUAL
TRT-001
Copyright © 2020 Andrew Winge MD
All rights reserved. No part of this book may be used or reproduced in any manner whatsoever
without prior written consent of the author, except as provided by the United States of America
copyright law.
This publication is designed to provide accurate and authoritative information with regard to the
subject matter covered. It is sold with the understanding that the publisher and author are not
engaged in rendering legal, medical or other professional advice. This book is not intended as a
substitute for consultation with a licensed healthcare practitioner, such as your physician. Before
you begin any healthcare program, or change your lifestyle in any way, you should consult your
physician or another licensed healthcare practitioner to ensure that you are in good health and
that the examples contained in this book will not harm you.
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Doc Simpson
Foreword:
In my early 40’s, after spending the majority of my adult life in
exceptional physical shape, I found myself struggling. Before I get to
that, let me provide some background for context:
At age 18, I enlisted in the United States Army and became an Airborne
Ranger. For those not familiar, life in Ranger Regiment is comparable
to that of any professional athlete, with the added twist that the stakes
are much higher than scoreboards and rankings. Following my time in
the Rangers, I volunteered for Special Forces training, and was subjected
to one of the most physically and mentally grueling selection processes
in the world. For over a decade, I was constantly honing my mind and
body into the ultimate weapon, as I lived the challenging yet rewarding
life of a Special Forces Operator.
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With 17 years of service behind me, I decided to seek a career as a
physician, and hoped to continue my career in Special Operations,
providing battlefield care to those who fight at the tip of the spear. It
was during medical school, in my late 30’s, that I truly struggled with
my physical fitness for the first time in my life. During other difficult
times in my life I had always found a way to keep fit, but during medical
school and Emergency Medicine residency something had changed.
I put on 15 pounds of fat during medical school and another 15 pounds
during my first year of residency despite my best efforts to stay healthy.
The combination of shift work, job stress, and my aging metabolism was
taking a toll. I realized that my goal of returning to the Special
Operations Community was in peril if I couldn’t get into shape. That’s
when I turned to Dr. Andrew Winge for help. After assessing where I
was physically, and what my goals and needs were, Dr. Winge
uncovered that I was suffering from very low testosterone levels and
developed a treatment plan as well as a diet and exercise program to help
get me back on track.
Almost immediately, I felt like I was a young Ranger again, and was
able to lose fat and build muscle like I had in my youth. Thanks to the
guidance of Dr. Winge, I was able to maintain a high state of physical
fitness and was able to return to the Special Operations Community and
keep up with operators half my age over the next 10 years including five
more combat deployments.
Today, I am 54 years old, and although I am retired from the military, I
continue to live the “Operator Lifestyle”. I am a practicing SWAT
physician, a practitioner of Brazilian Jiu Jitsu and Muay Thai, and an
avid fitness enthusiast. I am also a husband and a father, who always
has the energy and endurance to do whatever I am required to in order to
fulfill my role.
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Testosterone replacement has enhanced both the quality and the quantity
of my life, and for that I am truly grateful.
Rangers Lead the Way/De Oppresso Liber
Mike Simpson, M.D.
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TESTOSTERONE REPLACEMENT THERAPY FIELD
MANUAL
TABLE OF CONTENTS
Page
PREFACE
CHAPTER 1. INTRODUCTION
1-1. TESTOSTERONE DECLINE ............................... 14
1-1-A. ENVIRONMENTAL EXPOSURES .........................19
1-1-B. LIFESTYLE FACTORS: DON’T BE FAT… .......... 24
1-2.
WHY YOU NEED TESTOSTERONE ..................... 28
1-3.
TRT vs. “JUICING” .............................................. 30
CHAPTER 2. DIAGNOSIS
2-1. INITIAL LABS… ................................................. 32
2-1-A. WHAT IS A “LOW” TESTOSTERONE LEVEL?. ...... 36
2-2. SYMPTOMS ....................................................... 39
2-3. PRIMARY HYPOGONADISM… ......................... 45
2-4. SECONDARY HYPOGONADISM….................... 50
CHAPTER 3. ELEVATING TESTOSTERONE NATURALLY
3-1. REDUCE BODYFAT ................................................. 54
3-2. DIETARY CONSIDERATIONS… ............................... 57
3-3. NATURAL TESTOSTERONE BOOSTING
ORDER OF OPERATIONS… ..................................... 60
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CHAPTER 4. TREATMENT OPTIONS
4-1.
4-2.
4-3.
4-4.
4-5.
4-6.
4-7.
4-7-1.
4-7-2.
4-7-3.
4-7-4.
4-7-5.
4-8.
INTRAMUSCULAR TESTOSTERONE… ..............61
TRANSDERMAL TESTOSTERONE… ............... 68
BUCCAL TESTOSTERONE… ............................. 69
ORAL TESTOSTERONE… ............................... 70
TESTOSTERONE PELLETS… ............................ 72
NASAL TESTOSTERONE .................................73
TESTOSTERONE ALTERNATIVES .................. 74
HCG… ..............................................................75
CLOMIPHINE................................................... 79
AROMATASE INHIBITORS. ............................. 82
KISPEPTIN-10 ....................................................84
HMG ................................................................. 85
MANAGING ESTROGEN… .............................. 87
CHAPTER 5. POTENTIAL SIDE-EFFECTS
5-1. DHT & HAIRLOSS… ........................................... 91
5-2. ACNE.................................................................. 93
5-3. ERYTHROCYTOSIS (ELEVATED HEMATOCRIT). 93
5-4. SLEEP APNEA ..................................................... 97
5-5. TESTICULAR ATROPHY/INFERTILITY… ............. 98
5-6. GYNECOMASTIA .............................................. 99
CHAPTER 6. TESTOSTERONE MYTHS
6-1. HEART DISEASE ............................................... 103
6-2. PROSTATE DISEASE .......................................... 106
6-3. CHOLESTEROL… ...........................................107
6-4. AGGRESSION… ..............................................108
6-5. BLOOD CLOTS… ..............................................109
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CHAPTER 7. MONITORING .............................................. 111
CHAPTER 8. INJECTION TECHNIQUE
8-1.
8-2.
8-3.
8-4.
INTRAMUSCULAR INJECTION… ...................... 114
SUBCUTANEOUS INJECTION............................ 118
SYRINGE AND NEEDLE TYPES… ..................... 120
INJECTION TECHNIQUE… ............................... 121
CHAPTER 9. STOPPING TESTOSTERONE
9-1. COLD TURKEY .................................................. 122
9-2. ASSISTED RECOVERY… .................................... 123
CHAPTER 10. MAINTAINING FERTILITY .......................... 129
CHAPTER 11. DISCUSSING TESTOSTERONE WITH YOUR
DOCTOR
11-1. ASKING FOR THE TEST… ................................ 131
11-2. ADAM AND AMS SCORES… ............................ 132
11-3. “YOU’RE NORMAL” .......................................... 132
CHAPTER 12: SAMPLE TRT PROTOCOL
12-1. INJECTABLE TRT… ........................................... 138
12-2. TOPICAL TESTOSTERONE ..................................139
12-3. HCG/CLOMID PROTOCOL… .............................. 140
CHAPTER 13: FEELING BETTER
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13-1 : SETTING EXPECTATIONS… .............................. 141
13-2 : TRT TIMETABLE ...............................................142
Final Comments .................................................................... 145
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STANDING ORDERS FOR OPTIMAL
TRT
1. KEEP your testosterone in the normal range. TRT
is not “juicing”.
2. OBTAIN regular lab work to monitor your health.
At least twice a year for otherwise healthy men
is necessary. More frequent monitoring may be
needed depending on your medical history.
3. FOLLOW your doctor’s orders.
4. EXERCISE regularly.
5. GET your body fat under control. NOW.
5. DO NOT eat junk food.
6. MONITOR your blood pressure.
7. INJECT only in the proper anatomical locations.
8. DO NOT reuse syringes.
9. CARRY a copy of your prescription when you travel.
This is especially true for overseas travel.
10. EXPECT push back from primary care physicians.
Not all physicians understand the need to treat low
testosterone. Just move on and find an experienced
provider.
11. GET adequate sleep.
12. DO NOT go “on” and “off” testosterone. TRT is for life.
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NOTES
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PREFACE
Perhaps the biggest trend in men’s health over the past ten years has
been recognition of the importance of optimal testosterone levels and
their contribution to the overall health and well-being of the aging man.
For decades the medical establishment has recognized the signs and
symptoms experienced by women who enter menopause. The relatively
rapid and abrupt onset of these symptoms and the easily detectable and
precipitous drop in measurable hormone levels makes the diagnosis of
menopause a relatively straightforward process. In 1942 the FDA
approved Premarin, the most commonly used estrogen preparation used
to treat menopausal symptoms. Since then, millions of women have
taken hormone replacement (HRT). Despite a reduction in female
hormone prescriptions following the 2002 Women’s Health Initiative
study, millions of women worldwide continue to have easy access to
HRT. There is no social stigma and virtually no controversy when a
woman visits her doctor requesting HRT for symptom relief in the
perimenopausal or menopausal time frame.
Though things are slowly moving in the right direction, men do not
receive the same early recognition of symptoms of low testosterone and
still lack similar access to appropriate treatment in the way that women
do. Many primary care physicians, as well as endocrinologists, continue
to suffer from a number of misconceptions regarding the role healthy
testosterone levels play in both men’s physical and psychological health.
They also continue to perpetuate a number of myths regarding the
hazards of testosterone therapy. These range from fear of prostate cancer
to cardiovascular disease. These myths and many others will be
addressed in this manual.
The purpose of this manual is to provide men with a concise reference
that can provide the following:
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1. An understanding of the fundamental aspects of evidence-based
testosterone replacement therapy. There are few things more
frustrating to a physician than a patient who has no idea what
medications he takes or why he takes them. Don’t be that guy.
Know exactly what you are putting into your body, why you are
doing it, and what proper monitoring should look like. This will
help you not only stay on track, but also recognize when your
physician may not be up to date on the latest information in regard
to male hormonal optimization.
2. A reference you can use prior to visiting your physician for the
first time so that you can speak and ask questions in a wellinformed manner. Each page will be footnoted with references to
recent scientific research articles that you can provide to your
physician if they lack understanding or wish to learn more about
testosterone replacement therapy (TRT).
3. A source of information you can easily share with your male
friends and family who may be suffering from symptoms
associated with low testosterone. This book is formatted and
printed in a way similar to generations of U.S. military field
manuals designed to be read and passed easily between soldiers. If
you have a friend or colleague who you think may benefit from the
information in this book, then consider passing on your copy to
them.
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CHAPTER ONE
TESTOSTERONE LEVELS
ARE DROPPING
1-1. TESTOSTERONE DECLINE
The gradual decline in a man’s testosterone levels after about age 30 is a
well-described phenomenon. Studies vary, but most demonstrate about a
1.5% annual decline in total testosterone in otherwise healthy men after
about age 301. The decline in free testosterone, which is the testosterone
actually available for use by the body and not bound up by various
proteins, is much more profound, however. Free testosterone can
decline but up to 50% or more between the ages of 25-752. This is
primarily a result of the increased levels of SHBG (steroid hormone
binding globulin), which binds to testosterone and prevents it from
binding to the androgen receptor, essentially removing it from the
testosterone available to the body.
These normal age-related changes in testosterone are insufficient,
however, to explain the marked prevalence of symptomatic low
testosterone now being recognized as a worldwide issue for modern
men. In fact, testosterone levels have been dropping every generation
since they were first measured 3. A number of studies show age-matched
1 Feldman HA, Longcope C, Derby CA, et al: Age trends in the level of serum testosterone and other hormones in middle -aged men: longitudinal
results from the Massachusetts male aging study. J Clin Endocrinol Metab 87:589–598, 2002.
2 Yeap BB, Almeida OP, Hyde Z, et al: In men older than 70 years, total testosterone remains stable while free testosterone declines with age.
The Health in Men Study. Eur J Endocrinol 156:585–594, 2007.
3Andersson AM1, Jensen TK, Juul A, Petersen JH, Jørgensen T, Skakkebaek NE. J Clin Endocrinol Metab. Secular decline in male testosterone
and sex hormone binding globulin serum levels in Danish population surveys. 2007 Dec; 92(12): 4696-705. Epub 2007 Sep 25.
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men living today have significantly lower testosterone levels than their
predecessors one or two generations prior.
Studies also confirm what many of you have suspected, which is that the
average “millennial” man is physically weaker than those of the same
age tested as recently as 19854. With one look at the physical state of
young men entering military basic training today and the preponderance
of emasculated “soy-boys” roaming college campuses today and it’s not
difficult to see this study likely has some validity. Many of them have
grown up sitting on the couch texting and playing video games while
consuming a steady diet of processed junk food since they were toddlers.
The outcome of this lifestyle is predictable. If you are a father to a young
boy, it is up to you to prevent this. Lead by example.
4 Fain, Elizabeth, et al. Comparative study of millennials' (age 20-34 years) grip and lateral pinch with the norms. Journal of Hand Therapy ,
Volume 29 , Issue 4 , 483 – 488.
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Results from a 2007 study looking at testosterone levels in American
men. This graph shows an over 50+ point drop in 60-year-old men in
the early 2000s vs. 60-year-old men in the late 80s. This trend, based
on this data, appears to hold true for younger men as well5.
Travison, TG, AB Araujo, AB O’Donnell, V Kupelian, JB McKinlay. 2007. A population-level decline in serum testosterone levels in
American men. Journal of Clinical Endocrinology and Metabolism 92:196–202.
5
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A study published in the Journal of Sexual Medicine showed a
greater than 150-point drop in average testosterone levels in young
men (ages 15-39) between 2000 and 2016.
Younger men have not been spared from this ongoing testosterone
decline. A study published in 2020 sampling 4,045 males showed that in
the year 2000 mean testosterone levels were 605.39 ng/dL in young men
aged 15-39. By 2016 the mean testosterone level in 15-39-year-old men
had dropped by 154 ng/dL to 451.22 ng/dL.
The observed decline was partially explained by the rise in obesity in
young men (average BMI increased from 25.8 to 27.96) but even in men
with normal BMI (18.5-24.9) there was still a 135.5 ng/dL decline
suggesting that other factors are contributing to this phenomenon6.
6 P. Patel, R. Fantus, S. Lakeshwar, J. Halpern, C. Chang, A. Kargi, R. Ramasamy, Trends in Serum Testosterone Levels Among Adolescent and
Young Adult Men in the United States, The Journal of Sexual Medicine, Volume 17, Issue 1, Supplement 1, 2020, Pages S3-S4, ISSN 17436095,
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The decline in male testosterone levels noted over the last half-century
are mirrored by similar declines in male fertility (as measured by sperm
counts). A landmark study performed by researchers in Denmark and
Scotland published in 1992 demonstrated a nearly fifty percent decline
in sperm counts in the preceding fifty years as well as an increase of
birth defects involving male reproductive organs as well as prostate and
testicular cancers7.
Along with declining testosterone levels, sperm counts
have also been steadily declining over the last 50+
years. Adapted from: Carlsen E, Giwercman A, Keiding N, Skakkebaek NE. Evidence for decreasing quality of
semen during past 50 years. BMJ. 1992;305(6854):609-13.
7 Carlsen, E., Giwercman, A., Keiding, N., & Skakkebaek, N. E. (1992). Evidence for decreasing quality of semen during past 50 years. BMJ,
305(6854), 609–613.doi:10.1136/bmj.305.6854.609
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The cause of the global decline in men’s testosterone levels above and
beyond that seeing with natural aging is an area of ongoing research. Its
causes, however, can be distilled into two broad categories: Lifestyle
and environmental exposures:
1-1-A. ENVIRONMENTAL EXPOSURES
“The evidence for adverse reproductive outcomes
(infertility, cancers, malformations) from exposure to
endocrine disrupting chemicals is strong, and there is
mounting evidence for effects on other endocrine
systems, including thyroid, neuroendocrine, obesity
and metabolism, and insulin and glucose
homeostasis.”
-Endocrine Society Scientific Statement on EndocrineDisrupting Chemicals, 2009.
There are over 800 chemicals used in industry that are known to
interfere with healthy hormone balance in both humans and animals8.
Very few of these have been adequately studied, and even fewer are the
subjects of legal restrictions. The most well-known endocrine disrupting
chemicals (EDCs) are DES (diethylstilbestrol), phthalates, BPA
(bisphenol), PCBs (polychlorinated biphenyls), and dioxin, but there are
many others. All of these EDCs are implicated in a variety of conditions
affecting male reproduction. These include decreasing sperm production,
8 Bergman A, Heindel JJ, Kasten T, et al. The impact of endocrine disruption: a consensus statement on the state of the science. Environ Health
Perspect. 2013;121(4):A104-6.
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increased rates of testicular and prostate cancer, and low testosterone
levels.
The widespread use of these substances makes complete avoidance
practically impossible. Nearly all men have some level of one or more of
these compounds in their system. If you work with or for a company that
manufactures BPA related products your levels may be up to 70 times
higher than other men9. Your exposure likely began in utero and has
continued throughout your life.
Common Sources of Phthalates
PVC products (flexible plastic
products)
Personal care products:
Perfume
Deodorants
Nail Polish
Hair Gel
Shampoos
Food/Water storage containers
Medical Devices: IV tubing
Catheters
Flexible plastic children’s toys and
drinking cups.
Despite the near impossible
task of completely avoiding
these substances you can
attempt to limit your use of
products that contain them.
The table below shows just a
few of the more common
sources of these chemicals that
you may encounter in your
day-to-day life. The ones that
may surprise you are canned
sodas and fast food
hamburgers. Both these
substances are high in BPA
and their intake should be
limited as much as possible10.
9 Cynthia J. Hines, Matthew V. Jackson, James A. Deddens, John C. Clark, Xiaoyun Ye, Annette L. Christianson, Juliana W. Meadows, Antonia
M. Calafat; Urinary Bisphenol A (BPA) Concentrations among Workers in Industries that Manufacture and Use BPA in the USA, Annals of
Work Exposures and Health, Volume 61, Issue 2, 1 March 2017, Pages 164–182, https://doi.org/10.1093/annweh/wxw021
10 Lesliam Quirós-Alcalá, et al. Determinants of urinary bisphenol A concentrations in Mexican/Mexican–American pregnant women.
Environment International. Volume 59, September 2013, Pages 152-160
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Common Sources of BPA
Cash register receipts
Children’s toys
Canned food plastic lining
Plastic food containers
Recycled toilet paper
Canned soft drinks including beer
Reusable water bottles
Fast food hamburgers.
An Army specialist refills a bottle of water during a break in Kunar province, Afghanistan in 2012.
Digital photograph, Army Times, accessed 26 Mar 2020, < https://www.armytimes.com/news/your-army/
2019/10/28/soldiers-bottled-water-consumption-is-unsustainable-in-the-next-war-army-report-says/>
Plastics, including those used in water bottles are a common source
of endocrine disrupting compounds.
In the United States almost all plastic containers and bottles have a
recycling symbol that will help you identify the type of plastic used in its
manufacture. You can therefore identify the products that contain the
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highest levels of EDCs. While none of them can be considered 100
percent safe, some have a greater potential for harm than others.
Generally speaking, products with recycling symbols 1, 2, 4, and 5 have
the lowest risk. Those with 3, 6 or 7 should generally be avoided.
Common Recycling symbols use on plastic products in the United
States.
AVOID PLASTICS WITH THESE SYMBOLS:
Flexible or rigid plastics (PVC) found in a wide range of products
including medication blister packs, tamper resistant lids, some children’s
toys, medical devices, artificial leather, etc. These products contain high
levels of one or more phthalates.
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These products contain polystyrene or “Styrofoam”. They are commonly
used in packaging for food products (cups, plates, fast food containers,
etc.), yogurt and pudding containers, foam packing material, etc. Styrene
is linked to a number of cancers (leukemia and lymphoma) as well as
infertility in animals11. It has been found in human breast milk.
This symbol designates a family of plastics that don’t fit into the six
other recognized types of plastics or are formed from a combination of
agents. These types of plastics are widely used in reusable water bottles,
condiment bottles and various packaging materials. They tend to be a
strong source of BPA (bisphenol A).
11 https://www.atsdr.cdc.gov/ToxProfiles/tp53-c1-b.pdf
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1-1-B. LIFESTYLE FACTORS: DON’T BE FAT
In just a few short years the obesity epidemic has caused a
morphological change in the average man not seen in over 50,000 years.
At no point in human history has the average man carried so much body
fat and been so physically deconditioned. Our Paleolithic ancestors
would be shocked at what we have become.
The average 19-year-old West Point cadet born between 1875-1879 had
an average BMI of 21.0 12. Presumably, these cadets were representative
of other young men their own age across the country. As of 2010, the
average 19-year-old male has a BMI of 25.213. No doubt that number is
higher today. Keep in mind a BMI over 25 is considered overweight by
current standards.
It also goes without saying that BMI is an imperfect measure of fatness.
Many muscular athletes have BMI measurements that would classify
them as overweight or obese. Those individuals aside, BMI is a
reasonable way of tracking obesity in sedentary non-athletes which
describes the vast majority of modern Americans.
12
Hiermeyer, M. (2010). The height and BMI values of West Point cadets after the Civil War. Economics & Human Biology, 8(1), 127–
133.doi:10.1016/j.ehb.2009.09.004
13 Fryar CD, Gu Q, Ogden CL. Anthropometric reference data for children and adults: United States, 2007 –2010. National Center for Health
Statistics. Vital Health Stat 11(252). 2012.
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BMI
18.5-24.9
25.0-29.0
30-39
40+
Normal
Overweight
Obese
Extreme Obesity
It should surprise nobody that carrying around large amounts of body fat
will negatively impact one’s health. Most are aware of the association
between obesity with conditions such as type 2 diabetes, high blood
pressure, and heart disease. What most men don’t know is how strongly
excess body fat is associated with low testosterone levels and infertility.
In fact, obesity has a very significant effect on testosterone levels. Low
testosterone is so common among obese men that it has now been
recognized as a unique clinical syndrome known as MOSH (Male
Obesity Secondary Hypogonadism) 14.
A number of studies have shown a very high prevalence of low
testosterone in obese men, in some cases exceeding 40%15. With BMI
levels over 40, or those who are diabetic, the prevalence can be even
higher, often exceeding 50% 16. In fact, obesity is the single greatest risk
factor for low testosterone, even more so than age or other medical
conditions such as diabetes or sleep apnea.
MOSH can dramatically lower testosterone levels two important ways:
1. Fat tissue is an abundant source for the aromatase enzyme that
converts testosterone into estradiol. Estradiol then is detected by
the pituitary gland and leads to the shutdown of LH (luteinizing
hormone), the primary signal for testicular testosterone production.
14
De Lorenzo, A.; Noce, A.; Moriconi, E.; Rampello, T.; Marrone, G.; Di Daniele, N.; Rovella, V. MOSH Syndrome (Male Obesity Se condary
Hypogonadism): Clinical Assessment and Possible Therapeutic Approaches. Nutrients 2018, 10, 474.
15 Hofstra J, Loves S, van Wageningen B, Ruinemans-Koerts J, Jansen I, et al. High prevalence of hypogonadotropic hypogonadism in men
referred for obesity treatment. Neth J Med 2008; 66: 103–9.
16 Dhindsa S, Miller MG, McWhirter CL, et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care. 2010;33:11861192.
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2. Excess fat tissue secretes a variety of substances that can directly
inflame the brain further suppressing the signal to maintain healthy
testosterone levels.
A cycle then ensues where low testosterone levels contribute to
increasing levels of body fat and decreased levels of muscle mass, which
in turn lead to further lowering of testosterone levels. This downward
spiral is often referred to as the “Hypogonadism-Obesity Cycle”
(HOC)17.
The good news is that this effect is reversible. Losing a significant
amount of body fat can help restore normal testosterone levels 18. There
are also a number of medical interventions other than simple
testosterone replacement that can help restore your own testosterone
production while you lose weight. Assuming you haven’t permanently
suppressed your testicular function, you keep the weight off long-term,
and you have built a significant amount of lean muscle mass then it may
be possible maintain normal, healthy testosterone levels without any
sort of medical intervention at all. More on this in later chapters.
17 Lamm S, Chidakel A, Bansal R. Obesity and hypogonadism. Urol Clin North Am 2016; 43: 239–45.
18 Corona G, Rastrelli G, Monami M, Saad F, Luconi M, et al. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a
systematic review and meta-analysis. Eur J Endocrinol 2013; 168: 829–43
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The Hypogonadism-Obesity Cycle
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1-2. WHY YOU NEED TESTOSTERONE
You may think the answer to this question is obvious. Testosterone is
what makes you a man. It is the primary hormone responsible for
transforming a scrawny, squeaky-voiced boy into a muscular, adult
male. Yet the importance of testosterone goes far beyond its pubertyrelated effects and extends well into adulthood and into advanced old
age. In fact, maintaining a healthy testosterone level is one of the
fundamental cornerstones to maximizing a man’s health and quality of
life. THE BOTTOM LINE: Testosterone deficiency leads to a lower
quality of life, earlier death, and increased risk of chronic disease 19.
19
Giannoulis MG, Martin FC, Nair KS, Umpleby AM, Sonksen P. Hormone replacement therapy and physical function in healthy older men.
Time to talk hormones?. Endocr Rev. 2012;33(3):314–377. doi:10.1210/er.2012-1002
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1. Testosterone is crucial for both building and
maintaining muscle mass
2. Testosterone helps maintains a man’s bone density.
3. Testosterone maintains healthy sperm levels.
4. Testosterone maintains a healthy libido and normal
sexual function.
5. Testosterone helps burn body fat.
6. Testosterone helps your bone marrow maintain normal
red blood cell production.
7. Testosterone helps maintain healthy immune system
function.
8. Testosterone improves memory, cognitive function and
fights depression.
9. Testosterone maintains the health and flexibility of your
blood vessels.
10. Testosterone improves cardiac function.
11. Testosterone improves mood.
12. Testosterone makes you more attractive.
13. Testosterone can prolong your life.
14. Testosterone improves insulin sensitivity and helps
improve blood sugar.
15. Testosterone improves your immune system
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1-3. TESTOSTERONE REPLACEMENT THERAPY VS.
“JUICING”.
There is still a great deal of misunderstanding amongst the general
public and amongst physicians about what exactly testosterone
replacement is all about. It’s often viewed with suspicion by those
whose only frame of reference is what they have seen or heard about
performance enhancing chemicals in the world of bodybuilding or other
sports. As will become obvious, medically supervised testosterone
replacement and the use of anabolic steroids and other performance
enhancing drugs have nothing to do with each other. Before proceeding,
be certain that you have fully divested yourself of that fact.
Testosterone replacement therapy is the medically supervised
replacement of low or sub-optimal testosterone levels in men suffering
from symptoms of hypogonadism. Its goal is the alleviation of the
symptoms of testosterone deficiency and the promotion of optimal
physical and psychological well-being by bringing testosterone levels
back up to the healthy normal range. In this regard it is no different
that the medical replacement of any other hormonal deficiency such as
hypothyroidism or post-menopausal estrogen deficiency. It is generally
for life.
“Juicing” is the use of anabolic steroids (testosterone or chemical
derivatives of testosterone) for the purpose of performance enhancement
or physical augmentation without (or with very little) consideration for
optimal long-term health. It is typically done in “cycles” which coincide
with competitive events or the achievement of specific physique related
goals.
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Drug
Purpose
Duration
Side Effects
Legal Status
“Juicing”
Testosterone and
synthetic derivatives
of testosterone.
Health Optimization Performance
enhancement and
cosmetic effects.
For Life
Cycles lasting weeks
or months
Very few
Dose and drug
dependent but
generally significant
Legal with physician Illegal
supervision
TRT
Testosterone
Testosterone replacement therapy and anabolic steroid use for
performance enhancement are not the same thing.
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CHAPTER TWO
DIAGNOSIS
The diagnosis of testosterone deficiency is made using BOTH blood
tests and an assessment of signs and symptoms performed by your
doctor. Men without symptoms, even with low blood testosterone levels,
are not candidates for TRT and are less likely to benefit. Similarly, men
with symptoms of testosterone deficiency with blood testosterone levels
in the upper normal range likely have another explanation for their
symptoms and are less likely to benefit from testosterone replacement.
2-1. INITIAL LABS
The initial battery of tests ordered by your physician will vary based on
your specific medical history and symptoms. The following basic tests
are considered standard and, if not ordered by your doctor, should be
requested to fully evaluate you for testosterone deficiency.
1. Total Testosterone: This is the total amount of testosterone
circulating in the bloodstream. It includes all the testosterone
which is bound to various proteins (like SHBG) plus the small
amount that is not attached to anything and is actually free to
perform its function. The most common mistake made by
inexperienced physicians is to check only the total testosterone
while omitting the free testosterone. It is not uncommon to have a
low-normal total testosterone level yet have profoundly low free
testosterone levels20.
20 Leen Antonio, Frederick C. W. Wu, Terence W. O'Neill, Stephen R. Pye, Tomas B. Ahern, Michaël R. Laurent, Ilpo T. Huhtaniemi, Michael
E. J. Lean, Brian G. Keevil, Giulia Rastrelli, Gianni Forti, György Bartfai, Felipe F. Casanueva, Krzysztof Kula, Margus Punab, Aleksander
Giwercman, Frank Claessens, Brigitte Decallonne, Dirk Vanderschueren, the European Male Ageing Study Study Group; Low Free Testosterone
Is Associated with Hypogonadal Signs and Symptoms in Men with Normal Total Testosterone, The Journal of Clinical Endocrinology &
Metabolism, Volume 101, Issue 7, 1 July 2016, Pages 2647–2657, https://doi.org/10.1210/jc.2015-4106
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2. Free Testosterone: This is the small fraction of total testosterone
(2-3%) that is not attached to any binding proteins21. It is the
testosterone that is biologically active and is the most useful in
terms of both diagnosis low testosterone as well as monitoring
response to therapy. Insist that your physician order this test for
you.
3. “Bioavailable” Testosterone (BioT): This is a less often used test
which measures the sum of the free testosterone plus the
testosterone loosely bound to the protein albumin. It is thought that
some of the testosterone bound to albumin may be available for
use by the body, though this is somewhat controversial22. Most
physicians no longer use this test and it is not necessary if you
already have a total and free testosterone value.
4. SHBG (Steroid Hormone Binding Globulin): This protein strongly
binds testosterone (and other hormones) effectively preventing it
from interacting with the body. The decrease in free testosterone
that occurs naturally with aging is largely due to increased
production of SHBG.
5. Estradiol (E2): Obtaining a baseline estradiol level can be useful
for some men. In particular, those who are obese, have
gynecomastia or other signs of estradiol excess. This baseline
value can then be compared to those obtained after several months
on testosterone therapy in the event that a man develops symptoms
concerning for excess estradiol. Those symptoms will be covered
in detail later. It is important to insist that your physician orders a
“high sensitivity” or “ultra-sensitive” estradiol panel. Standard
21 Alex Vermeulen, Lieve Verdonck, Jean M. Kaufman; A Critical Evaluation of Simple Methods for the Estimation of Free Testoster one in
Serum, The Journal of Clinical Endocrinology & Metabolism, Volume 84, Issue 10, 1 October 1999, Pages 3666–
3672, https://doi.org/10.1210/jcem.84.10.6079
22 ANDREA MANNI, WILLIAM M, WILLIAM CEFALU, BRUCE C. NISULA, C. WAYNE BARDIN, STEVEN J. SANTNER, RICHARD J.
SANTEN; Bioavailability of Albumin-Bound Testosterone, The Journal of Clinical Endocrinology & Metabolism, Volume 61, Issue 4, 1 October
1985, Pages 705–710,
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estradiol panels are intended for use in women and can be
inaccurate in men.
Additional basic tests that will likely be ordered include:
1. CBC (complete blood count which will include your hematocrit)
2. CMP (comprehensive metabolic panel testing kidney and liver function
as well as major electrolytes)
3. TSH (thyroid stimulating hormone) and T4/T3 if indicated by your
symptoms and examination
4. Lipid Panel
5. PSA (prostate specific antigen) if you opt for prostate cancer screening.
This is a somewhat controversial test in much older men. It can be
elevated from a number of other non-cancer related causes and may
result in unnecessary biopsies and worry when falsely elevated.
6. FSH/LH (follicle stimulating hormone and luteinizing hormone). These
two hormones are secreted by the pituitary gland and are responsible for
normal sperm and testosterone production respectively. These levels will
help your physician determine if your low testosterone is due to the
inability of your testicles to produce testosterone (primary
hypogonadism) or if their low production is due to lack of an adequate
signal from the brain or pituitary gland (secondary hypogonadism).
7. Prolactin: for men with very low testosterone levels and/or
gynecomastia screening for a rare non-cancerous tumor of the pituitary
gland (prolactinoma) may be indicated. Prolactin elevations may also be
related to poor thyroid function, kidney/liver disease, high estrogen
levels and various medications as well. Both high and low prolactin
levels may adversely affect men’s sexual function.
This is NOT a comprehensive list of all the testing you may require.
Based on your health history there may be a number of additional lab
tests your physician may wish to order.
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It is important to understand the type of assay your lab is using to test
your testosterone levels.
There are multiple different ways of obtaining these values and they can
vary widely in the results they produce.
The gold standard for total testosterone testing is isotope dilution mass
spectrometry (MS). Cost concerns prevent widespread use of this assay
and instead various liquid chromatography tandem mass spectrometry
(LC-MSMS), radioimmunoassay (RIA), and nonradioactive assays are
commonly used with automated nonradioactive assays being the most
common.
Many physicians are not aware that identical samples analyzed using
these various automated methods can vary by up to 20% and become
even more unreliable when levels are very low (under 100 ng/dL) 23.
As with total testosterone, there are various methods used to measure
free testosterone the results of which can vary widely. In some cases, in
order to cut costs, some labs provide a calculated free testosterone rather
than a direct measurement. They use various algorithms based on total
testosterone and SHBG to arrive at a calculated free testosterone (FT).
The accuracy of a calculated FT depends heavily on the accuracy of the
total testosterone level measurement which, as mentioned above, can
sometimes be problematic 24. Therefore, you should insist on a direct
measurement of your FT levels.
23
Christina Wang, Don H. Catlin, Laurence M. Demers, Borislav Starcevic, Ronald S. Swerdloff, Measurement of Total Serum Testosterone in
Adult Men: Comparison of Current Laboratory Methods Versus Liquid Chromatography-Tandem Mass Spectrometry, The Journal of Clinical
Endocrinology & Metabolism, Volume 89, Issue 2, 1 February 2004, Pages 534–543, https://doi.org/10.1210/jc.2003-031287
24
Sartorius G, Ly LP, Sikaris K, McLachlan R, Handelsman DJ. Predictive accuracy and sources of variability in calculated free testosterone
estimates. Ann Clin Biochem. 2009;46(Pt 2):137‐143. doi:10.1258/acb.2008.008171
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2-1-A. What is a “low” testosterone level?
Various medical societies have published guidelines regarding the
diagnosis of male hypogonadism. Most use only a total testosterone
level which, as mentioned above, may miss men whose free testosterone
levels are low and who are suffering symptoms of low testosterone
despite “normal” total testosterone levels.
Below are a few commonly referenced lab definitions for hypogonadism
from various medical societies. The majority of US primary care
physicians will rely on The Endocrine Society guidelines and likely to
be unaware that other equally prestigious societies have published
alternative recommendations.
Society
The Endocrine
Society25
American Society of
Andrology26
European
Association of
Urology27
International Society
for the Study of the
Aging Male 28
Total Testosterone
Free Testosterone
<300ng/dL or “lower
lab limit of normal”
“lab lower limit of
normal”
<350 ng/dL
<6.5 ng/dL
<349 ng/dL
<6.35 ng/dL
<350 ng/dL
<6.5 ng/dL
25
2010 U.S. Endocrine Society Guidelines: Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, et al. Testosterone Therapy in
Adult Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2010
Jun;95(6):2536-2559
26
International Society of Andrology (ISA), International Society for the Study of the Aging Male (ISSAM), EAU, European Academy of
Andrology (EAA) and Americal Society of Andrology (ASA) Joint Recommendations: Wang C, Nieschlag E, Swerdloff R, Hermann BM,
Hellstrom WJ, et al. Investigation, Treatment, and Monitoring of Late-Onset Hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA
Recommendations. Eur Urol. 2009;55:212-130.
27
European Association of Urology (EAU): Dohle GR, Arver S, Bettocchi C, Kliesch S, Punab M, et al. Guidelines on male hypogona dism.
Arnhem: European Association of Urology, 2012 p2-28.
28
Lunenfeld, B., Mskhalaya, G., Zitzmann, M., Arver, S., Kalinchenko, S., Tishova, Y., & Morgentaler, A. (2015). Recommendations on the
diagnosis, treatment and monitoring of hypogonadism in men. The aging male : the official journal of the International Society for the Study of
the Aging Male, 18(1), 5-15.
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All of these societies recommend that an initial value be obtained,
preferably in the morning (before 10 AM), as values tend to be higher in
the morning. If low, this should be confirmed with a repeat morning
value. In older men (over 55) the daily variation in testosterone levels is
significantly blunted, however. For these men checking values later in
the day may be appropriate 29.
The problem with using these values as hard cutoffs for defining what
constitutes hypogonadism in all men is the now well-recognized genetic
variability among individuals in terms of response to a given level of
testosterone. It is now known that this variability is largely due to
genetic variations in the androgen receptor between men, specifically the
number of cysteine-adenosine-guanine repeats (CAG-R) the receptor
possesses30. The more CAG repeats a receptor has, the lower its ability
to properly bind testosterone for use in the cell. This trait is genetically
mediated31.
For this reason, two men with identical serum testosterone levels may
feel quite differently. A man with a very sensitive receptor may feel
great and have no symptoms of testosterone deficiency at levels that
would make a man with a less sensitive receptor lose interest in sex,
experience muscle weakness, and suffer erectile dysfunction.
29
Crawford ED, Barqawi AB, O’Donnell C, Morgentaler A. The association of time of day and serum testosterone concentration in a large
screening population. BJU Int 2007;100:509–13.
30 Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain
affect transactivation function. Nucleic Acids Res 1994;22: 3181–6.
31 Kim JW, Bae YD, Ahn ST, Kim JW, Kim JJ, Moon DG. Positive Correlation between Androgen Receptor CAG Repeat Length and
Metabolic Syndrome in a Korean Male Population. World J Mens Health. 2018 Jan;36(1):73-78. https://doi.org/10.5534/wjmh.17029
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There is genetic variability in the sensitivity of the androgen
receptor among men. This is a major reason why at a given
testosterone level, one man may have symptoms while another may
not.
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2-2. SYMPTOMS
The second part of the diagnosis of low testosterone is the presence of
symptoms. This is the key component to the diagnosis; in many ways it
is more important than the actual level as measured by a blood test. As
mentioned above, there is wide variation among men as to what level of
testosterone is “optimal”. This, again, is likely due to differences in the
sensitivity of the androgen receptor. It is quite possible, and not
uncommon, for men who have objectively low blood levels of
testosterone to have no symptoms. Those men DO NOT need
testosterone therapy and are unlikely to benefit from it.
Conversely, there are large numbers of men with “low-normal”
testosterone levels who have a significant number of symptoms
(most commonly low libido, fatigue, and loss of rive and motivation)
that DO benefit from testosterone therapy. Unfortunately, many
primary care physicians and endocrinologists are not well versed in the
nuances of testosterone therapy and are unwilling to even consider
therapy unless a patient’s blood levels are profoundly low. This leaves a
large number of men (and their partners) to continue to suffer in silence
with a decreased quality of life and suboptimal health.
There are several commonly used testosterone deficiency symptoms
scores used by physicians to screen patients suspected of having low
testosterone. The most commonly used is the ADAM (Androgen
Deficiency in the Aging Male) score and the AMS (Aging Male
Symptom) score. Both are fairly sensitive at detecting androgen
deficiency but are not terribly specific; meaning that there are a number
of other potential causes for the listed symptoms other than sub-optimal
testosterone. This is why a positive symptom score should be combined
with a blood test to make the diagnosis AND your physician should
consider exploring other causes for your symptoms other than
testosterone deficiency, especially if they do not improve with treatment.
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Typically, the first symptoms experienced by men with declining
testosterone levels are psychosexual in nature. Over time there can be a
gradual decline in libido, fatigue, loss of interest in daily activities, and a
general loss of vitality. Many men suffer with these symptoms for years
or decades before being properly diagnosed. As levels continue to
decline, men may experience unfavorable increases in body fat putting
them at risk for developing diabetes and other obesity-related conditions.
Cognitive symptoms such as poor concentration and inability to sustain
focus for prolonged periods of time may occur. Erectile dysfunction and
poor sleep are very common. Men with profoundly low levels may
experience bone loss as well as vasomotor symptoms similar to the “hotflashes” experienced by menopausal women.
The chart below shows some of the more common symptoms associated
with declining testosterone levels. Again, there can be wide variations
among men based on genetic and lifestyle factors. In some cases, the
symptoms listed could occur at either higher or lower levels but the
order in which these symptoms appear is fairly uniform as testosterone
levels decline.
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Common Symptoms Associated with Declining Testosterone Levels
adapted from: Michael Zitzmann, Stephanie Faber, Eberhard Nieschlag, Association of Specific Symptoms and Metabolic Risks with Serum
Testosterone in Older Men, The Journal of Clinical Endocrinology & Metabolism, Volume 91, Issue 11, 1 November 2006, Pages 4335–
4343, https://doi.org/10.1210/jc.2006-0401
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The ADAM and AMS Questionnaires are both scientifically validated
screening tools for detecting men who may have low testosterone levels.
If you score positively on either screen, bring the result to your
physician and obtain blood testing to confirm the diagnosis.
ADAM (Androgen Deficiency in the Aging Male)
Questionnaires
1. Do you have a decrease in libido (sex drive)?
2. Do you have a lack of energy?
3. Do you have a decrease in strength and/or endurance?
4. Have you lost height?
5. Have you noticed a decreased "enjoyment of life"
6. Are you sad and/or grumpy?
7. Are your erections less strong?
8. Have you noticed a recent deterioration in your ability to
play sports?
9. Are you falling asleep after dinner?
10. Has there been a recent deterioration in your work
performance?
If you Answer Yes to number 1 or 7 or if you answer Yes to more than
3 questions, you may have low Testosterone.
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The AMS is scored from 17 to 85.
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< 26 means you have no significant symptoms consistent with a low
testosterone level 27-36 means you have mild symptoms consistent with
a low testosterone level
37-49 means you have moderate symptoms consistent with a low
testosterone level
> 50 means you have severe symptoms consistent with a low
testosterone level
Scores of 27 or greater warrant blood testing for low testosterone.
Notes
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Once you have blood tests documenting a low testosterone levels and
your doctor confirms that you have a set of symptoms compatible with
low testosterone there are two important steps that must be undertaken.
The first is determining WHY your levels are low. It is not appropriate
in the majority of cases to just start therapy and not investigate any
further. Many patients with low testosterone do not have any serious
underlying medical problem causing their condition or the cause remains
unknown, but there are a number of serious, potentially life-threatening
disease processes that should be ruled out.
2-3.
PRIMARY HYPOGONADISM
The first broad category of causes for low testosterone are of conditions
that affect the testicles themselves and prevent them from adequately
producing testosterone and/or healthy sperm. Under these circumstances
the signals from the brain are often being broadcasted loud and clear, but
the testicles are unable to “hear” this signal and respond with normal
testosterone and sperm production. In response the brain ramps up its
signal volume but no avail.
The classic lab findings in primary hypogonadism are a low testosterone
level and decreased sperm production with high FSH and LH (the
primary signal from the pituitary gland to the testicles). Men with high
levels of FSH/LH have increased activity of the aromatase enzyme and
so often have elevated levels of estradiol, which can further suppress
testosterone production by lowering LH and FSH. This can complicate
the diagnosis by keeping FSH and LH within the upper limits of the
normal range32.
32 Naftolin F, Garcia-Segura LM, Horvath TL, Zsarnovszky A, Demir N, Fadiel A, Leranth C, Vondracek-Klepper S, Lewis C, Chang A,
Parducz A. Estrogen-induced hypothalamic synaptic plasticity and pituitary sensitization in the control of the estrogen-induced gonadotrophin
surge. Reprod Sci. 2007 Feb; 14(2):101-16.
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Conditions your doctor should evaluate you for if you have primary
hypogonadism:
1.
Genetic Conditions:
Klinefelter Syndrome: A condition where a male patient has the
abnormal addition of a second X-chromosome. Normal males have
one X chromosome from their mother and one Y chromosome
(XY). Patients with Klinefelter Syndrome have an XXY pattern.
They tend to have a set of physical findings that a trained physician
will be able to recognize. The diagnosis is confirmed with genetic
testing. If you don’t have the physical signs you don’t need to be
tested.
There are a variety of rare genetic conditions including various
defective enzymes required for testosterone production, defective
receptors unable to respond to FSH/LH, certain forms of muscular
dystrophy among others. Many of these are exceedingly rare and
routine tests to confirm them are not commonly available outside
of research centers.
2. A history of undescended testicles (cryptorchidism):
This condition is usually recognized at birth and should be
surgically corrected as quickly as possible. If only a single testicle
is involved, then testosterone levels and fertility are usually
normal, at least through young adulthood. If both are affected, then
patients often suffer from low sperm counts and may develop low
testosterone levels later in life. Men with a history of undescended
testicles are at increased risk for testicular cancer and should be
vigilant with regular testicular self-exams.
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3. Infections:
Mumps can affect the testicles and severely damage fertility and
possibly testosterone production. This is rare now due to
widespread immunization. If you have not been immunized, you
should be. Mumps more commonly affects the testicles when it is
acquired as an adult. A severe bacterial or viral infection of the
testicles (epididymo-orchitis), often, but not always, sexually
transmitted, can permanently damage the testicles and potentially
lead to decreased testosterone production.
4. Direct Trauma:
This includes blunt trauma (sports injuries, IED blasts, etc.) or a
history of testicular torsion where the testicle can twist on itself,
cutting off its blood supply, resulting in damage or death of the
testicle unless promptly recognized and corrected by a physician.
Radiation therapy for cancer can also damage the testes.
5. Drugs:
Chemotherapy drugs: A wide variety of these drugs can either
temporarily or permanently reduce testosterone production and
sperm production. If you are about to undergo chemotherapy you
should discuss this with your physicians.
Antifungal drugs: Ketoconazole and its cousins are used for a
variety of fungal infections involving the skin, nails as well as
other organs. It can block the production of testosterone and other
hormones when taken orally for prolonged periods of time33.
33 33 Pont A, Williams PL, Azhar S, et al. Ketoconazole Blocks Testosterone Synthesis. Arch Intern Med.1982;142(12):2137–2140.
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Corticosteroids: These drugs (prednisone is a commonly used
example) can decrease testosterone production and can cause a
host of very serious side effects when used long term34. Chronic
use is usually reserved for patients with very severe medical
conditions refractory to other forms of treatment.
NSAIDS: Ibuprofen, and presumably other non-steroidal antiinflammatory drugs have been shown in small studies to interfere
with testosterone production in the testicles. If the pituitary gland
is capable, this is compensated for by increased LH production 35.
In men with dysfunction of the pituitary or hypothalamus
(secondary hypogonadism) ibuprofen use could potentially lead to
lower testosterone levels when used chronically.
6. Liver and kidney disease.
Men with chronic kidney disease and kidney failure have high
rates of testosterone deficiency. In fact, only 23% of men with endstage kidney disease have normal testosterone levels 36. Treatment
can alleviate the common symptoms of testosterone deficiency and
also address the muscle wasting, fatigue, and anemia common in
these patients37. If you or a family member have chronic kidney
disease, strongly consider having your physician test for
testosterone deficiency.
Testosterone deficiency is also common among people suffering
from liver disease. Low testosterone levels are strongly associated
34 Odell WD. Testosterone Treatment of Men Treated With Glucocorticoids. Arch Intern Med. 1996;156(11):1133–1134.
35 Kristensen DM, Desdoits-Lethimonier C, Mackey AL, et al. Ibuprofen alters human testicular physiology to produce a state of compensated
hypogonadism [published correction appears in Proc Natl Acad Sci U S A. 2018 Apr 16;:]. Proc Natl Acad Sci U S A. 2018;115(4):E715‐E724.
doi:10.1073/pnas.1715035115
36 Carrero JJ, Qureshi AR, Nakashima A, Arver S, Parini P, Lindholm B, Bárány P, Heimbürger O, Stenvinkel P. Prevalence and clinical
implications of testosterone deficiency in men with end-stage renal disease. Nephrol Dial Transplant. 2011 Jan; 26(1):184-90.
37 Johansen KL, Mulligan K, Schambelan M. Anabolic effects of nandrolone decanoate in patients receiving dial ysis: A randomized controlled
trial. JAMA. 1999;281:1275–81.
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with hepatitis C virus infection and treatment of the infection does
not always restore testosterone levels to normal levels38.
Similarly, hereditary hemochromatosis, a genetic condition where
the body becomes overloaded with iron, is strongly associated with
low testosterone levels. Up to 10% of individuals of Northern
European decent carry at least one copy of this genetic mutation
and it is particularly common among those with Celtic ancestry39.
Fortunately, with ongoing blood donation (phlebotomy) iron levels
can be brought down and testosterone levels often return to normal
if the condition is diagnosed before permanent liver damage
ensues40.
Fatty liver disease, also referred to as non-alcoholic fatty liver
disease (NAFLD) or the more severe non-alcoholic steatohepatitis
(NASH), is strongly associated with low testosterone levels 41. This
condition is driven by obesity and often present along with other
obesity-related conditions such as hypertension, elevated blood
lipids and diabetes. Worldwide, NAFLD affects almost 25% of the
world’s population as of 2016 42.
Low testosterone levels can both contribute to and be exacerbated
by NAFLD. Treatment with testosterone addresses a number of
conditions associated with NAFLD and NASH by promoting fat
loss, reducing inflammation, and fat accumulation in the liver. It
seems likely that reversal of NAFLD with aggressive fat loss and
38 Chloe S Chaudhury, Thomas Mee, Cheryl Chairez, Mary McLaughlin, Rachel Silk, Chloe Gross, Sarah Kattakuzhy, Elana Rosenthal, Shyam
Kottilil, Takara L Stanley, Colleen Hadigan, Testosterone in Men With Chronic Hepatitis C Infection and After Hepatitis C Viral
Clearance, Clinical Infectious Diseases, , ciy965, https://doi.org/10.1093/cid/ciy965
39 Byrnes V, Ryan E, Barrett S, Kenny P, Mayne P, Crowe J. Genetic hemochromatosis, a Celtic disease: is it now time for populat ion
screening?. Genet Test. 2001 Summer. 5(2):127-30.
40 Kelly TM, Edwards CQ, Meikle AW, Kushnder JP. Hypogonadism in Hemochromatosis: Reversal with Iron Depletion. Ann Intern Med.
1984;101:629–632. doi: 10.7326/0003-4819-101-5-629.
41 Sumida et al. The Association of Low Free Testosterone with Histological Severity of Nonalcoholic Fatty Liver Di sease in Japanese Men.
Gastroenterol Hepatol 2015 (2 ) 4: 00052;
42 Younossi, Z. M. et al. Global epidemiology of nonalcoholic fatty liver disease — meta-analytic assessment of prevalence, incidence,
and outcomes. Hepatology 64, 73–84 (2016)
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exercise could restore normal testosterone levels though more
studies in this area are needed. It is possible that testosterone
therapy could be discontinued in this particular case once
significant weight loss has been achieved.
7. HIV:
The HIV virus can directly affect the ability of the testes to
produce testosterone as well as blunt the signal (FSH/LH) from the
pituitary. The mechanism by which this occurs is complex and, in
most cases, multi-factorial. If you think you are at risk you need to
get tested.
2-4.
SECONDARY HYPOGONADISM
In this form of hypogonadism low testosterone results not from an
inability to produce testosterone, but in the brain or pituitary gland’s
inability to produce an adequate signal to the testicles to initiate
testosterone production. Without a strong enough signal, the testicles
will not produce optimal levels of testosterone. Sperm production is also
impaired. Usually, if that signal can be restored, they will respond
normally, and testosterone levels will rise.
Conditions resulting in secondary hypogonadism:
1. Elevated prolactin levels:
Prolactin is a hormone secreted by the pituitary gland. High levels
can decrease the signals from the pituitary gland and brain that
stimulate the testicles to produce testosterone.
Abnormally high prolactin levels can result from a number of
causes:
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a. Prolactinoma: a non-cancerous tumor of the pituitary gland that
secretes prolactin. These are usually treated with medication
and/or surgery.
b. Drugs: seizure medications, antihistamines, anti-psychotic
drugs, opiates, and many more.
c. Benign and malignant tumors involving the brain and pituitary
gland.
d. High estradiol levels.
e. Kidney or liver disease.
f. Hypothyroidism (low thyroid).
Very high prolactin levels (usually over 100ng/dL) should prompt your
doctor to order an MRI of the brain and pituitary gland.
2. Drugs:
a. Long-term use of opiate drugs is a well-known cause of
secondary hypogonadism. Discontinue them if at all possible.
b. Corticosteroids (prednisone)
c. Previous anabolic steroid use (may be permanent)
3. Chronic Diseases: serious liver, kidney, and lung disease can
cause secondary hypogonadism
4. Obesity: This is probably the most common cause. Obesity
increases the aromatization of testosterone into estradiol which
suppresses FSH and LH, causes changes in SHBG concentration,
and produces a direct inflammatory effect on the hypothalamus,
and may have other, as yet undiscovered, effects. If you are obese
you need to address it as soon as possible. Keep in mind you do
NOT have to be medically obese (BMI >29) to impact your
testosterone levels. Just being overweight, especially if you carry
a lot of visceral fat (around your organs), is enough to lower
your testosterone levels.
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5. Sleep apnea:
It is unclear if obstructive sleep apnea (OSA) directly causes
secondary hypogonadism or if it is related to the obesity that
frequently causes it. Regardless, if you suspect you have OSA it is
strongly recommended you have a sleep study.
6. Head trauma:
Traumatic brain injury (TBI) is strongly associated with not just
secondary hypogonadism but in wide-ranging hormonal
dysfunction including low growth hormone, low thyroid, and
adrenal insufficiency. Some studies have shown a prevalence of
long-term secondary hypogonadism in up to 23% of men with a
history of serious traumatic brain injury 43. If you have a history of
TBI or recurrent concussions it is strongly recommended you
undergo a complete hormonal evaluation.
43 Clark JDA, Raggatt PR, Edwards OM. 1988 Hypothalamic hypogonadism following major head injury. Clin Endocrinol (Oxf).
29:153–165.
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Low testosterone typically results from either primary or secondary
causes. Primary hypogonadism occurs when the testicles are no
longer able to manufacture testosterone. LH and FSH levels are
elevated. In secondary hypogonadism the hypothalamus or pituitary
gland no longer produce sufficient LH no normalize testosterone
levels.
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CHAPTER THREE
ELEVATING TESTOSTERONE
NATURALLY
Once the diagnosis of low testosterone has been made the next step is
deciding on therapy. In general, there are two broad categories:
1. Men who have lost the ability to produce adequate amounts of
testosterone and are unlikely to ever regain it.
For these men the only good option is replacement with
pharmaceutical grade testosterone. The various methods for
delivery are discussed below. Additional medication must be
added for the subset of men in this category who want to maintain
fertility.
2. Men with low testosterone due to a reversible cause (like
obesity).
There are several options for improving the body’s own
testosterone production while treatment is directed at treating the
underlying cause for the testosterone deficiency. This typically
involves lifestyle changes, removing offending medications and
changing body composition.
3-1. Reduce Body Fat:
It is important to recognize that in some cases low testosterone resulting
from poor lifestyle, excessive body fat, nutrient deficiencies, and toxic
exposures can be reversed with aggressive life changes.
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High body fat levels are known to lower testosterone levels. The reason
for this is complex and is due largely to excess estradiol production and
direct suppression of the hypothalamic-pituitary axis. Meeting modern
standards for obesity (BMI >30) is not required for excess body fat to
exert a negative effect on testosterone levels. Generally speaking, men
with higher body fat percentages and lower quantities of lean mass have
lower testosterone levels than men with more lean mass and less body
fat, even when not obese44.
Current standards for men call body fat percentages up to 24% as
normal. This does not mean that body fat levels this high have no
adverse health consequences. Nearly one quarter of your body weight
as adipose tissue is not healthy, nor should it be considered normal.
The optimal body fat percentage for healthy men who want to maximize
their testosterone levels is likely in the mid-to low teens. If you are
above 20% you likely have some work to do.
Men who get their lives in order and lose body fat are often able to
improve their testosterone levels. Greater body fat reductions are
associated with greater improvements in testosterone 45.
44 J. Grant Mouser, Paul D. Loprinzi, Jeremy P. Loenneke,
The association between physiologic testosterone levels, lean mass, and fat mass in a nationally representative sample of men in the United
States, Steroids, Volume 115, 2016, Pages 62-66,ISSN 0039-128X,
https://doi.org/10.1016/j.steroids.2016.08.009.
45 Endocrine Society. (2012, June 25). Overweight men can boost low testosterone levels by losing weight. ScienceDaily. Retrieved November
24, 2019 from www.sciencedaily.com/releases/2012/06/120625124914.htm
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The fatter you are the lower your testosterone levels. Notice that
even men who are not considered “Obese” (BMI >30) still
experience lower testosterone levels than men with lower BMIs. 46
Huhtaniemi, Ilpo. (2013). Late-onset hypogonadism: Current concepts and controversies of pathogenesis, diagnosis and treatment. Asian journal
of andrology. 16. 10.4103/1008-682X.122336.
46 Julien Dagenais*, Ye Wang, Adam Althaus, Martin Kathrins, Steven L Chang, Prevalence and predictors for testosterone deficiency in the
United States. The Journal of Urology Vol. 195, No. 4S, Supplement, May 10, 2016
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3-2. Dietary Considerations:
Several micronutrient deficiencies are linked to lower testosterone
levels. These are easy and inexpensive fixes and should be addressed in
all men with low testosterone either through diet or through
supplementations.
Vitamin D:
Very low vitamin D levels are associated with lower levels of
testosterone. Vitamin D deficiency (defined as a level less than 50
nmol/L) is very common. Almost 40% of the US population is vitamin
D deficient and certain darker skinned populations, African Americans
in particular, may have prevalence rates as high as 82.1%47
Low vitamin D levels are also associated with a number of chronic
health conditions including diabetes, heart disease, certain cancers and
rheumatoid arthritis among many others 48.
Supplementation with 2000-5000 IU per day should be sufficient to
correct vitamin D deficiency in most otherwise healthy adults.
Zinc:
Zinc deficiency is uncommon in the western world but is fairly prevalent
in third world countries and in older adults with poor nutrition and/or
poverty, among vegans49. Zinc is crucial for proper testosterone
production. Generally, zinc supplementation is not required if you are
eating a healthy diet. If you do supplement, your daily intake should not
exceed 40mg daily. Higher levels are associated with a number of health
47 Parva NR, Tadepalli S, Singh P, et al. Prevalence of Vitamin D Deficiency and Associated Risk Factors in the US Population (2 0112012). Cureus. 2018;10(6):e2741. Published 2018 Jun 5. doi:10.7759/cureus.2741
48 The vitamin D epidemic and its health consequences. Holick MF. J Nutr. 2005;135:2739–2748.
49 Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper,
Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc . Washington, DC: National Academy Press, 2001
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problems including copper deficiency, anemia, poor immune function,
among others50.
Magnesium:
Magnesium deficiency is surprisingly common with up to 48% of the
US population not consuming enough magnesium from foods51.
Suboptimal magnesium intake is associated with lower testosterone
levels and supplementation with magnesium can improve testosterone
levels in deficient men 52. The RDA for magnesium is about 420mg but
athletes and other active individuals will likely need more. It is not
unreasonable to supplement with up to 800-1000mg daily in divided
doses if you are otherwise healthy.
Sleep:
Circadian rhythm disturbances and sleep deprivation have long been
known to reduce testosterone levels through a variety of mechanisms 53.
Obtaining adequate sleep and minimizing changes in sleep wake cycles
are crucial to maintaining normal testosterone levels.
Exercise:
Regular high-intensity resistance exercise has been shown to boost short
term testosterone levels. Over time the reduced body fat and improved
muscle tissue created by this type of training also leads to long term
improvements in testosterone levels54. Conversely, long-distance,
endurance training can lower testosterone levels, especially if adequate
50 Willis MS, Monaghan SA, Miller ML, McKenna RW, Perkins WD, Levinson BS, et al. Zinc-induced copper deficiency: a report of three
cases initially recognized on bone marrow examination. Am J Clin Pathol 2005;123:125-31. [PubMed abstract]
51 Rosanoff A, Weaver CM, Rude RK. Suboptimal magnesium status in the United States: are the health consequences underestimated? Nutr
Rev 2012;70:153–64. 10.1111/j.1753-4887.2011.00465.x
52 Maggio M, De Vita F, Lauretani F, et al. The Interplay between Magnesium and Testosterone in Modulating Physical Function in Men. Int J
Endocrinol. 2014;2014:525249. doi:10.1155/2014/525249
53 Cote KA, et al. Sleep deprivation lowers reactive aggression and testosterone in men. Biol Psychol. (2013)
54 O’Leary CB, Hackney AC. Acute and chronic effects of resistance exercise on the testosterone and cortisol responses in obese males: a
systematic review. Physiol Res (2014).
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recovery is not achieved in between workouts 55. You should, therefore,
focus your training around short bursts of very difficult, high intensity
exercise and minimize the amount of slow, prolonged low-intensity
exercise you perform if your goal is improving your testosterone levels.
Limit your exposure to plastics as described in the introduction.
“Testosterone Boosters”:
They are all bullshit. Don’t waste your money56.
The Bottom Line:
If you have low testosterone and are carrying excess body fat, then
your NUMBER ONE PRIORITY is dropping your fat percentage as
significantly as possible. A very close second is beginning a highintensity weight training program and building as much muscle tissue
as possible.
55
Hackney AC, Aggon E. Chronic Low Testosterone Levels in Endurance Trained Men: The Exercise - Hypogonadal Male Condition. J Biochem
Physiol. 2018;1(1):103.
56 Clemesha CG, Thaker H, Samplaski MK. ‘Testosterone Boosting’ Supplements Composition and Claims Are not Supported by the Academic
Literature. World J Mens Health. 2020 Jan;38(1):115-122. https://doi.org/10.5534/wjmh.190043
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Natural Testosterone Boosting Order of Operations:
GET your body fat percentage down. Preferably well under 20%.
IF you are a type 2 diabetic you need to get it under control
ASAP. See #1 above.
PERFORM regular (at least 3 times per week) high-intensity
resistance training.
BUILD as much muscle mass as possible.
CLEAN up your crappy diet.
PRIORITIZE your sleep. Get at least 8 hours of quality,
uninterrupted sleep every night.
GET tested for sleep apnea. If you have it, use your CPAP
machine every night and lose weight.
STOP smoking.
STOP using marijuana regularly.
STOP using opiates.
SUPPLEMENT with vitamin D, magnesium, and a multivitamin
at a minimum.
AVOID plastics of all kinds as much as possible.
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CHAPTER FOUR
TREATMENT
The purpose of testosterone therapy is to alleviate symptoms and
improve overall health by restoring normal physiologic levels of
testosterone. This can be accomplished in a number of ways all of which
have advantages and disadvantages. The method you and your physician
ultimately chose will be based on your individual medical history and
personal preferences.
4-1. INTRAMUSCULAR TESTOSTERONE:
This is by far the most common and arguably the most effective method
of testosterone replacement. There are a variety of preparations that
differ primarily in how quickly they are metabolized. Injectable
testosterone can be compounded in a variety of carrier oils. Grape seed
oil is the most commonly used due to its cost, low viscosity, and low
incidence of injection site allergic reactions but other oils such as
cottonseed oil, MCT oil, and sesame oil are available from compounding
pharmacies.
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Testosterone Cypionate (200mg/ml) is the most common form of
testosterone used for replacement in the United States.
Testosterone Cypionate/Testosterone Enanthate:
Typical Dose: 100mg to 200mg every 7 days.
Advantages: Reliable and predictable testosterone levels. Enanthate
MAY cause less water retention.
Disadvantages: Requires either intramuscular or subcutaneous
injections weekly. May have higher than necessary levels for the first
few days and potential for return of symptoms in the few days prior to
the next injection. This is can be ameliorated by weekly or biweekly
dosing at lower dosages.
Cost: Variable but 10ml vials typically cost about $100.
A word on optimal dosing intervals for testosterone cypionate and
enanthate: It is not uncommon for physicians to prescribe injections of
testosterone every 14-21 days. This often leaves men feeling much
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improved for the first week after their injections with the gradual return
of symptoms during the later parts of the second week. This type of
dosing frequency often leaves men symptomatic for significant periods
of time.
Examining the pharmacokinetics of testosterone cypionate or enanthate
quickly demonstrates why dosing less frequently than once a week is
suboptimal. The graph below shows that after a single testosterone
injection, subjects return to pre-injection levels roughly between days
12-14. Weekly injections can, as shown below, result in steady state
levels above whatever threshold is desired. Therefore, it is advantageous
to use smaller, but more frequent dosing protocols as opposed to large,
infrequent boluses of testosterone.
Testosterone levels after a single intramuscular injection of
testosterone enanthate. After two weeks there has been a significant
decline. This makes every fourteen-day dosing suboptimal for many
men.
Adapted from Cunningham GR, Silverman VE, Kohler PO (1978) Clinical evaluation of testosterone enanthate for induction and maintenance of
reversible azoospermia in man. In: Patanelli DJ (ed) Hormonal control of male fertility. Department of Health, Education and Welfare. National
Institutes of Health, Bethesda, Md, Publ No (NIH) 78-1097, pp 7l-87
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Weekly injections of lower doses of testosterone cypionate (or
enanthate) are more likely to maintain levels above symptom
thresholds than less frequent dosing. This graph shows how weekly
subcutaneous injections of 100mg of testosterone enanthate
maintain testosterone levels in roughly the upper third of the
normal range in most men.
Adapted and modified from: Jed Kaminetsky, Jonathan S. Jaffe, Ronald S. Swerdloff, Pharmacokinetic Profile of Subcutaneous Testosterone
Enanthate Delivered via a Novel, Prefilled Single‐Use Autoinjector: A Phase II Study, Sexual Medicine, Volume 3, Issue 4, 201 5, Pages 269279, ISSN 20501161, https://doi.org/10.1002/sm2.80.
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Testosterone propionate is the most common short-acting injectable
testosterone preparation.
Testosterone Propionate:
Typical Dose: 30-50mg every other day.
Advantages: Reliable and predictable testosterone levels. Frequent
dosing makes achieving precise levels easier.
Disadvantages: Increasingly difficult to acquire. Requires more
frequent injections. Painful injections
Costs: Variable. Typically, about $120
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Testosterone Undecanoate (Aveed/Nebido):
This long-acting testosterone formulation was FDA approved in 2014
though it has not achieved widespread use largely due to its cost.
Typical Dose: 750mg intramuscularly every 4 weeks x2 then once every
10 weeks.
Advantages: Infrequent dosing is appealing for some with needle
phobias. Fairly reliable, steady levels are achieved for most of the time
between injections. Lower incidence of erythrocytosis.
Disadvantages: The large injections (3ml) are painful and can be
associated with embolization of the oil to the lungs causing cough, chest
pain, shortness of breath and allergic reactions. Can only be given in a
doctor’s office and you must remain there for 30 minutes afterwards to
monitor for side effects. Once given, levels cannot be titrated, and levels
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may drop below an individual’s symptom threshold in the final few
weeks before the next injection 57.
Cost: High. Without insurance the cost can range between $800-$1100
per 3ml dose.
Total testosterone levels following a single injection of 750mg of
testosterone undecanoate.
Adapted from: Abraham Morgentaler, Adrian S. Dobs, Joel M. Kaufman, Martin M. Miner, Ridwan Shabsigh, Ronald S. Swerdloff, Christina
Wang, Long Acting Testosterone Undecanoate Therapy in Men With Hypogonadism: Results of a Pharmacokinetic Clinical Study, The Journal
of Urology, Volume 180, Issue 6, 2008,Pages 2307-2313,ISSN 0022-5347,
https://doi.org/10.1016/j.juro.2008.08.126.
57 Wang C, Harnett M, Dobs AS, Swerdloff RS. Pharmacokinetics and safety of long-acting testosterone undecanoate injections in hypogonadal
men: an 84-week phase III clinical trial. J Androl. 2010;31(5):457-465
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Topical testosterone comes in both custom compounded
formulations as well as commercially available products.
4-2. TRANSDERMAL TESTOSTERONE (Androgel, etc.)
Typical Dose: Gel 1%,2%, 5%, or 10% strength or compounded cream
with doses up to 200mg/ml. Dose is variable based on concentration.
Typically, 50-100mg applied to skin daily or half that twice per day.
Advantages: Avoidance of injections. Well tolerated. Less
erythrocytosis than injectable testosterone.
Disadvantages: Must be used daily. Day to day blood levels are
variable and may be influenced by body temperature, perspiration, and
location of application. There is greater conversion to DHT
(dihydrotestosterone) potentially accelerating hair loss or prostate
enlargement in genetically susceptible men. Potential for transfer to
others with skin-to-skin contact.
Cost: Variable. Brand name preparations may cost up to $300 per
month.
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Buccal delivery methods transfer testosterone across the mucous
membranes of the mouth or gums.
4-3. BUCCAL TESTOSTERONE (Striant SR)
Testosterone can be dosed using a small oral tablet that is placed
between the gums and cheek. Some versions have an adhesive that keeps
it in place. While in the mouth, testosterone is absorbed through the oral
mucous membranes and into the blood stream.
Typical Dose: 30mg mucoadhesive tablet dosed every 12 hours.
Compounded troches are available at various strengths (100mg
commonly)
Advantages: Oral dosing without need for injections or topical
application.
Disadvantages: Twice daily administration. May cause gum and/or lip
irritation, bad taste, cost.
Cost: Highly variable. Compounded troches $6-$10 per troche.
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Oral testosterone undecanoate has been available for years in
Europe and other countries and has recently been approved for use
in the United States.
4-4.
ORAL TESTOSTERONE (Testosterone Undecanoate)
The first commercially available oral testosterone therapy,
methyltestosterone, became available in 1936. It was used to treat a
variety of conditions, usually hormone-sensitive cancers. Unfortunately,
it’s harsh side effect profile and liver toxicity made it an unsuitable
option for long-term testosterone replacement in men. It is now no
longer widely available.
The next oral option for testosterone replacement, testosterone
undecanoate, came in the early 1980s and has been widely available
outside the United States under the brand name Andriol. This
formulation avoids the significant liver toxicity associated with oral
methyltestosterone. After a number of failed attempts, oral testosterone
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undecanoate became available in the U. S. under the brand name
Jatenzo58.
Typical Dose: Capsules are available in 158 mg, 198 mg, and 237 mg
sizes. Typical starting dose is 237mg twice a day, preferably with a fatty
meal. Doses are then adjusted based on follow up blood levels drawn six
hours after the morning dose after being on therapy for at least one
week59.
Advantages: Oral dosing. No injections. Blood levels peak within 6
hours after dose. Possibly less erythrocytosis.
Disadvantages: Must be dosed twice per day making compliance
difficult for some. Very low bioavailability that can lead to widely
variable serum levels60. Should be taken with a fatty meal for optimal
absorption.
Cost: Not yet available in the US. Likely high.
58 https://www.fda.gov/news-events/press-announcements/fda-approves-new-oral-testosterone-capsule-treatment-men-certain-formshypogonadism.
59 http://www.jatenzo.com/pdf/jatenzo-pi.pdf
60 U. TAUBER, K. SCHRODER, B. DDsTERBERG and H. MATTHES. Absolute bioavailability of testosterone after oral administration of
testosterone-undecanoate and testosterone. EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 1986, Vol. 11, No
2, pp. 145-149
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Testosterone pellets are inserted under the skin during a minor
surgical procedure and can last for up to four months in some cases.
4-5. TESTOSTERONE PELLETS
Typical Dose: Variable. Pellets range in size from 25mg to 200mg.
Typically multiple pellets are inserted at one time. Typically inserted
once every 4-6 months.
Advantages: Long interval between insertions. Fairly steady levels are
achieved with gradual decline over time.
Disadvantages: Requires a surgical procedure. Pellets can extrude from
the body in up to 10% of cases. Unable to titrate testosterone levels after
pellets are implanted. May result in supratheraputic levels in first month
or two and inadequate levels, with return of symptoms, in final months.
Cost: Variable and dependent on number of pellets required. Typically,
over $1,000.
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Nasal testosterone spray is available but is not a popular option for
most men.
4-6. NASAL TESTOSTERONE SPRAY (Natesto Nasal Gel)
Typical Dose: One spray (about 5.5mg) per nostril three times per day.
Advantages: No need for injections or topical administration. Rapid rise
in testosterone levels with peak levels within about 40 minutes.
Disadvantages: Requires dosing three times daily making compliance
difficult. Sinus irritation, sinus infection, runny nose. Not all patients
will reach therapeutic levels.
Cost: Price varies. Approximately $440 per 11g61.
61 https://www.drugs.com/price-guide/natesto
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4-7. ALTERNATIVES AND ADJUNCTS TO TESTOSTERONE
Three additional medications are commonly used in the treatment of low
testosterone, either alone or in combination with testosterone. For men
with reversible causes of low testosterone and the ability to still produce
adequate amounts of testosterone, these medications can serve as useful
ways to normalize testosterone levels while the underlying cause is
corrected.
For example, if obesity is suppressing your testosterone levels, these
medications can raise your own production of testosterone and assist you
in losing body fat. When you have lost enough weight, these
medications can be discontinued without suppressing your own natural
production of testosterone and your levels will remain in the normal
range (assuming you don’t gain the weight back).
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4-7-1. hCG (HUMAN CHORIONIC GONADOTROPIN)
hCG is a protein hormone produced by the mammalian placenta and first
discovered in the early 1900s. This finding led to the development of the
first pregnancy tests in the 1930s62. Injections of hCG were later found
to induce ovulation in women and have since been widely used to treat
female infertility. HCG also increases the secretion of testosterone from
the male testicle by mimicking the action of LH (luteinizing hormone).
It also has enough similarity to FSH (follicle stimulating hormone) that
it can help maintain sperm production as well 63.
In order for hCG to be useful clinically, the testicle has to retain the
ability to both recognize hCG and to produce testosterone. This capacity
is diminished in a variety of scenarios (primary hypogonadism), but
most commonly is associated with aging, testicular trauma, and a variety
of other medical conditions. In particular, insulin resistance and type 2
diabetes can limit the testicles ability to respond to hCG64. This is yet
another reason, if you are carrying excess body fat, to get your weight
under control. Therefore, if you have primary hypogonadism (the testicle
has lost the ability to make adequate testosterone) you are unlikely to
respond adequately to HCG alone.
Therefore, with advancing age the testicle may become less responsive
to hCG therapy. While it works well in younger men, men over the age
of 50 may not obtain enough of a response to achieve therapeutic
testosterone levels or improved fertility 65.
Typical Dose: Variable. 250 IUs to 2000 IUs dosed 2-3 times per week
via subcutaneous injection. There is no additional benefit from doses
62 Shapiro, H. A.; Zwarenstein, H. (1934-05-19). "A Rapid Test for Pregnancy on Xenopus lævis". Nature. 133 (3368): 762–
762. doi:10.1038/133762a0. ISSN 0028-0836
63 Tawfik Rizkallah, Erlio Gurpide, Raymond L. Vande Wiele, Metabolism of HCG in Man, The Journal of Clinical Endocrinology &
Metabolism, Volume 29, Issue 1, 1 January 1969, Pages 92–100.
64 Nelly Pitteloud, Megan Hardin, Andrew A. Dwyer, Elena Valassi, Maria Yialamas, Dariush Elahi, Frances J. Hayes, Increasing Insulin
Resistance Is Associated with a Decrease in Leydig Cell Testosterone Secretion in Men, The Journal of Clinical Endocrinology & Metabolism,
Volume 90, Issue 5, 1 May 2005,
65 NANKIN, H. R., LIN, T. , MURONO, E. P. and OSTERMAN, J. (1981), The Aging Leydig Cell: III. Gonadotropin Stimulation in Men.
Journal of Andrology, 2: 181-189.
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>2000 IU. After a single injection of HCG there is a small rise in
testosterone that peaks within a few hours and then a second, much
larger, rise in testosterone that peaks approximately 48-72 hours later
and then returns to baseline between 96-120 hours later. A repeat dose
before the 72-hour peak does NOT lead to higher testosterone
production66. Therefore, larger or more frequent dosing will lead to
desensitization and lack of efficacy for subsequent doses and could
promote antibody formation 67.
Advantages: Preserves testicular size and sperm production. Stimulates
production of endogenous testosterone. Will not produce supraphysiologic levels of testosterone.
Disadvantages: Dosed 2-3 times per week. Must be refrigerated. Less
effective in older men (> age 50). Long-term use could result in the
production of antibodies that reduce its effectiveness and require higher
doses to achieve the same effect though this is uncommon. Long-term
use could suppress LH production. Will not work well in primary
hypogonadism.
Cost: Highly variable. $12-$30 per 2000 I.U. is not uncommon. Almost
always must be obtained from a compounding pharmacy in the U.S. In
March 2020 FDA legislation restricted compounding pharmacies from
creating a host of medications deemed to be “biologic products”. HCG
was included on this list. Pharmacies now must have an expensive
biologics license which greatly limits the number of U.S. pharmacies
able to manufacture HCG. Expect HCG prices to rise significantly as a
result.
Side Effects: Few. Local reactions at the injection site. There is an
associated rise in estradiol along with testosterone.
66
ANTHONY G. H. SMALS, GERLAG F. F. M. PIETERS, JULES HIRSCH, JAN I. M. DRAYER, THEO J. BENRAAD, PETER W. C.
KLOPPENBORG, Leydig Cell Responsiveness to Single and Repeated Human Chorionic Gonadotropin Administration, The Journal of Clinical
Endocrinology & Metabolism, Volume 49, Issue 1, 1 July 1979, Pages 12–14, https://doi.org/10.1210/jcem-49-1-12
67 R. J. Dash, P. S. Lamba, R. Sialy. Single vs. Multiple Dose hCG Stimulated Leydig Cell Responses in Eugonadal and Hypogonadal Subjects.
Horm. metab. Res. 26 (1994) 347-348.
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hCG is typically used in the following scenarios:
1. Monotherapy for younger men with low testosterone who wish to
maintain fertility and still have the ability to produce their own
testosterone.
2. An adjunct to TRT where it is used to maintain fertility and prevent
testicular atrophy.
3. After a cycle of anabolic steroids (often in conjunction with
clomiphene or an aromatase inhibitor) to restore testicular size and
testosterone production.
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HCG mimics the effects of LH (and to a lesser degree FSH) on the testicles and stimulates
the production of testosterone.
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4-7-2. CLOMIPHENE CITRATE (CLOMID)
Clomid belongs to a class of medications known as SERMs (selective
estrogen receptor modulator). These medications can bind to the
estrogen receptor with effects that vary depending on the location in the
body. Its action on the hypothalamus and pituitary gland are what make
it useful for raising testosterone in some men.
Clomid works by blocking the ability of the hypothalamus and pituitary
gland to detect circulating estradiol. As discussed, estradiol lowers the
production of LH and FSH via a negative feedback loop. By effectively
blinding the brain to the amount of circulating estradiol, it tricks the
pituitary gland into releasing more LH and FSH. In a man whose
testicles still have the ability to produce testosterone the increase in LH
directly leads to greater testosterone production while at the same time
maintaining normal sperm production and avoiding testicular atrophy.
For this reason, it can be a highly effective, though often underutilized,
method to boost testosterone levels, particularly in young men.
Clomid, in many ways, is the ideal treatment for younger men (less than
age 35) whose low testosterone levels are related to reversible causes
such as obesity and poor lifestyle choices. In many cases, treatment with
Clomid can more than double baseline testosterone levels (see table
below).
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The effect of clomiphene on young men with low testosterone.
Clomiphene significantly increased LH and FSH levels resulting in
more than doubling of total testosterone and a near-fourfold
increase in free testosterone while preserving fertility. Adapted from: Katz, D. J.,
Nabulsi, O. , Tal, R. and Mulhall, J. P. (2012), Outcomes of clomiphene citrate treatment in young hypogonadal men. BJU International, 110:
573-578.
Typical Dose: 25mg to 50mg daily or every other day.
Advantages: Oral medication that does not suppress the HPG axis.
Easily obtained and inexpensive. Low side effect profile. Maintains
testicular size and sperm production. Can be easily discontinued without
side effects.
Disadvantages: Less effective in older men. May suppress IGF-1 and
stimulate estrogen production. May become less effective over time (>1
year). May elevated SHBG and therefore lower free testosterone in some
men68. Variable response.
Cost: Variable but can be as low as $10-$20 per month.
68 Adamopoulos DA, Vassilopoulos P, Kapolla N, Kontogeorgos L. The effect of clomiphene citrate on sex hormone binding globulin in
normospermic and oligozoospermic men. Int J Androl. 1981 Dec;4(6):639-45.
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Side Effects: There are rare case reports of various visual disturbances
in patients using Clomid. These have included shimmering and flashes
in the peripheral vision, blurred vision, blind spots, and light sensitivity.
In almost all cases these symptoms quickly resolve with discontinuation
of the medication and seem to be associated with prolonged use and
higher doses69. There are also case reports of Clomid exacerbating
psychiatric symptoms like anxiety and depression and should, therefore,
be used cautiously in men with these conditions.
69 L. Racette, et al. An investigation of the visual disturbances experienced by patients on clomiphene citrate. Fertility and Sterility Vol. 93, No.
4, March 1, 2010.
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4-7-3. AROMATASE INHIBITORS (Anastrazole, Letrozole, etc.)
Aromatase inhibitors are medications that block the aromatase enzyme.
This enzyme is responsible for the conversion of androgens like
testosterone into estradiol in both men and women. In men this enzyme
is concentrated in the testicles, but fat tissue is also a significant source.
There is a subset of men, presumably those with higher levels of the
aromatase enzyme or a particularly active variant of the aromatase
enzyme, that develop symptomatic elevations of estradiol while on
testosterone therapy. These men may benefit from the addition of an
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aromatase inhibitor for a limited amount of time, though this is
controversial.
There are also subsets of men whose low testosterone levels and/or
infertility thought to be secondary to elevated estradiol levels that can
normalize their testosterone levels with aromatase inhibitor therapy
alone70.
The aromatase enzyme converts testosterone to estradiol. This
conversion is a major source of estradiol in men.
Typical Dose: Anastrazole: 0.5-1.0 mg once or twice per week.
Letrozole: variable dosage. Typically, 0.5-2.5mg once or twice a week.
Advantages: Avoidance of injections. Well tolerated. Reliably lowers
elevated estradiol levels. Does not suppress endogenous testosterone
production. Can be discontinued at any time without side effects. In men
70 Benjamin Z. Leder, Jacqueline L. Rohrer, Stephen D. Rubin, Jose Gallo, Christopher Longcope, Effects of Aromatase Inhibition in Elderly
Men with Low or Borderline-Low Serum Testosterone Levels, The Journal of Clinical Endocrinology & Metabolism, Volume 89, Issue 3, 1
March 2004, Pages 1174–1180.
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with low testosterone and/or infertility related to obesity AIs can
normalize testosterone levels and improve sperm counts71.
Disadvantages: May not be as effective as clomiphene in terms of
raising testosterone levels. May place men at risk for osteoporosis if
estradiol is driven too low for prolonged periods of time 72 . No long-term
data on safety or efficacy. May worsen cholesterol. Could increase risk
of cardiovascular disease when used long-term73.
Cost: Variable. Letrozole up to $10 per tablet. Anastrazole also variable
but may be up to $6 per tablet.
Note: There are other available AIs such as testolactone, formestane and
exemestane collectively known as “suicide inhibitors” that permanently
bind the aromatase enzyme. These are rarely used and are not considered
mainstays of hormonal therapy in men.
4-7-4. KISSPEPTIN-10
Kisspeptin is an emerging peptide that has potential for use as a
replacement for HCG in men for whom HCG is ineffective or in the
event that HCG is unavailable. It works much higher in the
hypothalamic pituitary axis by increasing gonadotropin releasing
hormone (GnRH) which, in turn, elevates LH and FSH. Research on
kisspeptin in humans with low testosterone or as an adjunct to
testosterone for men wishing to maintain fertility is very sparse at this
time but it appears to have potential in both these areas.
71 The Endocrine Society. "Letrozole is a promising new treatment of male infertility." ScienceDaily. ScienceDaily, 6 March 2015.
<www.sciencedaily.com/releases/2015/03/150306102509.htm>.
72 Burnett-Bowie SA, McKay EA, Lee H, Leder BZ: Effects of aromatase inhibition on bone mineral density and bone turnover in older men
with low testosterone levels. J Clin Endocrinol Metab 2009, 94:4785-4792.
73
Foglietta J, Inno A, de Iuliis F, et al. Cardiotoxicity of Aromatase Inhibitors in Breast Cancer Patients. Clin Breast Cancer. 2017;17(1):11-17.
doi:10.1016/j.clbc.2016.07.003
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Typical Dose: Optimal dose is unknown. Maximal LH production
seems to be somewhere around 100 mcg injected subcutaneously three
times per week, but more studies are needed to confirm this74.
Advantages: Stimulates endogenous production of both FSH and LH
theoretically maintaining both fertility and testosterone production in
men with secondary hypogonadism.
Disadvantages: Expensive and potentially subject to FDA restrictions in
the United States.
Cost: Highly variable and subject to potential FDA restrictions in the
future.
4-7-5. HMG (HUMAN MENOPAUSAL GONADOTROPIN)
HMG is a rarely used, but potential very helpful, adjunct for men with
low testosterone and/or infertility. Many physicians have never heard of
this medication despite the fact it has been available since the early
1960s.
HMG is mixture of various gonadotropins (FSH, LH, HCG) isolated
from the urine of post-menopausal women. As such, it can serve as
either a replacement for, or adjunct to, HCG for men wishing to
maintain testicular function while on TRT. HMG alone is not likely to
be sufficient to treat low testosterone but is often combined with HCG.
The most common use for HMG is in combination with HCG to
maximize fertility in men for whom HCG (or HCG and Clomid) alone
74
George JT, Veldhuis JD, Roseweir AK, et al. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. J Clin
Endocrinol Metab. 2011;96(8):E1228‐E1236. doi:10.1210/jc.2011-0089
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has not adequately raised sperm counts 75. The FSH provided by HMG is
often enough to make a significant difference in sperm counts76.
Despite being considered less effective by some physicians than
recombinant FSH (rFSH), HMG remains a viable, lower cost, option for
many men.
Typical Dose: 75-150 IU three times per week.
Advantages: Contains FSH which is often required for optimal sperm
production. Also contains LH and HCG which can help stimulate
testosterone production. Less expensive than rFSH.
Disadvantages: More expensive than HCG. May be insufficient for
testosterone elevation when used alone. As a human derived product,
there is theoretical risk of infectious disease transmission.
Cost: Variable. May be as high as $30 per 75 IU dose.
4-7-6. rFSH (RECOMBINANT FOLLICLE STIMULATING
HORMONE)
rFSH is a highly purified, synthetic version of the gonadotropin FSH. In
men FSH is crucial for the production of healthy sperm. rFSH is an
option for men who do not adequately raise their sperm counts using
HCG, clomid or HMG. It may be more effective than HMG in
improving fertility but few head to head comparison studies exist77.
Typical Dose: 75-150 IU three times per week.
75
Finkel DM, Phillips JL, Snyder PJ. Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. N Engl J
Med. 1985;313(11):651-655. doi:10.1056/NEJM198509123131102
76 El Meliegy A, Motawi A, El Salam MAA. Systematic review of hormone replacement therapy in the infertile man. Arab J Urol.
2017;16(1):140-147. Published 2017 Dec 30. doi:10.1016/j.aju.2017.11.011
77
Behre HM. Clinical Use of FSH in Male Infertility. Front Endocrinol (Lausanne). 2019;10:322. Published 2019 May 24.
doi:10.3389/fendo.2019.00322
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Advantages: purified FSH with no other ingredients.
Disadvantages: High cost.
Cost: Variable. May be up to three times the cost of HMG78.
4-8. MANAGING ESTRADIOL
The testes produce 20% of a man’s estradiol. The remainder is created in
peripheral tissues like fat tissue, skin, bone and brain through the
conversion of testosterone to estradiol via the aromatase enzyme 79.
There are no long-term studies or consensus on how to manage estradiol
levels in men. It has become common place to routinely place men using
TRT on an aromatase inhibitor (AI) in order to maintain estradiol levels
within a “normal” reference range of 10-40 pg/ml though there is no
evidence supporting this practice in asymptomatic men and emerging
evidence that doing so may be harmful.
Estradiol has long been recognized as crucial for maintaining healthy
bone structure in women and has now been recognized, along with
testosterone, as equally important in men80. Estradiol is also thought to
be protective for heart disease in both men and women. The testosterone
to estradiol ratio (T/E ratio) may be an important factor in mediating this
effect. There is evidence that both a very high and very low T/E ratio
may put men at risk 81. The optimal T/E ratio for overall health in men is
a subject of debate. It is therefore likely to be important for your longterm health not to drive estradiol levels too low nor allow them to rise to
symptomatic levels. Of note, there is significant overlap in the
78
Al-Inany HG, Abou-Setta AM, Aboulghar MA, Mansour RT, Serour GI. HMG versus rFSH for ovulation induction in de veloping countries: a
cost-effectiveness analysis based on the results of a recent meta-analysis. Reprod Biomed Online. 2006;12(2):163-169. doi:10.1016/s14726483(10)60856-5
79 Vermeulen A, Kaufman JM, Goemaere S, van Pottelberg I. Estradiol in elderly men. Aging Male 5: 98–102, 2002.
doi:10.1080/tam.5.2.98.102.
80 Finkelstein JS, Klibanski A, Neer RM, Greenspan SL, Rosenthal DI, Crowley WF, Jr. Osteoporosis in men with
idiopathic hypogonadotropic hypogonadism. Ann Intern Med 1987;106:354–61
81 Gong Y, Xiao H, Li C, Bai J, Cheng X, et al. (2013) Elevated T/E2 Ratio Is Associated with an Increased Risk of Cerebrovascular Disease in Elderly Men. PLoS
ONE 8(4): e61598. doi:10.1371/journal.pone.0061598
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symptoms of both low and high estradiol levels in men. Joint pain,
however, is a consistent symptom of low estradiol levels associated with
AI use and may be one of the more significant symptoms indicating your
levels are too low82.
There are three primary factors which determine estradiol levels:
1. The amount of aromatase enzyme available to act on
testosterone. This is largely dictated by one’s body fat
percentage.
2. The amount of available testosterone. Higher testosterone
levels provided more substrate for the aromatase enzyme. It
is therefore important to maintain your testosterone levels
within the normal range. Even in lean individuals, excessive
testosterone can lead to estradiol elevations.
3. Genetic variations in the activity of the aromatase enzyme.
Individuals may inherit versions of the aromatase enzyme
with either a greater or lesser ability to convert testosterone
to estradiol83.
Aromatase inhibitors can be used to reduce estradiol levels, but the best
long-term solution to managing estradiol is to reduce body fat. It is rare
for lean men on TRT to develop symptomatic estradiol elevations.
The other important point to emphasize is that the development of
gynecomastia, both during normal puberty and with TRT or anabolic
steroid use is largely a genetically mediated phenomenon. This is
especially true in lean men who develop this while on TRT. The best
82 Donnellan PP, Douglas SL, Cameron DA, Leonard RC. Aromatase inhibitors and arthralgia [letter]. J Clin Oncol 2001;19:2767.
83 Hammoud A, Carrell DT, Meikle AW, et al. An aromatase polymorphism modulates the relationship between weight and estradiol
levels in obese men. Fertil Steril. 2010;94(5):1734–1738. doi:10.1016/j.fertnstert.2009.10.037
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long-term strategy for treating gynecomastia in these men is surgery.
Life-long treatment with aromatase inhibitors may possibly expose men
to adverse effects and is not recommended.
In general, AIs should not be used routinely in men receiving
TRT unless they are experiencing symptoms of elevated
estradiol and have lab evidence showing substantial estradiol
elevations. In those cases, a very low dose of an AI could be
considered.
Symptoms of Elevated
Estradiol
1. Gynecomastia (enlarged
Symptoms of Low
Estradiol
1. Joint Pain
male breast tissue)
2. Low libido
2. Low libido
3. Erectile dysfunction
3. Erectile Dysfunction
4. Water retention
4. Water retention
5. Decreased fertility
5. Decreased fertility
6. Body fat accumulation
6. Body fat accumulation
7. Generalized
Malaise/Fatigue
8. Poor quality orgasm
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The key to managing estradiol is to maintain low levels of
body fat and keeping your testosterone level within the
normal rage.
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CHAPTER FIVE
POTENTIAL SIDE-EFFECTS
5-1. HAIR LOSS
Male pattern baldness, also referred to as androgenic alopecia, is a
genetically mediated trait that affects up to 50 percent of men to some
degree. It typically presents by age 40 though many men begin to
experience hair loss in their early 20s.
Though the mechanism of male-pattern hair loss is complex, the
hormone dihydrotestosterone (DHT) plays a significant role in nearly all
cases. DHT is produced from testosterone and then interacts with hair
follicles contributing to hair loss. It appears that topical testosterone
creams and gels result in higher blood DHT levels than other means of
delivery. This is likely due to the high concentration of 5-alpha
reductase present in the skin 84.
Testosterone replacement in men with a genetic predisposition to male
pattern hair loss in many cases can accelerate the hair loss that would
have occurred anyway. In men lacking genes for hair loss, testosterone
replacement has little to no effect.
Options for treatment of androgenic alopecia are limited. Topical
minoxidil (Rogaine) and oral finasteride (Propecia) are the only options
with any proven efficacy though their effect is modest. Many men opt to
shave their heads or undergo transplant surgery.
84 Cunningham GR, Cordero E, Thornby JI. Testosterone Replacement With Transdermal Therapeutic Systems: Physiological Serum
Testosterone and Elevated Dihydrotestosterone Levels. JAMA. 1989;261(17):2525–2530. doi:10.1001/jama.1989.03420170069032
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The 5-alpha-reductace enzyme is responsible for converting
testosterone to DHT. Medications can be used to block this
conversion but should be used with caution.
Finasteride blocks the 5-alpha-reductace enzyme that converts
testosterone to DHT. At a dose of 1mg per day it is modestly effective in
at least slowing further hair loss and, in some cases, re-growing hair85.
Androgenic alopecia follows wellrecognized patterns and is
genetically mediated.
Hair follicles in the crown and
forehead are programmed to
become dormant when exposed to
the androgen DHT
(dihydrotestosterone).
DHT levels are largely dependent
on testosterone levels.
Typical male pattern hair loss
85 Drake L, Hordinsky M, Fiedler V, et al: The e¡ects of ¢nasteride on scalp skin and serum androgen levels in men with androgenetic alopecia.
J Am Acad Dermatol 41:550^554, 1999
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Though finasteride is generally well tolerated with few side effects, there
is a rare complication known as “post-finasteride syndrome” which can
lead to host of long term, possibly permanent, side effects including loss
of libido, erectile dysfunction, depression, suicidal ideation, anxiety,
panic attacks, penile shrinkage, chronic testicular pain, and many other
symptoms86. The cause is unknown but does seem to be related to
prolonged use.
The typical dose of finasteride for hair loss is 1mg daily.
5-2. ACNE
In some men, TRT can increase oil gland production in the skin resulting
in acne. This is generally mild and easily managed with topical therapy.
More severe cases may require oral medications. If this is a serious issue
you should discuss your options with your dermatologist.
5-3. ERYTHROCYTOSIS (ELEVATED HEMATOCRIT).
Testosterone is known to be crucial for maintaining bone health in men 87
What is often forgotten is that testosterone is a potent stimulator of red
blood cell (RBC) production in the bone marrow. In some men,
treatment of low testosterone levels with testosterone replacement can
produce a predictable increase in RBC counts as measured by
hemoglobin and hematocrit counts 88. This effect is likely related to both
dose and genetic factors.
86 86 Post-Finasteride Syndrome: Overview. Post-Finasteride Syndrome Foundation. Somerset, New Jersey: [Last cited on 2016 Jan 18].
Available from: http://www.pfsfoundation.org/post-finasteride-syndrome-overview/
87 Mohamad NV, Soelaiman IN, Chin KY. A concise review of testosterone and bone health. Clin Interv Aging. 2016;11:1317–1324. Published
2016 Sep 22. doi:10.2147/CIA.S115472
88 Palacios A, Campfield LA, McClure RD, Steiner B, Swerdloff RS. Effect of testosterone enanthate on hematopoiesis in normal men.
Fertil Steril. 1983 Jul;40(1):100-4.
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There is no evidence to suggest that the increase in reb blood cells
experienced with TRT is associated with dangerous blood clotting
leading to DVT (deep venous thrombosis), PE (pulmonary embolism),
stroke, and heart attack. This is common misconception among many
physicians.
The hematocrit level, if any, at which the risk of clotting becomes
significant is unknown, but there does not appear to be increased risk
with rising hematocrit levels89. Intramuscular testosterone also seems
to be more likely to cause erythrocytosis than topical preparations90
The Endocrine Society and American Urological Association both
recommend that hematocrit levels should be kept below 54% 91. It is not
unreasonable to donate blood if your level exceeds 54% but there is no
evidence to support routine donation at lower levels unless you are
symptomatic.
You and your doctor should monitor your hematocrit on a regular basis.
Drinking plenty of water will help your hematocrit from rising due to
dehydration.
Regular phlebotomy can lead to the development of iron deficiency.
This is particularly problematic as replacement of iron stores with oral
iron is a slow process and comes with a number of gastrointestinal side
effects. IV iron is an option, but this is expensive and does not solve the
underlying problem. If you require frequent phlebotomy while on
injectable testosterone it may be wise to switch to another delivery
method with a lower incidence of erythrocytosis:
89 Njølstad I, Wilsgaard T, Hansen JB. Hematocrit and risk of venous thromboembolism in a general population. The Tromso study. Braekkan
SK, Mathiesen EB, Haematologica. 2010 Feb;95(2):270-5. Epub 2009 Oct 14.
90 Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practi ce
guideline. J Clin Endocrinol Metab. 2018;103(5):1-30.
91 Mulhall, J. P., Trost, L. W., Brannigan, R. E., Kurtz, E. G., Redmon, J. B., Chiles, K. A., ... Lewis, R. W. (2018). Evaluation and Management
of Testosterone Deficiency: AUA Guideline. Journal of Urology, 200(2), 423-432. https://doi.org/10.1016/j.juro.2018.03.115
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Rates of Erythrocytosis (Hematocrit >50%) with various forms of
testosterone delivery:
Testosterone Cypionate or
Enanthate 100mg-200mg
per week
Testosterone Pellets 75mg
Transdermal Testosterone
50-100mg daily
Testosterone Undecanoate
(IM injection) 1000mg
Testosterone Undecanoate
(oral) 158-237mg twice a day
66%
35.1%
12.8%
7%
Unknown. Possibly as low as
0.003%
There are several options for dealing with elevated hematocrit
levels.
1. Hold therapy until levels decline to normal.
2. Perform blood donation (phlebotomy).
3. Decrease the dose of testosterone.
4. Consider switching from an injectable to a topical preparation or
testosterone undecanoate.
5. Consider bi-weekly (or daily) injections or subcutaneous injections.
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Addressing certain underlying conditions may help reduce hematocrit
levels below the threshold where phlebotomy is needed:
1. Sleep Apnea: this condition is associated with low levels of blood
oxygen while sleeping. The body reacts to this perceived threat by
increasing the number of red blood cells to increased oxygen carrying
capacity. If you have obstructive sleep apnea (OSA) it is imperative
that it be treated.
2. Smoking: smoking also leads to perceived hypoxia and can result in
increased red blood cell production. If you smoke, you need to stop.
Now.
3. Dehydration: while not increasing the number of red blood cells per
se, dehydration can lead to lower intravascular volume leading to
higher hematocrit levels. Diuretic drugs can exacerbate this. While on
testosterone you need to make adequate hydration a priority.
4. Altitude: prolonged at high elevations will consistently result in a
series of adaptations which include elevated hematocrit levels. This
process is often considered beneficial for athletes who frequently
train at high altitude to take advantage of this phenomenon. The
average hematocrit of healthy males aged 15-29 living in Bolivia at
altitudes greater than 4000m was 52.7%92. It is unclear if this
phenomenon is associated with increased risk.
5. Hemochromatosis: This genetic condition causes excess iron storage
in the body and may lead to a host of health problems. At least one
gene for this condition is present in up to 20% of individuals of Celtic
ancestry93. Ask your doctor to test you for the common genetic
variants that lead to this condition if you think you are at risk.
92 Vasquez R, Villena M, Normal Hematological Values for Healthy Persons Living at 4000 Meters in Bolivia. High Altitude
Medicine & Biology, Vol 2, No. 3. Sep 2001. 361-367
93
Byrnes V, Ryan E, Barrett S, Kenny P, Mayne P, Crowe J. Genetic hemochromatosis, a Celtic disease: is it now time for population
screening?. Genet Test. 2001;5(2):127-130. doi:10.1089/109065701753145583
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5-4. OBSTRUCTIVE SLEEP APNEA (OSA)
Sleep apnea is a common disorder resulting from repeated episodes of
upper airway obstruction during sleep that results in repeated bouts of
low oxygenation and cardiovascular stress. The most common cause of
this obstruction is airway occlusion related to obesity involving the head
and neck.
OSA is strongly associated with low testosterone levels. The repeated
breakup of the sleep cycle has been shown to disrupt the rhythm of
nocturnal testosterone production94. Left untreated, OSA can worsen
high blood pressure, reduce sexual function, impair brain function, and
lead to congestive heart failure and premature death.
OSA is diagnosed by a sleep study and treated with a CPAP machine
that blows positive pressure into the airway throughout the night to keep
the airway open. Long-term remission can be achieved with weight loss
and occasionally surgery. It is not clear if treating OSA with CPAP will
improve testosterone levels as studies in this are mixed 95.
What is clear is that untreated OSA can get worse with testosterone
therapy and testosterone therapy should not be started in patients with,
If you have or suspect you have
obstructive sleep apnea
It MUST be properly treated BEFORE
beginning testosterone replacement therapy.
94 Luboshitzky R, Zabari Z, Shen-Orr Z, Herer P, Lavie P. Disruption of the nocturnal testosterone rhythm by sleep
fragmentation in normal men. J Clin Endocrinol Metab 2001; 86:1134-9
95 Meston N, Davies RJ, Mullins R, Jenkinson C, Wass JA, Stradling JR. Endocrine effects of nasal continuous positive airway
pressure in male patients with obstructive sleep apnoea. J Intern Med 2003; 254:447-54
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or suspected of having, OSA until it has been properly diagnosed and
treated96.
5-5. TESTICULAR ATROPHY/INFERTILITY
Treatment with testosterone alone, regardless of its delivery method, will
shut down what remains of your own body’s testosterone production.
For men who are permanently unable to make adequate amounts of
testosterone this is of little significance unless they wish to maintain
fertility or are concerned about testicular atrophy.
An important issue that is often overlooked in men using
testosterone is that after prolonged use the pituitary axis can be
permanently suppressed. This means that even if testosterone therapy
is discontinued, it may be impossible for the hormonal axis to recover
and return testosterone and sperm levels back to pre-treatment
baseline97. The longer testosterone is used the more likely this scenario
is to occur, though recovery rates will vary greatly between
individuals98. This is yet another reason why TRT should only be used
by men who have PERMANENTLY lost the ability to produce adequate
levels of testosterone.
In all men, treatment with testosterone will reliably reduce sperm counts.
The degree of reduction is variable and, therefore, this should not be
used as a reliable means of birth control. Even while on TRT some men
will produce enough sperm to cause a pregnancy. Men who wish to
retain fertility while on TRT will need to add HCG to maintain sperm
production. Men using only HCG and/or Clomid to raise their own
testosterone production will not see a reduction in fertility and, in some
cases, sperm counts may improve 99.
96 Gottlieb DJ, Yenokyan G, Newman AB, O’Connor GT, PunjabiNM, Quan SF, et al. Prospective study of obstructive sleep
apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010; 122:3 52-60
97
Boregowda K, Joels L, Stephens JW, Price DE. Persistent primary hypogonadismassociated with anabolic steroid abuse. Fertil Steril 2011; 96:
e7–8
98 Liu PY, Swerdloff RS, Christenson PD, Handelsman DJ, Wang C. Rate, extent, and modifiers of spermatogenic recovery after horm onal male
contraception: an integrated analysis. Lancet 2006; 367: 1412–20.
99 Chua, M. E., Escusa, K. G., Luna, S. , Tapia, L. C., Dofitas, B. and Morales, M. (2013), Revisiting oestrogen antagonists (clomiphene or
tamoxifen) as medical empiric therapy for idiopathic male infertility: a meta‐analysis. Andrology, 1: 749-757. doi:10.1111/j.20472927.2013.00107.x
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The shutdown of endogenous testosterone production also leads to
testicular atrophy. For some men, this is an unwanted cosmetic side
effect for others it is not an issue. Testicular atrophy can also be avoided
with the addition of HCG. If you wish to avoid testicular atrophy and/or
maintain fertility it is ideal if HCG is started at the same time as
testosterone therapy. Attempting to reverse already present atrophy or
infertility may be less effective if HCG is started later.
5-6. GYNECOMASTIA
The development of abnormal breast tissue enlargement in men is one of
the more common fears experienced by men starting testosterone
therapy. Gynecomastia (“gyno”) occurs in many males around time of
puberty and typically resolves by age 17 or 18. In the vast majority of
cases it is caused by an imbalance in the testosterone to estrogen ratio
with excess estrogen stimulating the growth of breast tissue.
The most common cause for estrogen excess and development of
gynecomastia in men is obesity. The aromatase enzyme responsible for
the conversion of testosterone to estrogen is heavily concentrated in fat
tissue. More fat equals more estrogen. This is why the majority of obese
men have what is often referred to as “man boobs”. This condition is
cosmetically unappealing and often causes significant emotional distress
in affected men. Obese men who start TRT may experience worsening
of their gynecomastia if they don’t simultaneously engage in an
aggressive fat loss program. In many cases losing a substantial amount
of body fat will be sufficient to reduce estradiol levels back into the
normal range and cause regression of gynecomastia.
Not all men who develop gynecomastia either naturally or on TRT are
obese, however. Genetic variations on the aromatase enzyme (3′-UTR
TT genotype) have been shown to be prevalent in men with
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gynecomastia for which no other medical cause could be identified100.
Similarly, genetic differences in estrogen receptors may also predispose
an otherwise healthy, lean man to develop gynecomastia101.
A number of commonly medications are known to cause gynecomastia
in some men. These include 102:
1. Spironolactone (blood pressure medication)
2. Protease inhibitors and reverse transcriptase inhibitors (HIV
medications)
3. Prednisone
4. Finasteride (DHT blocker used for hair loss and prostate
enlargement)
5. Ketoconazole (antifungal medication)
6. Haloperidol (and other antipsychotic medications)
7. Omeprazole & Cimetidine (antacid medications)
8. Verapamil & Nifedipine (blood pressure medications)
9. Opiates and excess alcohol
There are many other medications that may also be culprits. If you are
concerned about a specific medication not mentioned on the above list
consult with your physician or pharmacist.
Treatment options for gynecomastia vary. The common approach
involves use of an aromatase inhibitor (AI). This will lower estradiol
levels and theoretically prevent further growth of breast tissue and, in
some cases, may lead to regression. As mentioned previously, long-term
use of an AI is not without risk and you should discuss with your
physician whether lifelong use of an AI is appropriate for you.
100
Czajka-Oraniec I, Zgliczynski W, Kurylowicz A, Mikula M, Ostrowski J. Association between gynecomastia and aromatase (CYP19)
polymorphisms. Eur J Endocrinol. 2008;158(5):721-727. doi:10.1530/EJE-07-0556
101 Korkmaz HA, Edgünlü T, Eren E, et al. GPR30 Gene Polymorphisms Are Associated with Gynecomastia Risk in Adolescents. Horm Res
Paediatr. 2015;83(3):177-182. doi:10.1159/000369013
102 Deepinder, Fnu & Braunstein, Glenn. (2012). Drug-induced gynecomastia: An evidence-based review. Expert opinion on drug safety. 11. 77995. 10.1517/14740338.2012.712109.
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The definitive treatment for established gynecomastia is surgery. In men
with substantial breast tissue, even long-term estradiol suppression may
not be sufficient to resolve the condition. In this case and especially in
men who are already lean, surgical removal should be considered first
line therapy.
If you have established gynecomastia or feel you are at risk for
developing it then you MUST lower your body fat percentage as much
as possible. It is not reasonable to opt for lifelong estrogen suppression
with an AI when you could lower your estradiol levels (and reap a
multitude of other benefits) by simply losing weight.
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Gynecomastia Treatment/Prevention
Order of Operations:
1. Lower bodyfat significantly. If you already have
gynecomastia or develop it during this process
you could consider a SHORT course of an AI to
control estradiol levels until you lose enough
weight to no longer require it.
2. Consider lower dose, more frequent injections to
reduce large fluctuations in testosterone levels
which may be driving estrogen production.
3. Surgical removal is the best option for lean men
or those who do not wish to use AIs indefinitely.
It effectively cures the condition and recurrence
rates are very low when performed properly by
an experience surgeon.
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CHAPTER 6
TESTOSTERONE MYTHS
6-1. HEART DISEASE
One of the most debated and controversial issues surrounding
testosterone replacement is its role in cardiovascular disease. Since a
much-publicized study in JAMA (Journal of the American Medical
Association) raised concerns about a possible increase in cardiovascular
events (heart attacks and strokes) there has been intense media scrutiny
and debate among physicians regarding testosterone therapy103. As a
direct result of this study the FDA has now mandated that all
testosterone products in the U.S. contain a “Black Box Warning”.
Per the FDA website:
“We are requiring that the manufacturers of all approved prescription
testosterone products change their labeling to clarify the approved uses
of these medications. We are also requiring these manufacturers to
add information to the labeling about a possible increased risk of heart
attacks and strokes in patients taking testosterone.”104
Since the publication of this study it has been widely criticized for
numerous methodological flaws. In 2014 over 130 scientists and
researchers from the Androgen Study Group, The International Society
for Sexual Medicine, The International Society for the Study of the
Aging Male, and The Sexual Medicine Society of North America
submitted a petition to JAMA urging them to retract the study citing
103. Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with
low testosterone levels. JAMA. 2013;310(17):1829-36.
104 Vigen R, O’Donnell CI, Barón AE, et al. Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men
With Low Testosterone Levels. JAMA. 2013;310(17):1829–1836. doi:10.1001/jama.2013.280386
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“gross data mismanagement” and claims that its conclusions were “no
longer credible”105.
JAMA has refused to retract the study and the FDA continues to
mandate a black box warning on testosterone products despite numerous
studies showing either no risk or reduction in cardiovascular risk in men
who use testosterone replacement therapy.
A petition from the Androgen Study Group to the FDA urging them not
to place a black box warning on testosterone products was ignored by
the FDA:
“There is thus no basis for adding restrictions on T products due
to misguided claims of increased CV risk. Placing unwarranted
restrictions on the appropriate use of T therapy will result in the
compromise of public health, denial of valuable treatment for
men suffering from an important medical condition, create an
unnecessary and unfair burden on healthcare providers and
affected patients, and would substantially increase the future
financial burden on the US health care system.”
Testosterone therapy has been shown in numerous studies to improve
risk factors that contribute to heart disease, including improvements in
cholesterol, blood sugar levels, and reduced body fat levels106. A 2018
study examining a large database of over 200,000 men treated with
testosterone found that the majority of the available research to date does
not show any increased risk of stroke, blood clots, or heart attack107.
105 https://www.androgenstudygroup.org/index.php/initiatives/letter-to-jama-asking-for-retraction-of-misleading-article-on-testosteronetherapy.
106 Cai X, Tian Y, Wu T, Cao CX, Li H, Wang KJ. Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2
diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. Asian J Androl. 2014;16(1):146–152. doi:10.4103/1008682X.122346
106 Traish AM. Testosterone and weight loss: the evidence. Curr Opin Endocrinol Diabetes Obes. 2014;21(5):313–322. doi:10.1097/MED.
107 Shores MM. Testosterone treatment and cardiovascular events in prescription database studies. Asian J Androl. 2018;20(2):138–144.
doi:10.4103/aja.aja_25_17
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This confirms the findings of a prior analysis in 2016 in a consensus
statement by the American College of Endocrinology and the American
Association of Clinical Endocrinologists which reported there was no
strong evidence to suggest testosterone therapy in hypogonadal men
posed an increased risk of cardiovascular events108. Their summary
statement is as follows:
“The data meta-analyzed here do not support any
causal role between TRT and adverse CV events. This
is especially true when hypogonadism is properly
diagnosed, and replacement therapy is correctly
performed”.
As with all medical therapies, you and your physician should discuss the
pros and cons of testosterone therapy as they relate to your individual
medical history and decide together if treatment is in your best interest.
108 Neil Goodman, Andre Guay, Paresh Dandona, Sandeep Dhindsa, Charles Faiman, Glenn R. Cunningham, and for the AACE Reproductive
Endocrinology Scientific Committee (2015) AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN
COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THE ASSOCIATION OF TESTOSTERONE AND CARDIOVASCULAR
RISK. Endocrine Practice: September 2015, Vol. 21, No. 9, pp. 1066-1073.
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6-2. PROSTATE DISEASE
One of the most persistent misconceptions about testosterone therapy is
that it can have an adverse effect on prostate health. Specifically,
generations of medical students were told that testosterone therapy could
not only cause prostate cancer, but also accelerate the growth of
preexisting prostate cancer. Both of these assertions have been shown to
false109. In fact, low testosterone levels, rather than high, may be more
strongly associated with the development of prostate cancer110.
Additionally, there are concerns among physicians not well versed in
testosterone therapy that supplemental testosterone could worsen
symptoms of benign prostate hypertrophy (BPH). BPH is a common
condition in aging men related to non-cancerous growth of the prostate
gland that can narrow the outflow tract from the bladder leading to
difficulty emptying the bladder, decreased strength of urine stream,
multiple episodes of awakening during the night to urinate, and in some
circumstances, complete urine obstruction requiring placement of a
catheter or even surgery. Prostate growth over a man’s life is stimulated
by testosterone and when men are either surgically or medically
castrated the prostate does tend to shrink.
A man who has had very low testosterone levels for many years may
have a prostate gland that has shrunk. When testosterone levels are
restored to normal there can be a sudden growth of the prostate gland
back to the size expected in men of the same age with normal
testosterone levels 111. This “volumizing” effect can be associated with a
109 Gustafsson O, Norming U, GustafssonS, Eneroth P, Astrom G, Nyman CR. Dihydrotestosterone
and testosterone levels in men screened for prostate cancer: a study of a randomized population. Br J Urol 1996;77:
433-40.
110 Mearini, L., Zucchi, A., Nunzi, E. et al.: Low serum testosterone levels are predictive of prostate
cancer. World J Urol 2013; 31: 247.
111 Behere HM. Prostate volume in treated and untreated hypogonadal men in comparison to age-matched controls. Clin Endocrinol.
1994;40:341-6
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small rise in PSA levels but is not associated with worsening prostate
symptoms or risk of prostate cancer 112.
Prostate cancer screening is beyond the scope of this book. However,
there has been a strong movement across multiple medical specialties
and organizations to move away from routine prostate cancer screening
with PSA testing and prostate exams due to the high number of false
positive tests and generally slow growing nature of prostate cancer. The
US Preventive Services Task Force (USPSTF) states that men 55-69
should discuss prostate cancer screening with their doctor decide based
on their individual risk and after weighing the risks and benefits of
testing. They do not recommend men over the age of 70 be screened
routinely using PSA testing113.
6-3. CHOLESTEROL
Anabolic steroids have long been known to induce unfavorable changes
in blood lipids. High doses of anabolic steroids, including testosterone,
will reliably increase LDL, the lipoprotein commonly associated with
development of heart and vascular disease, as well as lower HDL, which
is often considered protective 114.
As a result, there has been widespread fear among physicians that
testosterone, when used in replacement doses in hypogonadal men, may
have similar unfavorable effects on cholesterol levels.
Fortunately, this does not appear to be the case. The majority of studies
show reductions in total cholesterol and lowering of LDL cholesterol
112 Morgentaler A, Traish AM. Shifting the paradigm oftestosterone and prostate cancer: the saturation model
and the limits of androgen-dependent growth. Eur Urol2009;55:310–21.
113 Final Update Summary: Prostate Cancer: Screening. U.S. Preventive Services Task Force. April 2019.
https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/prostate-cancer-screening1
114 Hartgens F, Rietjens G, Keizer HA, Kuipers H, Wolffenbuttel BH. Effects of androgenic-anabolic steroids on apolipoproteins and
lipoprotein (a). Br J Sports Med. 2004;38(3):253–259. doi:10.1136/bjsm.2003.000199
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and triglycerides115. The effects on HDL are variable with most studies
showing no change but some showing small reductions. It is possible
that transdermal gels and creams may not lower HDL to the degree that
IM injections do116.
Testosterone is clearly shown to benefit men with elevated levels of
lipoprotein (a) aka LP(a). Elevated LP(a) levels are genetically inherited
and increasingly recognized as a risk factor for both heart disease and
stroke. LP(a) levels are minimally affected by diet and lifestyle changes
and common cholesterol medications (with the exception of niacin and
fibrate medications) will not lower it.
Testosterone, however, has been consistently shown to lower LP(a)
levels by up to 37% 117. Given the lack of alternate therapies, testosterone
replacement could be considered a first line therapy in men with very
high LP(a) levels who have not responded to other therapies.
6-4. AGGRESSION
While case reports of mood disturbances, including increased
aggression, are somewhat common in heavy anabolic steroid users, there
is virtually no scientific evidence to support the assertion that
testosterone, when taken in physiologic doses, leads to increased
aggression or worsening mood changes of any kind118. On the contrary
there is a significant body of literature supporting what many men
already know, that the treatment of low testosterone levels back into the
normal range improves mood, fatigue and feelings of vigor119.
115 Whitsel EA, Boyko EJ, Matsumoto AM, Anawalt BD, Siscovick DS. Intramuscular testosterone esters and plasma lipids in hypogonadal
men: a meta-analysis. Am J Med 2001; 111:261–269.
116 Pastuszak AW, Gomez LP, Scovell JM, Khera M, Lamb DJ, Lipshultz LI. Comparison of the Effects of Testosterone Gels, Injection s, and
Pellets on Serum Hormones, Erythrocytosis, Lipids, and Prostate-Specific Antigen. Sex Med. 2015;3(3):165–173. doi:10.1002/sm2.76
117 Zmuda JM, et al. Testosterone decreases lipoprotein(a) in men. Am Jour Card. 1996;77(14): 1244-1247.
Daryl B. O’Connor, John Archer, Frederick C. W. Wu, Effects of Testosterone on Mood, Aggression, and Sexual Behavior in Young Men: A
Double-Blind, Placebo-Controlled, Cross-Over Study, The Journal of Clinical Endocrinology & Metabolism, Volume 89, Issue 6, 1 June 2004,
Pages 2837–2845.
119 Walther A, Breidenstein J, Miller R. Association of Testosterone Treatment With Alleviation of Depressive Symptoms in Men: A Systematic
Review and Meta-analysis. JAMA Psychiatry. 2019;76(1):31–40. doi:10.1001/jamapsychiatry.2018.2734
118
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6-5. BLOOD CLOTS
For many years there has been concern amongst the medical community
that treatment with testosterone may increase the risk of abnormal blood
clotting, specifically clots in large veins known as deep venous
thrombosis (DVT). These clots sometimes break off and travel to the
lungs resulting in a potentially fatal pulmonary embolus (PE). This has
led to wariness on physicians’ part to prescribing testosterone
replacement, particularly in men who have had a personal or family
history of DVT or PE.
Fortunately, well-done scientific studies have begun to accumulate
showing that the risk of blood clots in men being treated for low
testosterone is either not elevated at all or greatly exaggerated.
A study published in the journal Urology looked at the rates of DVT/PE
in over 1000 men with low testosterone treated either with testosterone
or clomiphene. The researchers found no increased risk in treated men.
Testosterone levels were similar whether patients were treated with
testosterone or clomiphene and of the ten patients that did develop clots
(0.8% of the total), seven were found to have other causes for their clots
(prolonged immobility, recent orthopedic surgery, various genetic
conditions, etc.).120
Another large case-control study of over 30,000 men over the age of 40
with low testosterone levels found no increase in the incidence of DVT
or PE within the first 60 days of testosterone therapy 121. A longer-term
study of 41,000 Veterans Affairs patients with a mean age of 64 years
120
Kavoussi PK, Machen GL, Wenzel JL, et al. Medical treatments for hypogonadism do not significantly increase the risk of deep vein
thrombosis over general population risk. Urol. DOI:10.1016/j.urology.2018.11.009
121 Jacques Baillargeon, Randall J. Urban, Abraham Morgentaler, Charles J. Glueck, Gwen Baillargeon, Gulshan Sharma, Yong-Fang Kuo. Risk
of Venous Thromboembolism in Men Receiving Testosterone Therapy. Mayo Clinic Proceedings, 2015; DOI: 10.1016/j.mayocp.2015.05.012
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showed no increase in the rate of DVT/PE over approximately six
years122.
In the last decade a number of genetic conditions that increase the risk of
DVT/PE have been identified. Some are surprisingly common. The
Factor V Leiden gene, for example, is found in up to 25% of people with
DVT/PE 123. Five percent of North Americans of European descent carry
this gene, but it is much less common among individuals of Asian or
African ancestry124.
Given the relatively high prevalence of this gene, it can be assumed that
some of the men in the above study were carriers (likely unknown to
them). However, there are no large studies to date specifically looking at
men with known genetic risks for DVT/PE treated with testosterone. If
you have one of these genes, or a family history of DVT/PE, and are
interested in testosterone replacement discuss this with your physician.
122
Rishi Sharma, Olurinde Oni, Rajat Barua, Mukut Sharma, Ram Sharma, Guoqing Chen, Kamal Gupta, Effect of Testosterone Replacement
Therapy on Incidence of Deep Venous Thrombosis and Pulmonary Embolism, Journal of the American College of Cardiology, Volume 65, Issue
10, Supplement, 2015, Page A1422, ISSN 0735-1097, https://doi.org/10.1016/S0735-1097(15)61422-X.
(http://www.sciencedirect.com/science/article/pii/S073510971561422X).
123 Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP . Mutation in the gene coding for coagulation factor V
and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332: 912–917.
124 Lee DH, Henderson PA, Blajchman MA . Prevalence of Factor V Leiden in a Canadian blood donor population. CMAJ 1996; 155: 285–289.
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CHAPTER 7
MONITORING
Initial laboratory testing should focus on not only on diagnosing low
testosterone levels but also screening for medical conditions associated
with low testosterone. These should also include measures of overall
health. Some of these tests will be specific to your individual medical
history as determined by a detailed history and physical exam performed
by your physician.
Once therapy has begun, ongoing monitoring is essential. Testosterone
therapy is not “fire and forget”.
10. Total AND Free Testosterone levels:
After at least one month of steady therapy testosterone levels
should be measured to ensure you are in the normal, therapeutic
range. Adjustments can then be made taking into account your
symptoms. In general, the goal of therapy should be alleviation of
symptoms and not achieving a specific number on a lab test. If
using injectable testosterone, most physicians will want levels
drawn on the day of injection before your injection (a trough
level), though some will prefer measuring midway between
injection days. It is important that testosterone levels are checked
consistently on the same day so valid comparisons can be made.
After optimal levels are achieved, measurement at least twice a
year is adequate for most men.
11.
Blood Pressure:
Vital signs, including blood pressure should be obtained at every
follow up visit. For most men, goal blood pressure should be under
140/90, though your doctor may have a lower goal in mind based
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on your specific medical history. Low testosterone is a risk factor
for the development of high blood pressure 125. It is unclear if long
term therapy with testosterone improves blood pressure. Most
studies show no significant effect126. It is possible that untreated
sleep apnea and erythrocytosis could contribute to elevations in
blood pressure, but these conditions are easily identified and
treated with proper screening.
3. Cholesterol:
Men with low testosterone commonly have elevated cholesterol
levels. Bringing testosterone levels back into the normal range
typically results in reductions in total cholesterol, LDL cholesterol
and triglycerides127 The effect on HDL levels is variable, with
most studies showing no change or a small decrease 128.
Supraphysiologic dosing, as seen in anabolic steroid users, has
predictably negative effects on cholesterol levels and is not
recommended129. Measurements 1-2 times per year are adequate
for most men.
4. Body fat percentage:
Improvements in body composition (increased muscle mass and
decreased body fat) are common with testosterone therapy, but not
universal. Lifestyle modifications with these goals in mind are
125 Maggio M, Basaria S. Welcoming low testosterone as a cardiovascular risk factor. Int J Impot Res. 2009;21(4):261–264.
doi:10.1038/ijir.2009.25
126 Khaw KT, Barrett-Connor E. Blood pressure and endogenous testosterone in men: an inverse relationship. J Hypertens. 1988;6:329–332.
127 Kelly DM, Jones TH. Testosterone: a metabolic hormone in health and disease. J Endocrinol 2013; 217:R25–R45
128 M. Mercè Fernández-Balsells, Mohammad Hassan Murad, Melanie Lane, Julia na F. Lampropulos, Felipe Albuquerque, Rebecca J. Mullan,
Neera Agrwal, Mohamed B. Elamin, Juan F. Gallegos-Orozco, Amy T. Wang, Patricia J. Erwin, Shalender Bhasin, Victor M. Montori, Adverse
Effects of Testosterone Therapy in Adult Men: A Systematic Review and Meta-Analysis, The Journal of Clinical Endocrinology & Metabolism,
Volume 95, Issue 6, 1 June 2010, Pages 2560–2575, https://doi.org/10.1210/jc.2009-2575
129 Souza, Francis Ribeiro de et al.Diminished cholesterol efflux mediated by HDL and coronary artery disease in young male anabolic
androgenic steroid users.Atherosclerosis, Volume 283, 100 - 105
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crucial in optimizing testosterone’s favorable effects on adipose
tissue. As mentioned previously, lowering body fat is the key to
managing estradiol elevations occurring while on TRT. Therefore,
periodic measurements of your body fat percentage, either in your
doctor’s office or at home, are a useful way to evaluate your
response to therapy.
6. Hematocrit:
As mentioned previously, some men on testosterone therapy
experience elevations in hematocrit levels. In order to maintain the
safety of ongoing therapy, men prone to erythrocytosis should be
monitored 3-4 times per year.
6. Estradiol:
Your physician may elect to routinely monitor your estradiol levels
with the goal of maintaining them within established norms.
Conversely, they may only recommend checking estradiol levels if
you develop signs or symptoms of estradiol elevation. Again, the
best way to manage estradiol is to maintain a low body fat
percentage and keep your testosterone levels within normal ranges.
7. Prolactin
If you have a medical condition or take a medication that results in
prolactin elevation your physician may wish to monitor this
periodically. It is often checked in patients, along with estradiol
levels, who initially had a good response to testosterone therapy
but later develop lower libido and/or erectile dysfunction or
gynecomastia. Elevated prolactin levels are usual a sign of some
other health issue and should be fully evaluated before it is treated
with cabergoline or bromocriptine.
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CHAPTER 8
INJECTION TECHNIQUE
8-1. INTRAMUSCULAR INJECTION
This is the most popular way to inject testosterone. With a basic level of
anatomical knowledge, these injections are simple, safe, effective and
minimally painful. Rotating injections site while on long term therapy is
recommended.
ANATOMY AND SITE PREPARATION
Deltoid muscle:
For low volume injections (2cc or less) the mid deltoid is a viable
injection site. The injection should be delivered in the mid-upper deltoid
muscle. First locate the acromion process by following your collar bone
outward to its furthest point. You will eventually reach the most lateral
bony prominence of the shoulder. The injection site is roughly 2-3cm
directly down the shoulder in thickest part of the deltoid muscle. Try to
remain in the middle of the deltoid muscle. These injections can be more
painful than those in other areas. They should not be used in isolation for
long periods of time as scar tissue may develop.
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w
Gluteal Area:
This is the most common site chosen for IM injection. The large muscle
size and relative lack of sensory nerves makes the are able to handle
higher volumes (up to 3cc) with less discomfort.
The ventro-gluteal injection site is preferred as there is a much lower
chance of hitting blood vessels or nerves. To locate this area, place the
palm with fingers spread directly over the hip bone. Approximately 2cm
up from the webspace between the ring and middle finger is the proper
location (see diagram).
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Alternatively, a dorso-gluteal approach can be used. The injection
should be placed in the upper, outer quadrant of the gluteal muscle (see
diagram). Avoid the middle area of the gluteal muscle as there is risk of
hitting the sciatic nerve which can be very painful as well as injecting
into larger blood vessels. When injecting in this area it is recommended
to pull back on the syringe to check for blood before injecting. If blood
is present, then inject at another location.
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Lateral Thigh:
The lateral aspect of the thigh is another option for intramuscular
injection though is often not used as commonly as the others due to
discomfort. The area can be used for injections up to 2cc. The proximity
of the femur bone means that often shorter needles should be used (1
inch) in order to avoid hitting bone. The injection site is found by
palpating the space between the middle of the femur down to about 5-6
inches above the knee joint. Avoid injecting above or below this area or
injecting in the med thigh as the risk of injuring a nerve or blood vessel
is increased.
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8-2. SUBCUTANEOUS INJECTION
While intramuscular injection has been the standard for many years, an
increasing body of literature supports the use of subcutaneous injections
as an equally viable route for testosterone administration. Many men
prefer this route if they are injecting more than once a week and for its
safety profile.
Subcutaneous injections can theoretically be given anywhere you have
skin, but the most common injections sites are the skin around the belly
button, love handles, outer arms or thighs. The needles used are usually
much shorter and often smaller in diameter. These injections may sting a
bit more but are generally well tolerated.
To perform them, simply clean the skin with an alcohol wipe, loosely
pinch an area of skin between your thumb and index finger and inject
into the area. Release your pinch then slowly withdraw the needle.
Subcutaneous injections of testosterone are easy to perform and
result in blood levels similar to those obtained by intramuscular
injection.
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Common sites for subcutaneous injections include
the outer arms, abdomen around the belly button and anterior
or lateral thighs.
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8-3. SYRINGE AND NEEDLE TYPES
Needle gauge:
The diameter of an injection needle is measured using the term “gauge”.
The higher the gauge, the smaller the diameter of the needle. Needles
typically vary from very large bore needles used in emergency situations
(14-18 gauge) to very small needles use for subcutaneous injections such
as insulin (27-31 gauge).
Injectable testosterone is typically dissolved in a carrier oil (cottonseed,
grapeseed, or sesame oil). The viscosity of this oil can make injection
difficult if a higher gauge needle is used. Therefore, for intramuscular
injection, a needle of around 22-23 gauge is typically best. Subcutaneous
injection or smaller volume injections of aqueous solutions (like HCG)
can typically be performed with smaller 25-31-gauge needles.
Typical 23-gauge needle on a 3ml syringe and 31-gauge needle on a
1ml syringe.
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8-4. INJECTION TECHNIQUE
Both intramuscular and subcutaneous injections are simple and safe to
administer when performed properly.
The following is a stepwise approach to performing these injections:
1. Remove the metal or plastic cap over the top of the vial if present.
2. Clean the exposed rubber top with an alcohol wipe.
3. Open a clean syringe and needle from its wrapper and pull the plunger
back to fill the syringe with an amount of air roughly equal to the
volume of liquid you will be removing from the vial.
4. Insert the needle into the vial through the center of the rubber top and
inject the air inside.
5. Turn the vial upside down and slowly pull back on the plunger and fill
the syringe with the correct amount of medication. Ensure the needle
tip is below the level of the liquid in the vial. Withdrawing slowly will
minimize the amount of air which enters the syringe.
6. If a few small air bubbles are present then keep the syringe and vial in
the vertical position and, if needed, gently tap the side of the syringe so
the air rises to the surface. Then push the air back into the vial. Do not
worry about very small air bubbles. They are not harmful even if
injected accidentally directly into a vein.
7. Remove the needle from the vial.
8. Using an alcohol wipe, clean the area where you plan to inject.
9. Insert the needle into the desired area and dispense the medication by
pushing down on the plunger.
10. Discard the syringe and needle into an appropriate container. DO
NOT simply throw used needles into the trash.
11. Dispense with your used needle container in an approved location.
Most doctors’ offices will be able to safely dispose of these for you.
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CHAPTER 9
STOPING TESTOSTERONE:
In men without a reversible cause for their low testosterone levels,
testosterone replacement therapy should be considered a necessary,
lifelong intervention. Discontinuation of testosterone in these men will
result in a decline in testosterone levels likely down to previous values
or lower and the return of the symptoms that prompted the initiation of
therapy in the first place.
There may, however, be circumstances where TRT needs to be
discontinued. There are several approaches that can be taken to
accomplish this while minimizing the adverse effects experienced while
the hypothalamic-pituitary axis (HPTA) recovers and the body’s own
testosterone production begins again.
9.1 COLD TURKEY:
When testosterone is discontinued there will be a gradual decline in T
levels over several days. What follows will be a prolonged period of
very low testosterone levels well below the levels present when therapy
was initiated. This is because both FSH and LH, the pituitary hormones
responsible for prompting the testicles to produce both sperm and
testosterone, will be greatly suppressed.
With time, these levels will begin to rise, as will testosterone levels and
sperm count. This process, however, can take months to years and, in
some cases, may not return to pre-treatment baseline levels. In many
cases FSH and LH levels return to normal levels within 12 weeks of
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discontinuing testosterone, but it stands to reason that heavy and
prolonged anabolic steroid use could result in longer recovery times 130.
After starting testosterone, sperm production is typically maximally
suppressed by the third month. After stopping testosterone most men
return to normal sperm counts (but not necessarily the same as pretreatment values) in under one year, but in some cases, it may take up to
two years131. The average recovery time is roughly 3-6 months132.
The speed and extent of recovery is likely strongly influenced by
duration of testosterone exposure and age. Prolonged testosterone use
over several years and/or heavy doses of anabolic steroids are likely to
result in more prolonged suppression and more lengthy recovery times.
9.2 ASSISTED RECOVERY
There are various protocols available to accelerate the recovery of
endogenous testosterone production and restoration of fertility. These
protocols center on the discontinuation of testosterone and use of various
doses of clomiphene and/or HCG and HMG or recombinant FSH.
HCG will rapidly restore intra-testicular testosterone levels and help
restore serum testosterone levels as well, thus helping to ease the
symptoms of very low testosterone resulting from the discontinuation of
testosterone therapy. It is important to recognize, however that, while
HCG will stimulate testosterone and sperm production, it will not restore
the proper pituitary or hypothalamic function necessary to maintain
testosterone and sperm production without medication. LH and FSH
secretion from the pituitary gland will remain suppressed.
130 Alén M, Häkkinen K. Physical health and fitness of an elite bodybuilder during 1 year of self-administration of testosterone and anabolic
steroids: a case_study. Int J Sports Med. 1985;6(1):24–29
131 McBride JA, Coward RM. Recovery of spermatogenesis following testosterone replacement therapy or anabolic-androgenic steroid
use. Asian J Androl. 2016;18(3):373–380. doi:10.4103/1008-682X.173938
132 Ly LP, Liu PY, Handelsman DJ. Rates of suppression and recovery of human sperm output in testosterone-based hormonal contraceptive
regimens. Hum Reprod 2005; 20: 1733–40.
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To help restore natural production of LH and FSH medications such as
clomiphene or other estrogen modulating medications such as
anastrozole, tamoxifen and others may be required.
There are no studies at this time that have clarified which combination
of these medications is the most efficacious at restoring the HPTA axis.
The majority of data in this regard comes from men recovering from
short-term testosterone or anabolic steroid use (less than 12 weeks). It is
unknown what modifications, if any, would be required to restore HPTA
function in long term users of these drugs.
Sample protocols for HPTA and fertility restoration after prolonged use
of testosterone are provided on the following pages. It is critical to
understand that these protocols are NOT based on large, published,
randomized controlled studies but rather smaller published studies and
clinical experience by practicing andrologists and endocrinologists.
Your physician may recommend variations of this protocol or something
entirely different to assist with your recovery.
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Sample HPTA restoration protocol:
1. Discontinue Testosterone
2. Start HCG 2000 IU twice a week for two weeks. The first injection
should be seven days after the last injection of testosterone
Cypionate or Enanthate or 4 days after the last dose of testosterone
propionate. This will help temporarily alleviate some of the
symptoms of very low testosterone levels you will experience as
your HPTA reactivates.
3. Start clomid (clomiphene citrate) 50 mg once per day on the same
day as HCG.
4. Continue clomid for 30 days.
5. Measure FSH, LH, Total and Free Testosterone, and estradiol
levels at day 30.
6. If FSH/LH levels are in normal range, then consider
discontinuation.
7. If FSH/LH still suppressed and/or T levels remain low may
consider an additional 60 days of clomid. If after 60 days, there has
been no increase in LH/FSH you should consider consulting an
endocrinologist. Your recovery, if possible, will likely take many
months.
8. If clomid is continued and estradiol levels are elevated (>50 pg/ml)
or the testosterone to estradiol ratio is <10 consideration could be
given to adding Anastrazole 0.5-1.0 mg twice per week133 for 60
days.
9. If FSH and LH and testosterone levels return to normal clomid
could be continued or discontinued based on personal preference
and goal testosterone levels.
133 lder, N. J., Keihani, S. , Stoddard, G. J., Myers, J. B. and Hotaling, J. M. (2018), Combination therapy with clomiphene citr ate and
anastrozole is a safe and effective alternative for hypoandrogenic subfertile men. BJU Int, 122: 688-694. doi:10.1111/bju.14390
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10. If FSH and LH remain low, then consultation with a
knowledgeable endocrinologist should be pursued to work up
potentially more serious underling conditions.
Sample fertility restoration protocol:
1. Discontinue testosterone
2. Start HCG 2000 IU every third day PLUS clomid 50mg daily for
90 days.
3. Check FSH, LH, estradiol, testosterone levels and semen analysis.
4. If all are normal, then consider discontinuing medications or
perhaps remaining on clomid only.
5. If sperm counts are still low and estradiol levels are normal, then
consider continuing HCG and replacing clomid with rFSH (or
HMG) at 150 IU three days a week for 90 days.
6. If sperm counts remain low, but estradiol levels are high consider
adding anastrozole 0.5 to 1.0mg once or twice per week for another
90 days. If sperm counts remain low despite normalizing estradiol
levels, then urology evaluation should be considered.
7. If sperm counts normalize then remain on HCG and rFSH until
pregnancy is achieved.
8. If sperm counts remain poor despite both HCG and rFSH then
further evaluation by a reproductive endocrinologist or urologist is
recommended.
9. If pregnancy is achieved and you wish to resume TRT then strongly
consider continuing HCG with TRT if future fertility is desired.
Protocol for restoration of HPTA function after prolonged use of
testosterone or anabolic steroids.
Adapted from: Rahnema C.D., Lipshultz L.I., Crosnoe L.E., Kovac J.R., Kim E.D. Anabolic steroid-induced hypogonadism: Diagnosis and
treatment (2014) Fertility and Sterility, 101 (5), pp. 1271-1279
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Fertility Restoration Protocol after prolonged use of testosterone or
anabolic steroids - .
134 135
134 Tatem AJ, Beilan J, Kovac JR, Lipshultz LI. Management of Anabolic Steroid-Induced Infertility: Novel Strategies for Fertility
Maintenance and Recovery. World J Mens Health. 2019 Jan;37:e16. https://doi.org/10.5534/wjmh.190002
135 Mcbride JA, Coward RM. Recovery of spermatogenesis following testosterone replacement therapy or anabolic -androgenic steroid use.
AsianJournal of Andrology (2016) 18, 373-380.
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CHAPTER TEN
MAINTAINING FERTILITY
Men desiring fertility while taking testosterone are best served by
initiating fertility-preserving medications at the same time they initiate
testosterone. This typically involves regular injections of HCG but may
include other agents as well.
The dosage of HCG required to maintain fertility is typically less than
that required to restore fertility after it has been suppressed by prolonged
testosterone use.
The production of healthy sperm requires high levels of intra-testicular
testosterone (ITT). Testosterone therapy, while raising blood levels of
testosterone quite well, actually causes ITT levels to drop. This impairs
sperm production and leads to infertility.
Fortunately, HCG has been shown to effectively raise, and preserve ITT
levels, even when supra-physiologic doses of testosterone are taken.
Doses as low as 250-500 IU every other day have been found to
maintain ITT levels in men taking testosterone 136. Higher doses of HCG
(up to 2000 IU) given twice per week have also been shown to be
effective at maintaining both ITT and fertility. HCG protocols vary
widely. You and your doctor will determine the regimen that works best
for you. In general, as with most medications, starting with low doses
and adjusting upward as needed based on your response to therapy is
usually the best approach.
It is important to realize that while HCG therapy can maintain sperm
production in men on testosterone, there may still be a decrease in sperm
136 Andrea D. Coviello, Alvin M. Matsumoto, William J. Bremner, Karen L. Herbst, John K. Amory, Bradley D. Anawalt, Paul R. Sutton,
William W. Wright, Terry R. Brown, Xiaohua Yan, Barry R. Zirkin, Jonathan P. Jarow, Low-Dose Human Chorionic Gonadotropin Maintains
Intratesticular Testosterone in Normal Men with Testosterone-Induced Gonadotropin Suppression, The Journal of Clinical Endocrinology &
Metabolism, Volume 90, Issue 5, 1 May 2005, Pages 2595–2602, https://doi.org/10.1210/jc.2004-0802
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counts as compared to baseline pre-testosterone levels137. In men with
normal sperm counts this may not impact their fertility significantly, but
in men with already low counts this should be taken into consideration.
The addition of recombinant FSH or HMG may be required in these
cases.
There is insufficient evidence to support using clomid instead of HCG
while on testosterone to maintain fertility and as of this time is not
recommended.
A typical TRT protocol with HCG for fertility preservation
could look like this:
1. Testosterone Cypionate (200mg/ml): 0.5-1.0 ml per
week
PLUS
2. HCG: 2000 IU twice per week or
250-500 IU three times per week
(rFSH or HMG 75-150 IU 3x per week may be
required in some cases)
137 Depenbusch, M., von Eckardstein, S., Simoni, M., & Nieschlag, E. (2002). Maintenance of spermatogenesis in hypogonadotropic
hypogonadal men with human chorionic gonadotropin alone, European Journal of Endocrinology Eur J Endocrinol, 147(5), 617-624. Retrieved
Oct 27, 2019, from https://eje.bioscientifica.com/view/journals/eje/147/5/617.xml
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CHAPTER ELEVEN
DISCUSSING TESTOSTERONE
WITH YOUR DOCTOR
Obtaining blood work and discussing testosterone therapy with your
physician is the first step in deciding whether you are a candidate for
TRT. Unfortunately, familiarity with the proper treatment of low
testosterone levels is not common among primary care physicians and
even endocrinologists or urologists in some cases.
Management of low testosterone in men is not part of the standard
medical school curriculum and gets very little, if any, discussion in most
Family Medicine or Internal Medicine residency training programs. It
can be frustrating discussing testosterone with a primary physician, but
it’s important to keep in mind that male hormonal optimization is not
within the scope of most physician’s training. The skills they worked
over a decade in obtaining are focused on treating profoundly ill peoplefrom diabetics with kidney failure to gunshot wounds- and restoring
them to, at best, “normal” health. These are valuable skills and badly
needed by society. Most physicians are grossly overworked and very
few have the time or inclination to pay thousands of dollars to take
courses on how to properly prescribe testosterone. Remember this when
your internist or family doctor gives you blank stare or dismisses the
idea entirely when you bring up the subject of testosterone replacement.
With that in mind, your health is your primary responsibility and if your
physician has not brought up this aspect of your health then it is
incumbent on you to start the conversation.
11-1 ASKING FOR THE TEST
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Lab tests for testosterone are not generally part of the routine blood
work performed by primary care doctors. You therefore will need to
specifically ask for them. Some physicians may initially refuse. If so,
find another physician or consider obtaining this test on your own. A
quick Internet search will reveal a number of companies that allow
patients to order routine blood tests for themselves without a physician
order. Prices for these tests are usually reasonable. Once payment is
completed, they will direct you to a laboratory in your area where you
can have the test performed.
It is important to be sure you obtain both a “total” and “free”
testosterone level. As discussed previously, men may have normal total
testosterone levels yet still be symptomatic due to a low amount of free
testosterone. Many physicians will insist that these levels are obtained
before 10 AM and in a fasted state and then repeated. You should
comply with this to avoid one of the more common tactics used by
physicians who are not well versed in TRT to dismiss your results.
11-2 ADAM & AMS SCORE:
If you have not already done so, complete both the ADAM and AMS
questionnaires and show them to your physician if they suggest you have
symptoms of low testosterone. Both of these are scientifically validated
and considered part of the standard evaluation for low testosterone in
men.
11-3 “YOU’RE NORMAL”
This is a common response from physicians when a man with low
testosterone symptoms presents with serum testosterone levels within
the established reference range. Many physicians are not aware that the
reference ranges for normal testosterone were lowered in 2017.
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LabCorp, for example, previously considered 348-1197ng/dl to be the
normal range for adult men. In 2017 this was lowered to 264-916 ng/dl
based on an updated study138.
The previous used values were obtained from a 2011 study looking at
lean, healthy males. The new reference range includes overweight men
and per LabCorp “reflects a difference in average subjects with higher
BMIs”139. As discussed previously, higher body fat levels can
negatively influence hormonal profiles and referring to overweight men
as “healthy” is inappropriate.
Previous LabCorp Reference
Interval
Adult Male >18 years:
348-1197 ng/dL
Comment: Adult male reference
interval is based on a population
of lean males up to 40 years old.
New LabCorp Reference
Interval (effective July 17, 2017)
Adult Male >18 years:
264-916 ng/dL
Comment: Adult male reference
interval is based on healthy males
(including overweight BMI: 2529.9) ages 19-39.
Obese males (BMI 30+ were
excluded).
Adapted from: https://www.labcorp.com/assets/11476
The data is clear that men’s testosterone levels are declining. This is a
pathological process. Lowering standards to reflect a decline in the
health of the population as a whole is not appropriate. Normal lab values
should reflect the ranges found in healthy individuals in peak health and
not just averages among a population whose health is, on average, worse
than previous generations.
138 Kelsey TW, Li LQ, Mitchell RT, Whelan A, Anderson RA, Wallace WH. A validated age-related normative model for male total testosterone shows increasing variance but
no decline after age 40 years [published correction appears in PLoS One. 2015;10(2):e0117674]. PLoS One. 2014;9(10):e109346. Published 2014 Oct 8.
doi:10.1371/journal.pone.0109346
139 LabCorp Q&A: Testosterone Reference Internal Changes (Adult Males).
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The charts below was created using data from a study published in 1996
which reviewed a number of studies looking at healthy men across the
lifespan. The average testosterone level for each age group is shown.
These values match up well with subsequent studies including the
Framingham Heart Study and European Male Aging Study which your
physician may be more familiar with 140.
What you will notice is that in healthy men the decline in total
testosterone (TT) is not as significant as the decline in free testosterone
(FT)141. Therefore, it is important if you are an older male to insist on
obtaining a free testosterone level if you have symptoms of low
testosterone.
The following chart can give you an idea of how you compare to
average healthy men in your age group. Keep in mind that these were
men sampled in the early 1990s and the averages today are significantly
lower, reflecting the pathological drop in testosterone levels discussed
previously.
Unfortunately, many physicians are unaware of this decline and are
often reluctant to consider testosterone therapy for men in their thirties
with total testosterone levels in the 300-400 range despite the fact that
this range was considered near average for men 80-100 years old!
Also remember that just because you are below average for your age
group does not automatically mean you need to start testosterone
therapy. The presence or absence of symptoms should be the
determining factor. No symptoms then no testosterone.
140
Thomas G. Travison, Hubert W. Vesper, Eric Orwoll, Frederick Wu, Jean Marc Kaufman, Ying Wang, Bruno Lapauw, Tom Fiers, Alvin M. Matsumoto, Shalender Bhasin,
Harmonized Reference Ranges for Circulating Testosterone Levels in Men of Four Cohort Studies in the United States and Europe , The Journal of Clinical Endocrinology &
Metabolism, Volume 102, Issue 4, 1 April 2017, Pages 1161–1173, https://doi.org/10.1210/jc.2016-2935
141
A. VERMEULEN, Androgens in the Aging Male, The Journal of Clinical Endocrinology & Metabolism, Volume 73, Issue 2, 1 August 1991, Pages 221–
224, https://doi.org/10.1210/jcem-73-2-221
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It is important to reiterate to a reluctant physician that symptoms of low
testosterone can occur well above these arbitrary thresholds. 348 ng/dL
(or 264 ng/dL) is not a magical threshold above which there can be no
benefit to therapy and below which therapy is beneficial. The key to the
diagnosis and treatment of testosterone deficiency is recognizing
symptoms and not just a lab value.
Having said this, you may still encounter resistance from your physician.
If, once you have presented them with the information in this book or
from other scientific references, they still refuse to work with you, then
you will simply need to find another physician. Fortunately, there are a
growing number of clinics that specialize in men’s health and
testosterone replacement. You will need to locate one of these clinics
near you and schedule an appointment.
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Mean total and free testosterone levels in healthy males across adulthood. Adapted from:
Oddens, B. J., and A. Vermeulen. Androgens and the Aging Male: Proceedings of a Workshop Organized by the International Health
Foundation, Geneva, December 1995. Parthenon Pub. Group, 1996.
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ORDER OF OPERATIONS
FOR DISCUSSING TRT WITH YOUR PHYSICIAN
1. FAMILIARIZE yourself with the material in this book.
2. COMPLETE both an ADAM questionnaire and Aging Male
Symptom (AMS) symptom score. Print these out and bring them to
your appointment.
3. OBTAIN lab testing either independently or through your doctor.
Perform these fasted (>10 hours) and before 10 am. Your doctor may
insist on TWO tests at least one week apart. Jump through their hoops
and get it done.
4. KNOW your medical history with as much detail as possible. Bring a
list of all your current medications including supplements. Bring old
records if you have them. Doctors’ visits are typically 15-20 minutes.
Have your ducks in a row so you don’t waste time.
5. ADVOCATE for yourself. Describe your symptoms in detail with
emphasis on their effects on your health, quality of life, and
relationships.
6. SHOW your physician the information in this book or other
mainstream scientific references. Do this respectfully. Making your
doctor feel ignorant will not help your case.
7. DO NOT be rude, condescending, arrogant or disrespectful. You gain
nothing by being an asshole.
8. IF your doctor refuses to test you or treat you ASK for a referral to a
hormone specialist.
9. CONSIDER seeing a clinic that specializes in male hormone
replacement.
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CHAPTER TWELVE
TYPICAL TRT PROTOCOLS
Injectable and topical testosterone are the two most commonly used
protocols for TRT. Below are typical starting protocols using these
modalities. Your individual starting dose will be up to your prescribing
physician and may need adjustment based on lab results and your
clinical response. Current data does NOT support the automatic
inclusion of an aromatase inhibitor for all men starting TRT.
12-1. INJECTABLE TESTOSTERONE
Testosterone Cypionate or Enanthate (200mg/ml)
Once weekly: 0.5-1.0 ml
Twice weekly: 0.25-0.5ml twice per week.
Daily injections: 0.07-0.15 ml daily
It is very rare that a man will require more than 200mg of testosterone
per week to obtain optimal testosterone levels when injectable
testosterone is used. Dosages above this range, with rare exceptions, will
result in levels well outside of the normal range and increase the risk of
side effects.
Intramuscular vs Subcutaneous Injection: Injecting testosterone either
intramuscularly or subcutaneously is equally efficacious142.
Subcutaneous injections have the advantages of being easier to perform
142
McFarland J, Craig W, Clarke NJ, Spratt DI. Serum Testosterone Concentrations Remain Stable Between Injections in Patients Receiving
Subcutaneous Testosterone. J Endocr Soc. 2017;1(8):1095–1103. Published 2017 Jul 21. doi:10.1210/js.2017-00148
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and can involve a shorter needle. They sometimes can sting a bit more,
however. Lower dose, more frequent injections may have the additional
advantage of reducing the elevations in hematocrit (erythrocytosis) and
estradiol seen with injectable testosterone, though more studies are
needed to confirm this143.
Testosterone Propionate (200mg/ml)
Typical TRT Dose: 25-50mg three times per week.
Of the commonly available injectable testosterone esters, testosterone
propionate has the shortest half-life and highest bioavailability. As a
result, a lower weekly total testosterone dose can often be given with
similar clinical effects when compared to longer acting formulations
such as testosterone enanthate or cypionate. This comes at the cost of
more frequent and more painful injections. As a result, testosterone
propionate is not a popular first line choice for most patients requiring
TRT and is becoming increasingly difficult to obtain.
12-2. TOPICAL TESTOSTERONE
If you opt to use topical testosterone therapy, then a compounded daily
cream is preferable to the commercially available gels or transdermal
patches. Creams can be made with much higher concentrations of
testosterone by weight which allows for a lower volume to be applied.
This is especially true when applied to the skin of the scrotum which is
particularly permeable to testosterone 144. Creams also tend to be less
irritating to the skin than alcohol-based gels.
143
Yazdani N, Matthews Branch S. Daily subcutaneous testosterone for management of testosterone deficiency. Front Biosci (Elite Ed). 2018
Mar;10 334-343. doi:10.2741/e825. PMID: 29293461.
144 Iyer, R., Mok, S.F., Savkovic, S., Turner, L., Fraser, G., Desai, R., Jayadev, V., Conway, A.J. and Handelsman, D.J. (2017),
Pharmacokinetics of testosterone cream applied to scrotal skin. Andrology, 5: 725-731. doi:10.1111/andr.12357
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Typical dose: 25mg-100mg once or twice per day applied to scrotal skin
or inner thighs.
Other testosterone delivery methods such a buccal tablet, oral
testosterone undecanoate, nasal testosterone, and long-acting injectable
testosterone undecanoate all have various drawbacks which make them
unpopular first choices for many patients.
12-3. HCG & CLOMID
HCG and/or clomid is the preferred therapy for younger men (under 35)
who are interested in maintaining or improving their fertility.
HCG Typical Dose: 1000-2000 iu twice per week. Higher doses rarely
produce greater testosterone levels but may be necessary in long-term
users.
Clomid: 25-50mg daily or every other day.
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CHAPTER THIRTEEN
FEELING BETTER
Testosterone replacement therapy has effects on multiple systems, but
the onset of these effects varies significantly. Some effects occur quite
quickly, while others may take many months to manifest. For example,
men suffering low libido will notice very rapid improvements in this
domain while obese diabetics looking for fat loss and improved blood
sugar control may have to wait several months. Many men with erectile
dysfunction are often surprised to learn that it may take up to six months
of therapy for sustained improvements in this area.
There, obviously, can be wide variation in the onset of these effects
between men based on dose, genetic differences and lifestyle factors.
Obese men who make the radical lifestyle changes required can see fat
loss and muscle mass improvements almost immediately. Those who
simply take testosterone and make a weak effort to change the bad habits
that made them obese in the first place will be disappointed.
13-1. SETTING EXPECTATIONS
Initiating testosterone therapy can be a life-changing event for many
men. In many cases, men suffer from symptomatic low testosterone for
many years; often for so long that they have forgotten what it felt like to
have the energy, drive, motivation, libido, and drive that they had in
their twenties. When low testosterone levels are corrected some men
swear that the feel better almost immediately while others have a more
gradual and more subtle improvement in their symptoms over weeks to
months. A smaller subset of men notices no significant improvement in
their symptoms. For these men there will come a point where they
should consider discontinuing testosterone. When that point is will
depend on the effects they are hoping to achieve.
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13-2. TRT TIMETABLE
1. Libido: Effects on sexual interest occur fairly quickly, often within the
first four weeks. This effect typically does not improve further beyond
twelve weeks.
2. Vitality/Vigor: This effect refers to non-specific improvements in
quality of life, drive, motivation and energy. This effect is often noticed
by the by the eighth week of therapy and often even sooner.
3. Mood: Effects on mood are variable but men with symptoms of
depression often begin to notice improvements by the eighth week of
therapy with ongoing improvements that peak by six months.
4. Cholesterol: Changes in lipid profiles are often seen after the first month
of therapy but may continue to change over the course of the first year of
therapy.
5. Red Blood Cells: Men who are predisposed to developing elevated
hematocrit levels (erythrocytosis) will often see this manifest after about
three months of therapy. If a man has been on therapy for a year without
significant issues in this area, he is very unlikely to ever develop them.
6. Obesity/Fat loss: Changes in lean body mass are variable but often
manifest after 3-4 months of therapy and will plateau after about 12
months. Obviously, this effect will be in direct proportion to the amount
of effort on your part.
7. Blood Sugar Control: Testosterone therapy is known to improve blood
sugar control in obese diabetics as manifested by improvements in
hemoglobin A1C (HbA1c)145. This effect can be seen as early as four
Kristina Groti, Ivan Žuran, Blaž Antonič, Lidija Foršnarič & Marija Pfeifer (2018) The impact of testosterone replacement therapy on
glycemic control, vascular function, and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes, The Aging
Male, 21:3, 158-169, DOI: 10.1080/13685538.2018.1468429
145
142
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months after starting therapy and is greatly magnified by additional
efforts at fat loss and exercise.
8. Erectile Function: Many men are under the impression that their erectile
dysfunction will improve rapidly as soon as they start TRT. In most cases,
this is not what happens. While some men do have an increase in nocturnal
erections (“morning wood”) early in therapy, sustained improvements in
erections can take up to six months to manifest. Obviously, there are many
causes for erectile dysfunction. Men with poor blood flow in the setting of
total testosterone levels less than 350 ng/dL may see slow improvements
while those with primary psychological or lifestyle-related ED likely will
not146.
9. Bone Density: this effect begins slowly perhaps after up to nine months
of therapy and may slowly improve over several years147.
146
Yassin, A.A. and Saad, F. (2006), Dramatic improvement of penile venous leakage upon testosterone administration. A case report and review
of literature. Andrologia, 38: 34-37. doi:10.1111/j.1439-0272.2006.00705.x
147 Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older
Men With Low Testosterone: A Controlled Clinical Trial [published correction appears in JAMA Intern Med. 2017 Apr 1;177(4):600] [published
correction appears in JAMA Intern Med. 2019 Mar 1;179(3):457]. JAMA Intern Med. 2017;177(4):471‐479.
doi:10.1001/jamainternmed.2016.9539
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An approximate timetable for improvement in a number of
testosterone related symptoms. Nutrition, exercise, lifestyle, and
genetic factors can lead to significant variation in these estimates.
144
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Final Comments
Testosterone replacement therapy is a golden opportunity to reclaim
your health and vitality. The men who make the biggest improvements
with testosterone therapy are those who make the necessary lifestyle
changes. They clean up their diets. They exercise regularly and this
includes regular resistance exercise. They lower their body fat levels to
under 20%.
Men who refuse to lose weight, exercise or eat a healthy diet tend to
experience only mediocre improvements with testosterone therapy. In
some cases, they experience no improvements at all. These men assume
all the risks of taking testosterone and experience very few of the
potential benefits.
The benefits you obtain from TRT are directly proportional
to the work you put in to changing your habits. If you just
take testosterone and refuse to exercise and eat properly you
are wasting your time.
TRT is an opportunity to change your life.
DON’T WASTE IT!
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The author, Kirkuk, Iraq 2011
Andrew Winge MD is a graduate of the Uniformed Services University
and former Air Force lieutenant colonel. He is board certified in Family
Medicine and Emergency Medicine with additional certification in Age
Management Medicine.
His medical practice ranges from the care of the critically ill to
preventative health and wellness with a special emphasis on men’s
health, longevity, weight loss, and hormonal optimization. He has been
an advocate of testosterone therapy for men for over twenty years. His
approach places the emphasis on healthy lifestyle choices in the realm of
nutrition and exercise with strong personal accountability for one’s
health as the first approach to hormonal health and chronic disease.
Outside of medicine, Andrew has been a competitive powerlifter and
active Brazilian Jiu-Jitsu practitioner.
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NOTES
147