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MY CURRENT BEST THOUGHTS ON HOW TO ADMINISTER TRT FOR MEN

By Paula Edwards,2014-05-17 05:17
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MY CURRENT BEST THOUGHTS ON HOW TO ADMINISTER TRT FOR MEN

    MY CURRENT BEST THOUGHTS ON HOW TO ADMINISTER

    TRT FOR MEN

    -A RECIPE FOR SUCCESS-

    SECOND EDITION

     --John Crisler, DO

We have already learned a practical bit about the various hormones composing the metabolic

    “symphony” which constitutes our hormonal milieu. We know where these hormones are produced,

    largely what influences modulate their production, as well as the target tissues of their various and

    varied actions. But we still need to integrate this knowledge into a practical “recipe”, if you will, to

    enable the clinician to return to his/her practice, and immediately begin screening for, and

    successfully treating, male hypogonadism. In other words, how do we administer Testosterone

    Replacement Therapy (TRT) for men?

Should EVERY adult male patient who presents at your office be automatically screened for

    hypogonadism? About half of all men over the age of fifty are in fact hypogonadal (when tested for

    Bioavailable Testosteronemore on that later). Certainly the responses to Medical History will

    lead the way toward suspicion of same, yet subjective complaints related to this insidious condition

    are sensitive without being specific. Clinical suspicion is further clouded because there is no way to

    correlate either the number of individual complaints, or the relative magnitude of each, to the

    severity of the hypogonadotropic state upon laboratory assay. Additionally, the foibles of

    laboratory analysis--either due to variability of hormonal production or inaccuracy unavoidably

    inherent to testing methodologyrenders evaluation of hormonal state, at times, more an art than

    science.

The number one complaint which should hoist the proverbial red flag is Erectile Dysfunction. Lack

    of libido is simultaneously superior in sensitivity and specificity. This is also the symptom of

    hypogonadism which, aside from all the seriously deleterious effects of same (cardiovascular

    disease, diabetes, osteoporosis, increased risk of cancer, depression, dementia, etc.), is most likely

    to bring the patient to actively seek TRTand to remain compliant in your subsequent treatment regimen. As I told writer Pat Jordan, for his article named after me in Playboy Magazine, “Dr. T to

    the Rescue” (April 2007) “As long as you treat his sexual function, a man won‟t mind you also

    made him healthier”. What Mr. Jordan printed: “You know, it is all about sex”.

    INITIAL LABWORK

     1

Following a good Medical History, which laboratory assays should be run as part of your initial

    hypogonadism workup? Following is my list, but certainly other specialists in this area run

    expanded or attenuated panels, per individual clinical experience and expertise. Of note, additional

    tests which should be included to complete the true comprehensive Anti-Aging Medicine workup

    (i.e. inflammatory markers, insulin, good and true comprehensive thyroid study, etc.); this chapter

    is concerned solely with administering TRT. And as always, the panel is tailored to the individual

    patient. Here they are:

    ? Total Testosterone

    ? Bioavailable Testosterone (AKA “Free and Loosely Bound”)

    ? Free Testosterone (if Bioavailable T is unavailable)

    ? SHBG

    ? DHT (perhaps)

    ? Estradiol (specify “sensitive” assay for males)

    ? LH

    ? FSH

    ? Prolactin

    ? Cortisol

    ? Thyroid Panel

    ? CBC

    ? Comprehensive Metabolic Panel

    ? Lipid Profile

    ? PSA (age dependent)

    ? IGF-1, IGFBP-3 (if HGH therapy is being considered)

FOLLOW-UP LABS

Four weeks after initiating or changing dose for transdermal, six weeks for IM injection TRT. The

    time delay provides for stabilization via HPTA suppression and pharmacokinetics of medication:

    ? Total Testosterone

    ? Bioavailable Testosterone

    ? Free Testosterone (if Bioavailable T is still unavailable)

    ? Estradiol (specify “sensitive” assay for males)

    ? LH

    ? FSH

    ? CBC

    ? Comprehensive Metabolic Panel

    ? Lipid Profile

    ? PSA (for those over 40 with Family Hx of prostate CA, >45 yo. all others)

    ? IGF-1, IGFBP-3 (if GH Therapy has been initiated already)

INDIVIDUAL ASSAYS EXPLAINED

     2

TOTAL TESTOSTERONE

This is the assay your patients will most focus on, as will clinicians unpracticed in the art.

    Physicians who do not understand sex hormones will deny patients the testosterone

    supplementation they want--and need!--when Total T is at low-normal levels. Total T is important

    for titration of dosing, but its relevance is reduced in older men, by virtue of their increased serum

    concentrations of SHBG (and therefore lowered Bioavailable Testosterone), in favor of:

    BIOAVAILABLE TESTOSTERONE

Where we get the “bang” for the hormonal buck, so to speak. This is the actual amount the body

    has available for use, as the concentration of hormone available within the capillary beds before the

    androgen receptor approximates the sum of the Free Testosterone plus that which is loosely bound

    to other carrier proteins in the blood, primarily albumin. If Bio T is not readily available, Free T

    may be a second choice substitute, as Bio T and Free T serum concentrations are usually well

    correlated. Bioavailable Testosterone is the gold standard for serum androgen evaluation.

DHT

    This assay may be of value to draw, up-front and at follow-up, if a transdermal testosterone delivery system is preferred by the patient. I‟ll explain why later. DHT level may also help explain

    cause for ED symptoms. Experience drawing serum DHT, compared to urinary DHT and

    intracellular 5-AR metabolites, may show compartmentalization of same in difficult cases.

Instances where patient subjective report is very positive in the face of stable (or even reduced)

    Total T levels, status post initiation of TRT and compared to baseline, may be explained by

    increases in DHT; we must keep in mind it is three times more androgenic than testosterone. Of

    note, I do not believe placebo effect exists for TRT.

I do not consider DHT an “evil” hormone; finasteride and drugs of that class are to be avoided.

ESTRADIOL

There are several reasons why this assay is VERY important, and should not be ignored in ANY

    hypogonadism work-up (or subsequent regimen). First, you definitely need to draw a baseline.

    There are cases where T is adequate, yet E elevated or merely disproportionate. Elevated estrogen

    (in absolute value or proportion) can, in and of itself, explain hypogonadal symptomology. If E is

    elevated, controlling serum concentrations (usually with an aromatase inhibitor, which prevents

    conversion of T into E; or withdrawal of estrogen mimics such as soy or flax seed) may, in very

    rare cases, suffice in clearing the symptoms of hypogonadism. And finally, rechecking estradiol

    after beginning the initial dose of testosterone will give the astute physician valuable information as

    to how the patient‟s individual hormonal system functions, as well as making sure estrogen does

    not elevate inappropriately secondary to testosterone supplementation. This provides a very rough

    form of receptor mapping, if you will.

     3

E2 is the major player of interest in foundational TRT. Evaluation of the other members of the

    hormonal class “estrogen” (E1, E3, as well as other estrogen metabolites), via 24 hour urine panel, may help explain gynocomastia or water retention in the face of acceptable E2, indicate relative

    cancer risk, etc.

Unless you specify a „sensitive‟ assay for your male patients, the lab will default to the standard

    estradiol designed for females, which is useless for our purposes here. I have run the standard assay

    and the sensitive assay concurrently on a number of my patients, and the two results may be as

    night and day. However, patient symptomology is best described by the sensitive assay. The reason

    is the bell curve from which the test is designed sits well within the “normal” range for females;

    therefore the hormonal concentration range appropriate to adult males falls on a very flat slope of

    said bell curve. The same holds for Total Estrogens. Laboratory testing is best when small changes

    in concentrations result in large changes in subsequent reported result.

Some practitioners believe it is only the T/E ratio which is significant, and therefore, as long as E

    only “appropriately” rises with elevations in T, all is well. However, the absolute concentration of

    E is of concern, too, especially in light of new information pointing to elevated estrogen as cause,

    or adjunctively encouraging, several serious disease processes, including numerous cancers, as well

    as significant potential for induction of sexual dysfunction (no matter the accompanying androgen

    load). Therefore T/E ratio is only useful for describing the cause of symptoms, not as a treatment

    goal.

Estrogen is absolutely necessary for our physical health. Of note, same also provides the emotional

    component of a mature gentleman‟s sexual being. This is why estrogens must be evaluated and,

    when necessary, controlled. The “sweet spot” E concentration depends upon SHBG. Rule of thumb is mid-range for both.

LH

As everyone knows, it is Luteinizing Hormone (LH) which stimulates the Leydig cells of the testes

    to produce testosterone. A caveat, however: LH has a half-life of only minutes. When you combine

    this fact with the absolute pulsatile nature of its pituitary release, care must be taken to avoid

    placing too much weight upon a single draw. A luxury would be to acquire serial draws. However,

    such would be both inconvenient and probably prohibitively expensive for the patient. Therefore a

    single LH assay serves only as a proven example of just how much LH the pituitary can produce.

    The most important reason to assay the gonadotrophins is to differentiate between primary and

    secondary (hypogonadotropic) hypogonadism. This is especially true when a HPTA-recovery

    protocol, to “restart” LH production, is desired (the details of which remain beyond the scope of this document) secondary to anabolic steroid or prohormones use, as well as other hormone

    disrupting influences.

Rapidly attenuated LH can serve as proof a transdermal testosterone preparation is indeed

    penetrating. This can be quite valuable information in confusing cases, especially when the

    preferred 24 hour urine panels are not available.

     4

FSH

    The hours long half-life and less pulsatile production of Follicle Stimulating Hormone (FSH) makes it a better marker for gonadotropin production, at times, when evaluating HPTA activity. It is less an acute phase reactant to varying serum androgen and estrogen levels than LH. Greatly elevated FSH levels could signal a gonadotrophin-secreting pituitary tumor.

    FSH also provides valuable information for those patients undergoing TRT who are interested in the state of their fertility. Of note, while there are never guarantees where fertility medicine is concerned, I do not believe appropriate TRT will make a fertile man infertile. Constitutive expression is maintained.

    PROLACTIN

    A very important hormone, and must not be overlooked on initial work-up. Approaching five percent of hypogonadotrophic hypogonadism is associated with hyperprolactinemia, due to inhibition of hypothalamic release of LHRH. Its serum concentration must be maintained within physiological range (meaning neither too high NOR too low). Greatly elevated hyperprolactinemia, or hyperprolactinemia plus a Total Testosterone less than 150ng/dL, equals a trip to an Endocrinologist for a pituitary MRI.

CORTISOL

    True Anti-Aging medicine must be well-familiarized with the ins and outs of this hormone, the only one our bodies cannot live without. Elevated levels can cause secondary (hypogonadotropic) hypogonadism. I try controlling elevated cortisol with Phosphatidylserine, 300mg QD, with good results. It is just as important to watch for depressed or inappropriate cortisol production, AKA Adrenal Fatigue, as well. The assay of choice for that condition is a 24-hour urine, via summation of cortisone and adrenal metabolite production.

THYROID PANEL

    I have, for my own convenience, omitted the specifics of the obligatory thyroid function panel you certainly will want to run. Besides the fact thyroid is intimately associated with every function of the body, hormonal and otherwise, (even subclinical) hypothyroidism mimics hypogonadism in several of its effects.

CBC

    This is just good medicine. Ruling out anemia is important, of course, as it may be cause for the fatigue which drove the patient into your office. You also want to establish baseline H/H, for the small portion of cases where polycythemia becomes a problem (and we are reminded smokers and sleep apnea sufferers are at increased risk for polycythemia). Above 18.0/55.0 TRT is withheld, and therapeutic phlebotomy recommended.

     5

CMP

Again, just good medicine. Baseline for sodium (which may elevate initially secondary to androgen

    supplementation) is important. We also want to see LFT‟s, as elevations in same secondary to

    androgen supplementation are listed as a possible side effect in the product literature--although I

    have yet to see this actually happen. I like the BUN/creatinine ratio as marker for hormonal hemo-

    concentration, and also it gives me a hint of how compliant the patient will be (because I always

    tell them to make sure to drink their normal “plenty of water while fasting for the test). Of note,

    many of my patients consume prodigious amounts of protein each day, due to muscle building

    interests or specialty dieting, and this is remembered while reading BUN concentration.

Lipid Panel

This is drawn to provide your bragging rights when you drop the CHOL significantly, thanks to

    your own good administration of TRT. You should expect to see lowered TRIG and LDL‟s, too. Be

    advised, this will not happen if you choose to elevate their androgens above the top of “normal”

    range, i.e. providing what amounts to an anabolic steroid cycle. Of course, this would no longer

    constitute TRT, as the practitioner is then choosing to damage the health and well-being of the

    patient.

HDL does frequently drop a bit, is believed due to increased REVERSE cholesterol transport.

    Androgens also elevate hepatic lipase, and this may have an effect. The important thing to keep in

    mind is that TRT inhibits foam cell formation. For these reasons I provide my TRT patients a free

    10-12 point bump in HDL evaluation.

PSA

For all patients over 45, and over 40 if Family History of prostate cancer. Even though prostate CA

    is rare in men under the age of fifty, we don‟t want it happening on our watch. At this time,

    accelerations in PSA above 0.75 are a contraindication to TRT (until follow-up by an Urologist).

    You may find, at the initiation of TRT in older men, when serum androgen levels are rapidly rising,

    PSA may, too. This is especially true when transdermal delivery systems are employed, because

    they more elevate DHT. Once T levels have stabilized PSA drops back down to roughly baseline.

    New TRT patients need to be cautioned, and reminded, to abstain from sexual relations prior to the

    draw, as they may now be enjoying greatly elevated amounts of same.

    I get a PSA up front on my over 40 patients, at the one month follow-up in my more senior patients,

    and every six months after that. DRE (Digital Rectal Exam) is recommended twice per year as well,

    although the American Academy of Clinical Endocrinologists backs “every six to twelve months”

    in their 2002 Guidelines for treating hypogonadotrophic patients with TRT.

IGF-1

For those who are considering the addition of GH to their Anti-Aging regimen. IGF-1 will rise

    somewhat from testosterone supplementation, and vice versa. Let‟s grab a baseline now, before that happens. Current thinking is to also assay IGFBP-3.

     6

THINGS TO LOOK OUT FOR

CO-MORBIDITIES. Only breast and active prostate cancer are absolute contraindications for TRT,

    at this time. Patients with serious cardiac, hepatic or renal disease must be monitored carefully; this

    is true for any medical therapy, of course. Also, TRT may potentiate sleep apnea in some chronic

    pulmonary disease patients, although studies have also shown it can actually ameliorate the

    symptoms of same as well.

DRUG INTERACTIONS. TRT decreases insulin or oral diabetic medication requirements in

    diabetic patients. Therefore make sure to warn them to closely monitor their sugar. It also increases

    clearance of propranolol, and decreases clearance of oxyphenbutazone in those receiving such

    medications.

TRT may increase coagulation times as well. This is minimal, and easily accounted for by proper

    pre-surgical evaluation. The reverse risk of increased coagulation that terrifies surgeons and anesthesiologists results only in cases of severe polycythemia secondary to non-monitored TRT.

    Again, proper work-up removes risk. On this topic, I am absolutely amazed when surgeons,

    anesthesiologists, cardiologists, etc. hold TRT prior to their own labors. Let‟s take inventory of the results of their misguided actions: anabolism turns to catabolism, inflammation runs wild, weakness

    and fatigue, estrogen goes through the roof, depression, etc. as the body is generally thrown into a

    state of turmoil. Just what you want while undergoing surgery or an MI! Cases where “specialists”

    actually consult with the qualified administering physician are rare. Not only is this profoundly

    detrimental to the patient, same is also a gross violation of medical ethics.

TESTOSTERONE DELIVERY SYSTEMS

Now we have to decide, TOGETHER with our patient, what form of testosterone delivery system

    we will START with. There are two basic subsets of sametransdermals and injectables. Here are the current options:

TESTOSTERONE GELS AND CREAMS

The only way to go, in my professional opinion, if physician and patient agree on a transdermal

    (TD) delivery system. Or TRT at all. As I have gained knowledge and experience, my position is

    now that TD‟s are vastly superior to other modalities in TRT medicine. They are easy to apply,

    usually well absorbed, and rapidly establish stable serum androgen levels (by the end of the third

    day). I recommend all practitioners first try a testosterone gel for their TRT patients. Gels are better

    than creams, as I want the rapid T uptake into the dermal layer, which serves as reservoir for

    distribution throughout the day. Men do better on lower serum T levels on TD‟s than IM.

The constant variability of serum androgens provided by T gels mimic the hormones of a young

    man; the stable daily level provided by T injections mimic the hormones of an old man; those of

    implantable pellets mimic the hormones of no one. Entropic hormone levels are part and parcel of

    the process of youth.

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Much is made of the risk posed by accidental transferal of testosterone to others, such as children or

    sexual partners. Simply covering with a T-shirt has been shown to block transfer of the hormone.

    The testosterone sinks into the skin within an hour. One may shower, or even swim, without worry,

    usually after four hours. I remind my patients most of us have neither the time, nor the opportunity,

    for romance until evening (given the usual early morning application), and a quick shower is

    always nice for a gentleman to “freshen up” prior to same.

Gels and creams, like all transdermal delivery systems, provide a greater boost in DHT levels,

    compared to injectable testosterone preparations. As DHT is responsible for all the things of

    manhood--literally, AllThingsMale--the transdermals are better at treating sexual dysfunction than

    are injectables. However, issues of hair loss (which I treat with a compounded topical DHT

    blocking mixture) and possible prostate morbidity (a contentiously debatable point, to be sure, but

    resolved in the negative to my mind) then come into play. This might be a good time to mention I

    vehemently oppose adding finasteride or similar medication.

To end the debate on this topic, transdermal T gels/creams are more likely to elevate estrogen than

    injections, as long as the shots are properly administered once per week. That is because aromatase

    lives in the skin, along with higher concentrations of 5-AR, which converts T to E. Even so, the

    benefits of TD TRT outweigh the weekly convenience of shots.

Some have reported an increase in hair growth over the application area(s). All physicians who

    administer TRT must be prepared to disappoint their patients at this time by pointing out, sadly, this

    same effect cannot be achieved upon the scalp.

    TESTOSTERONE PATCHES

These can be effective, however many find inconvenient to use. Approaching 2/3‟s of your patients

    will develop a contact dermatitis from them at some point. Another drawback is some patients

    report they are constantly aware of their placement, and the patches are embarrassingly obvious to

    other gentlemen in certain public places, such as the locker room.

    The scrotal application variety is the most inconvenient. To see what I would be putting my

    patients through, I tried one. By the middle of the first day, I had more than enough. Most men

    generally do not enjoy shaving their scrotum. If you go to the gym during the day, they look strange

    affixed to the genitals, and must be removed, then reapplied, when showering. They do not adhere

    well in the first place, and even less so once they have been reapplied. Applying a hair dryer to the

    patch, as they must be warmed first, is also an annoyance, and generally not the type of activity

    relished in the locker room. Of the two options, I found only the type with the extra adhesive had

    any chance of remaining in place. The scrotal variety causes the largest increases in DHTwhich

    can be good or bad, as previously explained (this might be a good time to mention I never

    recommend applying a TD gel to the scrotum).

    TESTOSTERONE PELLETS

In my opinion, their use is absolutely Stone Age. Granted, they can provide extra revenue by virtue

    of a billable office based procedure. However, needlessly exposing patients to the risks ALL

    surgeries posehemorrhage and infectionis unwarranted. Some have issues with pellet extrusion,

     8

but same is highly dependent upon clinician‟s technique. And the area of insertion will be much

    tenderer than that following a mere IM injection. But the real issue which selects against pellet

    implantation is concerned with dosing. Let‟s say you attempt to establish a “usual” initial dose for

    the pellets. As will be described in the next section, there is absolutely no way to predict, up front,

    how a patient will react to a given dose of testosterone, regardless of the delivery system, or

    patient‟s body weight, activity level or composition. So you bury these pellets in your patient‟s

    backside, and (hopefully) draw follow-up labs in a month or so. What are you to do if the total

    testosterone ends up greatly exceeding the top of normal range (meaning the patient hyper-

    responded to the treatment)? And what if the pellets do not elevate T enough? Will you bring them

    back in to implant more? It may be difficult to sell them on this idea, since they probably are not

    yet feeling the advantages of TRT enough yet to motivate them into undergoing another surgical

    procedure. It just doesn‟t make sense, to my way of thinking. Worse, what if follow-up assay

    demonstrates markedly elevated DHT? Think about it.

Testosterone pellets do have some benefit in that selected patients may believe it more convenient

    to come in at longer interval, and then be done with it for a while. If your patient is on his way to

    conquer Mt. Everest, or extended safari, then TRT via pellet implantation is preferable to

    abstinence from TRT at physically challenging times.

TESTOSTERONE INJECTION

    I‟ll start out by describing the drawbacks of IM testosterone. They are inconvenient for patients who do not wish to give themselves their own injections, as they must then make weekly trips to

    your office for same. Why IM test MUST be dosed weekly will be described in detail in another

    section. And this TRT modality represents hundreds of holes poked in their body over a lifetime.

    Some patients, as you well know, just hate shots (although I have noticed patients who had initially

    claimed this, but admitted, once they had come to enjoy the benefits of TRT, came to very much

    look forward to their shot day). And no doubt an invasive delivery system brings more risk than,

    for instance, a testosterone gel or cream (the best choice for TRT), although I have yet to hear of a

    single bad outcome from any of the tens of thousands of IM injections my patients have self-

    administered.

As a good and proper Osteopathic Physician, I am loath to introduce any substance to the body not

    absolutely necessary. Therefore the oil and preservative necessary to the injectable preparation are

    best avoided when possible, in my professional opinion.

When considering dosing of testosterone cypionate, it is important to remember that, due to the

    weight of the cypionate ester, a 100mg injection delivers, at best, 70mg of testosterone. This is

    important to keep in mind when comparing the effects of a 100mg weekly injection of test cyp to

    the 35mg total initial dose provided by Androgel/Testim 5gms QD over the same period.

HCG

Many practitioners consider this incredible hormone treatment of choice for hypogonadotropic

    (secondary) hypogonadism. Such certainly is intuitive, as supplementing with a LH analog indeed

    increases testosterone production in patients who do not concurrently suffer primary hypogonadism.

     9

But for some unexplained reason, while serum T levels may be adequately elevated, the patients

    simply do not report realization of the subjective benefits of TRT, when HCG is administered as

    sole TRT. You also run the risk of inducing LH insensitivity at higher dosages, and therefore may

    actually cause primary hypogonadism while attempting to treat secondary hypogonadism. HCG,

    especially at higher doses (defined as >500IU per shot), also dramatically increases aromatase

    activity, thus inappropriately elevating estrogens. Progesteronea feminizing hormone in adult

    malesalso elevates at those dosages. Personally, I recommend giving no more than 100IU of

    HCG per day, as starting dose. And please give it some time to work.

A real benefit of HCG is that it will prevent testicular atrophy. I do not think we should ignore the

    aesthetics of that consideration. Your patients will feel the same way. I have provided a paper

    detailing some of HCG‟s amazing benefits for TRT medicine at

    http://www.allthingsmale.com/publications.html.

OTHER MEDICATIONS

I occasionally hear of physicians trying to use a SERM (Selective Estrogen Receptor Modulator)

    such as Clomid or Nolvadex, or even an Aromatase Inhibitor (AI), such as Arimidex, as sole

    “TRT”. All have been shown to elevate LH, and therefore Total Testosterone levels. However, patients usually report no long-term subjective benefits from these strategies. An added risk of

    using an AI is of driving estrogen levels too low, with deleterious consequences for the lipid profile,

    calcium deposition, endothelial function, libido, etc. The real problem with using these non-

    testosterone preparations as “TRT” is we do not know what they will do long term.

Finally, Deca-Durabolin (nandrolone), or Winstrol (stanozolol) have no place in TRT medicine.

    Deca has a nasty side effect profile, including uncontrollable progesterone-like effects (including

    gynocomastia), profound HPTA suppression, and substantial risk of long-term impotence. And

    there is no medical indication for the attainment of large amounts of muscle mass, other than in

    documented cases of wasting disease. Use of the word “steroid” should be avoided in our field.

    A FEW WORDS ABOUT LABORATORY ANALYSIS

The best matrix for following transdermal TRT is the 24 hour urine panel. Graphing the serum

    levels status post application shows why. The best time to draw a serum sample is two hours after

    applicationeven that is highly variable. However, a 24 hour urine panel catches all (for practical

    purposes) the T absorbed, and its metabolites, thus basically providing the area under the curve.

    Thus we are not merely taking snapshots on a roller coaster of serum T levels.

The astute practitioner must keep in mind proper assay evaluation in TD BID regimen. Serum T

    levels will appear artificially low with same because only half the daily dose is being measured. Of

    course, 24 hour urines are free of this, as they catch the area under the curve for the entire day.

I prefer serum testing when following IM TRT. Try to have the patient draw on the same day of the

    injection week each time. A draw on the second or third day will yield peak values, by the

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