note: This article was originally published in the International
Journal of Pharmaceutical Compounding (July/August 2005; 9 ) .
patients taking either levothyroxine (L-thyroxine) USP (e.g., Synthroid,
Levoxyl) or dessicated thyroid
USP (e.g., Armour Thyroid, Westhroid,
Naturethroid), it has become apparent that a significant percentage continue
to suffer from thyroid-related symptoms in spite of optimal blood levels
of thyroid hormones. This became even more apparent when the American Association
of Clinical Endocrinologists (AACE) changed its guidelines for optimal
thyroid-stimulating hormone (TSH) values in patients receiving thyroid
replacement. The old reference
values, while varying somewhat depending on the laboratory test kit used,
ranged from 0.5 to 5.0 µIU/mL. The new guidelines for TSH optimization,
adopted in 2003, range from 0.3 to 3.0 µIU/mL.
This change required that many patients' doses of thyroid replacement
be raised so that their serum levels would fall into the new range. Although
this change was intended to optimize treatment outcomes, many hypothyroid
patients have continued to suffer from a variety of hypothyroid symptoms,
because their dose of thyroid replacement is suboptimal. The most common
lingering complaints include fatigue, impaired concentration, and persistent
losing weight in spite of adequate exercise and reasonable caloric restrictions.
In 1996, I began tracking patients who were taking levothyroxine as their
thyroid replacement medication, and closely monitoring their symptoms. Although
dosages seemed adequate on the basis of serum testing, it became apparent
that more than 75% of the patients continued to suffer from common hypothyroid
I asked these patients to track their basal body temperature by keeping daily
records of either first morning axillary (armpit) temperatures or serial
oral temperatures three, six, and nine hours after rising. Both methods revealed
temperatures almost always below 98.0°F. Low temperature is commonly
reported as a sign of hypometabolism, as described eloquently by Broda Barnes,
the classic text Hypothyroidism: The Unsuspected Illness (see Suggested Reading).
Incidence of Hypothyroidism
It is estimated that approximately two percent of the US population – 5.8
million people – are afflicted with hypothyroidism. Women are more likely
to develop hypothyroidism than men, and the incidence increases with age. (See
the sidebar, "Signs and Symptoms of Hypothroidism," for a list
of the most common signs and symptoms of hypothyroidism.)
Adequacy of Synthetic and Glandular Thyroid Replacement
If a patient is taking thyroid replacement and symptoms persist, the condition
is not being optimally managed. The medication most commonly prescribed for
hypothyroidism is synthetic thyroid hormone, or levothyroxine (T4). But it
is the active form of the hormone, triiodothyronine (T3), that we use in
our cells and tissues. The conversion of T4 to T3 happens in the liver and
in the cells themselves. T4 is converted into both T3 and reverse T3. Reverse
T3 is a stereoisomer of T3 and has no biological activity. T4 can be compared
to a key that has not yet been cut by a locksmith to fit in the lock (the
thyroid receptor site). When it is cut properly (as T3), it fits in the lock
and opens the door. The reverse T3 stereoisomer of T3 is a mirror image of
the active T3 molecule – a key that is cut differently enough by the
locksmith that it fits in the lock (receptor site) yet doesn't open
the door. When there is an excess of reverse T3, no thyroid metabolism is
Reverse T3 is biologically essential to slow down metabolism as a natural
compensation mechanism during times of starvation or famine. In fact, reverse
more powerful negative feedback on the production of T3 than vice versa. Under
varying stressors such as extreme caloric restrictions, pregnancy, and emotional
stress, the conversion of T4 to T3 can become unbalanced as the body produces
excessive amounts of reverse T3. Reverse T3 exerts its negative feedback on
T3 and ties up thyroid receptors. Reverse T3 must be displaced by the proper
biologically active T3 if metabolism is to normalize. This is impossible, however,
if a patient is being given synthetic T4 only. In these cases, there is no
replacement source of the T3 that is needed to displace the excess accumulations
of reverse T3 in the circulation and receptors. In the absence of adequate
biologically active T3, symptoms of hypothyroidism remain, despite an adequate
level of T4 in the serum and a normal TSH level. Since most of the conversion
of T4 into T3 happens in the cells, serum levels of free T3 and reverse T3
may be normal even when T3 and reverse T3 levels are not in balance. It is
as though the cells are starving for biologically active T3 in the midst of
plenty. Unfortunately, the "plenty" is plenty of T4 and reverse
T3 rather than the essential biologically active T3. I see many examples of
this in my clinical practice. Many patients continue to suffer with hypothyroid
symptoms even though they are taking T4100 µg (0.1 mg) per day. Their
blood levels of TSH and T4 are normal, yet symptoms persist.
T3 is available as a manufactured drug in the form of liothyronine sodium (Cytomel).
This synthetic T3 is released immediately, without delay, and is manufactured
only in 5 µg and 25 µg doses. T3 is three to four times more biologically
active than T4 and exerts its effects more rapidly and vigorously than T4.
The half-life of T3 is 0.75 days, while that of T4 is 6.7 days (Table 1). Patients
are much more likely to experience side effects from Cytomel than from compounded,
slowly released T3. These side effects include, yet are not limited to, tachycardia,
arrhythmia, anxiety, nervousness, agitation, irritability, sweating, headaches,
increased bowel motility, and menstrual irregularities. Angina, congestive
heart failure, and atrial fibrillation can be aggravated or induced by excessive
doses of T3. Other physiological distinctions between T4 and T3 are worth noting.
They are best summarized by Williams and Williams in their Textbook
of Endocrinology (see Suggested Reading).
Table 1. Comparison of Triiodothyroxine
(T3) and Throxine (T4) in Humans
|Production rate (nmol/day)
|Fraction from thyroid
|Relative metabolic potency
• Total (nmol/L)
• Free (pmol/L)
|Fraction of total hormone in free form (x10-2)
|Distribution volume (L)
* To convert T4from
nmol/L to µg/dL
(total) or pmol/L to ng/dL (free), divide by 12.87. To convert
T3from nmol/L to ng/cL (total) or pmol/L to pg/dL
(free), multiply by 65.1.
USP dessicated thyroid or Armour Thyroid is made with a ratio of
four parts of T4 for every one part of T3. This ratio is comparable
to those in the human
and porcine thyroid glands, which produce 75% T4 and 25% T3. One grain of
Armour Thyroid contains 36 µg of T4and 9 µg of T3. The T3 is released
all at once, not slowly.
Another manufactured drug, liotrix (Thyrolar), contains T3 in a similar ratio
of 75% T4 to 25% T3. Again, the T3 in Thyrolar is not released slowly. Because
T3 is generally considered to be four times more potent than T4, a 25-µg
dose of T3 is equivalent to a 100-µg dose of T4.
The amount of slow-release T3 prescribed, whether formulated in combination
with T4 or taken separately from T4, should be about 25% more than the mathematical
equivalencies would suggest. This is because T4 blunts the utilization of
T3 to some extent. The compounded slow-release form seems to allow for less
drug absorption. This can vary considerably from patient to patient. The
best approach is to monitor serum levels of free T4, free T3, and TSH in
taking T4 and slow-release T3 replacement six to eight weeks after every
dose adjustment. Further dose adjustments can then be made if necessary.
has a short half-life and serum levels tend to peak three to four hours after
dosing of compounded slow-release T3, we instruct patients to not take their
morning slow-release medication until after their blood draw. This allows
measurement of their 24-hour lowest levels of circulating serum T4 and T3.
are summarized in the accompanying sidebar, "T4 and T3 Equivalencies.")
T4 and T3 Equivalencies
T4 100 µg = T325 µg
Armour Thyroid 1 grain = T4 36 µg, T39 µg
T3 9 µg x4 = T4 equivalency of 36 µg
Armour Thyroid 1 grain = T4 total equivalency of 72 µg
(36 µg directly from T4 and 36 µg from T3 9 µg x4)
Nutrients as Cofactors in Thyroid Metabolism
Selenium is an essential cofactor in the conversion of T4 into T3. T4 is converted
into T3 by the selenium-dependent enzyme 5'-deiodinase. Selenium depletion
of soil is common in many areas of the US, and many individuals do not supplement
adequately to counteract this deficiency. Iodine is also essential in the
conversion of T4 into T3. While iodine depletion is common in US soils, many
Americans use iodized salt to counteract this. Commercial farming methods
used in the last century, which fertilized soil only with nitrogen, phosphorus,
and potassium, have allowed soils formerly rich in selenium and iodine to
become fully depleted. Other nutrients essential to optimizing thyroid metabolism
are tyrosine, zinc, copper, and essential fatty acids. In a sense, all the
essential nutrients play a role in optimizing the health of the thyroid gland
(essential amino acids, essential fatty acids, vitamins, minerals, and trace
Over the years, I have developed several different replacement strategies as
alternatives to the use of the standard therapies (levothyroxine and dessicated
thyroid). These replacement strategies have in common some blend of T4 with
slow-release T3. The example used in the first case is best suited to the
patient who has higher demands for energy during the day and/or suffers from
some type of sleep disorder at night. The approach used in Case 1 is also
best for patients who have a hard time taking more than one pill daily or
those who have financial constraints, since this is the least expensive option.
In each of these cases, we start with a patient who is currently taking T4
100 µg as the starting dose. We will be changing each patient's
therapy to a blend of T4 and T3, slowly released.
This patient's starting TSH is 2.5 µIU/mL, and we have a target
of 1.0 µIU/mL to optimize quality of life and minimize hypothyroid symptoms.
The patient's dose of T4 should be increased to 125 µg or 150 µg
to drive the TSH level down from 2.5 to 1.0 µIU/ mL. For discussion purposes,
this final T4 dose is 150 µg. This dose of T4 must be converted to an
appropriate combination of slow-release T4 and T3 at the correct ratio. As
already discussed, the thyroid gland maintains a T4:T3 ratio of 4:1, but most
patients who are symptomatic are converting an excessive amount of T4 into
reverse T3. They need a ratio of T4:T3 of perhaps 3:1 or 2:1 or, rarely, even
more T3 relative to T4. This is especially the case at the beginning of therapy.
If we decide on a T4:T3 ratio of 2:1, converting 150 µg of T4 to a blend
of slowly released T4 and T3 mathematically calculates to 50 µg of T4
and 25 µg of T3. The 25 µg of T3 multiplied by 4 represents a T4
equivalency of 100 µg. Adding the 50 µg of T4 brings the total
T4 dose to 150 µg.
Keep in mind, however, that doses of slow-release combinations need to be
increased by approximately 25% because of differences in absorption. Mathematical
are just that, and often a delivery form can increase or reduce absorption
from what is mathematically assumed. If we increase this initial dose of
of T4 by 25% to accommodate this, the correct dose of T4 is 187.5 µg.
The equivalency of this dose in a T4:T3 ratio of 2:1 would be about 60 µg
of T4 and 30 µg of T3. The 30 µg of T3 multiplied by 4 equals 120 µg
of T4 on an equivalency basis; with the 60 µg of T4, this adds up to
a finished equivalency of 180 µg, slightly shy of the 187.5 µg
A formula can be used to make the calculations easier, as follows:
T4 dose divided by 3 = new T4 dose
T4 dose divided by 6 = new T3 dose
A 300 µg T4 dose would convert to (300/3 = 100 µg T4) plus (300/6
= 50 µg T3)
The same mathematics apply to increasing or decreasing the T4:T3 ratio in
subsequent prescriptions. From a practical perspective, however, the levels
of T4 and
T3 in the patient's serum should guide the prescriber to the proper
proportional or disproportional dose adjustments needed to reach targeted
serum levels of
free T4, free T3, and TSH.
If the degree of thyroid resistance and need for active T3 is not as extreme,
we might consider a T4:T3 ratio of 3:1. An equivalency of 187.5 µg would
convert to 81 µg of T4 and 27 µg of T3. Multiplication of 27 µg
T3 by 4 equals 108 µg; this added to the 81 µg T4 equals approximately
190 µg of T4. The easiest way to calculate this is to realize that the
amount of T3 will be slightly less than that needed for the 2:1 ratio (i.e.,
T4 60 µg/T3 30 µg). Multiply the 27 µg T3 by 3 to preserve
the 3:1 ratio and calculate the finished equivalency. These ratios are modified
as indicated by remaining symptoms, temperature log results, and balance
of free T4, free T3, and TSH in the blood.
In this case, the patient (who is initially taking 100 µg of T4) also
requires a dose increase to 150 µg to get her TSH level down to a target
of 1.0 µIU/mL. The patient could continue to take T4, yet at a lower
dose of 50 µg. These medications come in doses of 25, 50, 75, 88, 100,
112, 125, 137, 150, 175, 200, and 300 µg. Because it has no food dyes
or coloring added, I like to use the 50-µg tablet and divide the dose.
If the target desired dose is 60 µg as in Case 1, the closest we can
get is 50 µg. The 30 µg of T3 needed to make up the correct T4:T3
ratio is compounded as a slow-release tablet, either as 30 µg once daily
or 15 µg every 12 hours. I prefer the slow-release capsule to be taken
first, upon rising; ideally, the patient would then wait one hour before
eating breakfast and take the T4 pill three hours after the T3. The patient
then take the second T3 capsule, if appropriate, 12 hours after the first.
Some patients need their T3 slowly released over 24 hours, especially as
the doses are increased to avoid side effects or to optimize distribution
throughout the day to be more even and to avoid fatigue in the late afternoon
This dosage regime is more complicated for patients. Remember, these are
hypothyroid patients who will take medication daily for the rest of their
someone to take a morning dose, another dose three hours later, and a third
12 hours after the first can be a compliance nightmare. Some patients feel
best on this protocol, however, and are not significantly bothered by the
routine. It can be simplified by taking the entire day's dose of T3
in the morning and the T4 three hours later, or even further by taking the
T4 and T3 together
upon rising. (The T4 does not have to be released slowly, since its half-life
is seven days.) Most convenient for the patient is compounding the T4 together
with the slow-release T3 in one capsule, so that the patient has to take
only one capsule in the morning.
Armour and USP Thyroid
Recall that there is a good chance that a hypothyroid patient with lingering
chronic hypothyroid symptoms is converting too much T4 into reverse T3, which
is biologically inert. By replacing some of the prescribed T4 with slow-release
T3, the reverse T3 gets displaced by the active T3, and metabolism returns
Glandular Thyroid USP (Armour Thyroid) delivers approximately four parts T4
to one part T3. T3 is about four times more potent than T4 but is metabolized
three times faster. The T3 in Armour Thyroid is not released slowly and therefore
gets delivered unevenly throughout the day. This is not the way the thyroid
gland and tissues work. T3, owing to its high biological activity, should be
delivered in even amounts. Compounded slow-release T3 does just that. Furthermore,
accurately adjusting the dose of Glandular Thyroid USP is difficult. Amounts
of T4 and T3 can vary from batch to batch and from manufacturer to manufacturer.
USP thyroid comes in limited strengths, including one-quarter grain, one-half
grain, 1 grain, 2 grains, and 3 grains. Optimizing the dose in sensitive and
difficult cases may be very challenging.
Please note that I do not advocate treating hypothyroidism with slow-release
T3 alone, as the only form of thyroid replacement. T3 works best when combined
with T4. Too much T3 without T4 can cause other problems, including osteoporosis
and heart arrhythmias. T4 also helps blunt the risk of side effects from T3,
which can occur even with slow-release T3. Finally, T4 offers a reservoir of
thyroid hormone material with which to make more T3 as needed.
Many patients suffering from years of lingering hypothyroid symptoms while
being treated with synthetic T4 or Armour Thyroid will feel much better if
their treatment is changed. Appropriate changes include either a lowered dose
of the current medication combined with slow-release T3 or a customized compounded
blend of slow-release T4 and T3.
I urge patients to consult with their endocrinologist before making any change
in thyroid medication. They should be aware, though, that very few physicians
are knowledgeable about slow-release T3 and its proper use. Although some available
drugs deliver T3 (Cytomel, for example) or combine T4 with T3 (Thyrolar), the
T3 in these preparations is not released slowly. As a result, patients continue
to suffer from the symptoms that result from uneven T3 distribution.
Compounded Slow-Release T4 and T3
In making the medication, a compounding pharmacist uses properly aliquoted
concentrations of T4 and T3. The T4 and/or T3 are combined together with
cellulose derivatives that regulate their slow release. This mixture is then
either tumbled for at least six hours or blended fully in a V mixer to assure
even distribution of the active ingredients. The finished material is then
placed into capsules. Once swallowed, the capsule forms a bolus in the stomach
and slowly releases T4 and T3. The T4 and T3 used in compounding are synthetic,
yet they are biologically identical to the T4 and T3 made by the human thyroid
gland (T4= levothyroxine sodium or 3,3',5,5'tetraiodothyronine
sodium, and T3= L-triiodothyronine).
Monitoring Medication Adjustments
The T4:T3 ratio initially prescribed is arbitrary and will most likely be adjusted
up or down. Adjustments are based on ongoing symptoms, body temperatures,
and the balance of serum levels of free T4, free T3, and TSH reported after
six to eight weeks on a stable dose. In the most severe cases of thyroid
resistance, which require the highest doses of T3, the dose will need to
be adjusted until the serum TSH level is 0.2-1 µIU/mL, with the free
T4 level at the low end of normal or even below normal, while the free T3
level is at the high end of normal or even above normal.
Since T3 is so biologically active, we like to instruct our patients to take
no thyroid medication the morning of the blood draw. We have them come in for
this blood draw as the first patient scheduled in the morning (8 to 9 AM).
This allows us to capture their lowest level of circulating T3 in the 24-hour
period. They are instructed to take their medication immediately after the
When changing from T4 to a slow-release blend of T4 and T3, the initial dose
is an estimate. The guidelines already described are only guidelines; actual
dose varies from patient to patient, depending upon that patient's intestinal
health and absorption of thyroid hormone. In our initial change of prescription,
we authorize patients to return in three weeks for repeat blood work if they
are feeling poorly and in two months if they are doing well. Within three weeks
after a dose adjustment, the serum levels of T4 and T3 reach their new steady
state. If an individual is feeling poorly from either underdosing or overdosing,
we can check at this early juncture their circulating blood levels of free
T4 and free T3. TSH level will not stabilize for six to eight weeks after a
Drug-Drug and Drug-Nutrient Interactions
Thyroid hormone can potentiate the effects of warfarin, requiring a lowering
of blood warfarin level to avoid excessive anticoagulation. Digoxin level
can be potentiated by thyroid medication, requiring lowering the dose of
digoxin. Antidepressant drugs can be mildly potentiated by thyroid hormone.
Patients taking thyroid in excessive doses for weight loss can develop life-threatening
symptoms of toxicity and/or arrhythmia, especially when the thyroid is given
in association with sympathomimetic amines for their anorexic and weight
loss effects. No interactions of thyroid with alcohol or tobacco have been
documented. Estrogen replacement and estrogen dominance can increase the
need for thyroid replacement. As hypothyroid women approach menopause and
accumulate more estrogen dominance, their thyroid replacement dose may need
to increase. Similarly, estrogen replacement therapy can increase a woman's
need for thyroid replacement. Insulin requirements can increase as thyroid
replacement dose increases. Thyroid medication can increase the adrenergic
effects of epinephrine.
Calcium supplements can reduce utilization of thyroid hormone, especially when
taken in high doses. Thyroid hormone replacement is best taken in the morning,
and calcium is best absorbed in the evening. Taking calcium with dinner minimizes
any impairment of utilization of thyroid taken in the morning. High levels
of soy in the diet can impair thyroid hormone utilization. Soy is best eaten
in small amounts in the evening meal. Iodine and selenium potentiate the conversion
of T4 into T3, acting as cofactors in the conversion. Brassica vegetables (broccoli,
cauliflower, Brussels sprouts) can reduce thyroid hormone utilization.
Hypothyroidism is a common condition. A large percentage of patients remain
significantly symptomatic in spite of apparently adequate replacement therapy.
Symptoms may include intractable chronic fatigue, impaired concentration,
and weight gain. These symptoms may have devastating consequences on quality
of life. Changing medication to a blend of T4 with slow-release T3 resolves
many of these limitations of patients' quality of life. The compounding
of exact customized levels of T4 and T3 enables the clinician to achieve
optimal targeted serum levels of TSH, free T4, and free T3 with precision.
These levels can be carefully customized to optimize symptom resolution while
improving metabolic temperature status. Customized compounding allows dose
adjustments to achieve whatever balance of T4 and T3 is necessary to achieve
optimal health and resolution of symptoms.
Martin Milner, ND
Medical Director, Center for Natural Medicine, Inc.
1330 S.E. 39th Avenue
Portland, Oregon 97214
Martin Milner, ND, received his ND in 1983 from
NCNM. He has remained at his alma mater for the past 20 years as Professor
of Cardiovascular and Pulmonary Medicine. Dr. Milner is also the CEO
and Medical Director of the Center for Holistic Medicine (1983-1991)
and Center for Natural Medicine, Inc. (1991-present). He is world renown
for his natural treatment protocols for heart disease, menopause and
Barnes B, Galton L. Hypothyroidism: The Unsuspected Illness.
New York, NY: Thorruss Y. Crowell Co.; 1976.
Bayliss RI, Tunbridge WM. Thyroid Disease: The Facts. Third
Edition. New York, NY: Oxford University Press; 1998.
Bunevicius R, Kazanavicius G, Zalinkevicius R, et al. Effects of thyroxine
as compared with thyroxine plus triiodothyronine in patients with hypothyroidism.
N Engl J Med. 1999; 340(6): 424-429.
DeGroot LJ, Larsen PR, Refetoff S, et al. The Thyroid and Its
Fifth Edition. New York, NY: John Wiley; 1984.
De Rosa G, Testa A, Maussier ML, et al. A slightly suppressive dose
of L-thyroxine does not affect bone turnover and bone mineral density
in pre- and postmenopausal women with nontoxic goiter. Horm
1995; 27(11): 503–507.
Marcocci C, Golia F, Bruno-Bossio G, et al. Carefully monitored levothyroxine
suppressive therapy is not associated with bone loss in premenopausal
women. J Clin Endocrinol Metab. 1994;
Marcocci C, Golia F, Vignali E, et al. Skeletal integrity in men chronically
treated with suppressive doses of L-thyroxine. J Bone Miner
McDougall IR. Thyroid Disease in Clinical Practice. New
York, NY: Oxford University Press; 1992.
Milner M. Natural Medicine and Compounding Symposium.
Presented [Audiotape, Videotape] at: A symposium of Professional Compounding
Centers of America;
February 12-13, 1999; February 12-13, 1999; Houston, TX.
Milner M. Wilson's syndrome and T3 therapy: A clinical guide
to safe and effective patient management.
IJPC. 1999; 3(5): 344-351.
Muller CG, Bayley TA, Harrison JE, et al. Possible limited bone loss
with suppressive thyroxine therapy is unlikely to have clinical relevance.
Thyroid. 1995; 5(2): 81-87.
[No author listed.] Actual trends in thyroid physiopathology. Horm
Res. 1987; 26(1-4): 1-230.
Nuzzo V, Lupoli G, Esposito Del Puente A, et al. Bone mineral density
in pre-menopausal women receiving levothyroxine suppressive therapy.
Gynecol Endocrinol. 1998; 12(5):
Refetoff S. Resistance to thyroid hormone. In: Braverman LE, Utiger
RE, eds. Werner and Ingbar's The Thyroid: A Fundamental and
Clinical Text. Seventh Edition. Philadelphia,
PA: Lippincott-Raven Publishers; 1996: 1032-1048.
Rosenthal MS. The Thyroid Sourcebook.
Fourth Edition. New York, NY: McGraw-Hill; 2000.
Schneider DL, Barrett-Connor EL, Morton DJ. Thyroid hormone use and
bone mineral density in elderly women. Effects of estrogen. JAMA.
1994; 271(16): 1245-1249.
Schoutens A, Laurent E, Markowicz E, et al. Serum triiodothyronine,
bone turnover, and bone mass changes in euthyroid pre- and post-menopausal
women. Calcif Tissue Int. 1991; 49(2):
Williams AB, Williams RI. Textbook of Endocrinology.
Philadelphia, PA: Saunders; 2003: 342.
Wilson ED. Doctor's Manual for Wilson's Syndrome.
Third Edition. Lady Lake, FL: Muskeegee Medical Publishing Co.; 1997.
Wilson ED. Wilson's Thyroid Syndrome: A Reversible Thyroid Problem.
Orlando, FL: Cornerstone Publishing Co; 1991.