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HYPOTHYROIDISM
Trying to Have a Baby Is Making Me Tired! . . . . . . . Level II
Michael D. Katz, PharmD
A 31-year-old African-American woman who has been undergoing
an infertility workup by her OB-GYN is referred to an endocrinologist for consultation. She complains of fatigue which the patient
ascribes to stress, and she also has some menstrual changes, constipation, weight gain, difficulty in concentrating at work, and dry skin.
The infertility workup showed no male factor causes. Additionally,
the patient has no evidence of structural reproductive tract problems or endometriosis, and sex hormone and gonadotropin levels
are normal. Her thyroid stimulating hormone (TSH) is elevated at
9.8 mIU/L, and her free T4 level is low normal at 0.72 ng/dL. She
has evidence of thyroid autoimmunity with a positive antithyroid
peroxidase (anti-TPO) antibody level. Her low-density lipoprotein
(LDL) cholesterol is slightly elevated at 142 mg/dL. Two years ago,
the patient had a TSH of 4.2 mIU/L, which was within the reference range for that laboratory. While the patient’s TSH is in the
range usually considered as “subclinical” or mild hypothyroidism,
her infertility, thyroid autoimmunity, symptoms, and elevated LDL
cholesterol are evidence of overt hypothyroidism and indications
for thyroid replacement therapy. Levothyroxine (LT4) is the drug
of choice. Therapy may be initiated with a relatively low LT4 dose
(~50–75 mcg daily) that is titrated if necessary over time to the target TSH range (TSH target is midnormal, range 0.5–2.5 mIU/L, not
the laboratory-defined reference range). The calculated full replacement dose (1.6 mcg/kg per day, ~100 mcg daily) also may be used,
though this dose may be higher than necessary in patients with relatively mild hypothyroidism who have some residual gland function.
After thyroid function tests have normalized, evaluation of therapy
with TSH measurements every 6–12 months is sufficient in most
patients to monitor therapy. However, if the patient successfully
becomes pregnant, she will need monthly monitoring of her TSH,
and she likely will need a higher dose of LT4. Over-replacement of
thyroid hormone should be avoided, as it may lead to hyperthyroidism, which can result in decreased bone density and increased
fracture risk, as well as adverse cardiac effects.
QUESTIONS
Problem Identification
1.a. Identify this patient’s drug therapy problems.
• Hypothyroidism, not currently being treated; “subclinical”
(mild) by TSH criteria but the patient likely has overt hypothyroidism based on unexplained infertility, is symptomatic, and
has an elevated LDL cholesterol level.
• Infertility, possibly due to hypothyroidism
• Elevated LDL cholesterol, possibly related to hypothyroidism;
not receiving intervention with diet or drug therapy.
• Constipation, possibly due to hypothyroidism, but could
alternatively be due to or exacerbated by iron and calcium
supplements
1.b. What information (signs, symptoms, and laboratory values)
indicates the presence of hypothyroidism?
• Signs. Unexplained infertility, dry skin.
• Symptoms. Fatigue, cognitive impairment, menstrual changes,
constipation, and weight gain in the face of elevated TSH consistent with hypothyroidism.
• Laboratory values. Elevated TSH, and low-normal serum free
T4 level. In addition, hypercholesterolemia (total cholesterol =
212 mg/dL, LDL-C = 142 mg/dL) may be the result of or may
be worsened by existing hypothyroidism.
• Other. The patient is a 31-year-old woman who, 2 years ago,
had a TSH near the upper limit of the TSH reference range.
The incidence of hypothyroidism increases with age and is
more common in women than men, and in whites and Hispanics than blacks.1,2 Patients with mild hypothyroidism due
to autoimmune thyroiditis (ie, Hashimoto’s thyroiditis) often
will progress to overt hypothyroidism after several years, especially if serum antithyroid peroxidase antibodies are present
in serum.
1.c. Could hypothyroidism be a cause of her infertility?
• Hypothyroidism has a variety of effects on the female reproductive axis,3,4 including changes in estrogens, androgens,
gonadotropins, and prolactin. Hypothyroidism often is associated with menstrual changes, including changes in the amount
of bleeding and cycle length. Hypothyroidism has been linked
to infertility in women, particularly in those with evidence of
thyroid autoimmunity and concomitant endometriosis. LT4
replacement therapy has been shown to increased conception
rates in infertile women with subclinical hypothyroidism.
1.d. List examples of medications that are known to cause hypothyroidism. Could any of the patient’s complaints have been
caused by drug therapy?
• Several medications can cause hypothyroidism. Examples
include amiodarone, lithium, interferon-α, antithyroid drugs
(propylthiouracil, methimazole, and tyrosine kinase inhibitors), and others. While the patient does not appear to be
receiving any of these agents, it would be important to confirm
that she is not taking any unreported prescription or nonprescription medications or complementary/alternative products.
Exposure to internal or external radiation can precipitate hypothyroidism. Iodine excess and deficiency can interfere with
TSH synthesis and result in hypothyroidism, but this is uncommon in adults in North America. Certain foods (cassava, lima
beans, maize, bamboo shoots, sweet potatoes, and cruciferous
vegetables) can have an antithyroid effect if ingested in large
quantities, so it would be reasonable to obtain more information regarding the patient’s diet.
• This patient’s constipation could be the result of her hypothyroid state, ferrous sulfate therapy, and/or calcium therapy.
1.e. What was the significance, if any, of her previous TSH of
4.2 mIU/L?
• The current reference range for TSH does not have a normal
distribution.1 Further, the upper limit of the reference range
for TSH is skewed in patients with subclinical hypothyroidism.
Many experts feel that the upper limit of the TSH reference
range should be reduced to 2.5 or 3.0 mIU/L.5 It would have
been reasonable 2 years ago to have assessed the patient for
thyroid autoimmunity, since patients with positive antithyroid
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Hypothyroidism
CASE SUMMARY
• History of iron deficiency anemia as a teenager; not currently
anemic on low-dose iron.
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• Menstrual changes, possibly due to hypothyroidism
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SECTION 8
antibodies have a greater likelihood of rapidly progressing to
overt hypothyroidism.
refills. Bioequivalent products are not necessarily therapeutically equivalent.9,10
• Many patients with “subclinical” hypothyroidism (TSH
<10 mIU/L) do, in fact, have symptoms that may improve with
LT4 therapy. If she was completely asymptomatic 2 years ago,
it was reasonable to withhold LT4 therapy, but she should have
received more frequent TSH monitoring (every 6–12 months).
• Liothyronine (T3) is also a synthetic product, but it has clinical
disadvantages that include a higher incidence of cardiac side
effects, difficulty in monitoring with conventional laboratory
tests, and higher cost than levothyroxine. There is strong
evidence that combined LT4/T3 therapy provides no outcome
advantage over LT4 monotherapy.11
Desired Outcome
Endocrinologic Disorders
2.What are the goals of pharmacotherapy for this patient?
• Alleviate the clinical signs and symptoms of hypothyroidism.
• Normalize thyroid laboratory tests and maintain long-term
control. The target TSH level is the mean normal value
(1.4 mIU/L, range 0.5–2.5 mIU/L).6
• Facilitate conception and successful pregnancy; appropriately
monitor and dose LT4 during pregnancy.
• Prevent complications of overtreatment and undertreatment
with LT4.
• Assure adherence with the pharmacotherapy regimen.
Therapeutic Alternatives
3.a. What nondrug therapies might be useful for this patient?
• Dry skin may be improved by using a nonallergenic lotion to
provide moisture until she is euthyroid. The patient can also
avoid using harsh soaps to avoid contributing to the itchiness
and dryness.
• This patient’s constipation may be secondary to her hypothyroid state, ferrous sulfate, and/or calcium. As her thyroid status
improves, the constipation may also improve. In addition, reassessment of her need for ferrous sulfate therapy is indicated.
Increased dietary fiber may also help her constipation.
• Exercise and improved diet could help her level of stress and
assist in losing the weight she has gained, as well as reduce her
LDL cholesterol level.
3.b. What feasible pharmacotherapeutic alternatives (including
complementary/alternative medicine products) are available for treatment of hypothyroidism?
• There are several natural or synthetic thyroid preparations that
may be used; refer to the section on hypothyroidism in the
textbook chapter on thyroid disorders for a complete listing.
• Thyroid USP is a natural T4/T3 product that is nonphysiologic
for humans, may have an unpredictable biologic response,
may be allergenic, and can be expensive. Products containing
thyroid USP should no longer be used for thyroid replacement
therapy.
• Liotrix (a combination product containing T4 and T3 in a
nonphysiologic 4:1 ratio) is a high-cost product that lacks
therapeutic rationale.
• Levothyroxine (LT4) is the drug of choice for thyroid replacement therapy because it is a synthetic formulation that is most
physiologic, chemically stable, has more uniform potency, is
not allergenic, and is relatively inexpensive. There is evidence
that the FDA-specified methodology for bioequivalence testing is faulty for endogenous substances such as LT4 and cannot
distinguish relatively large differences in bioavailability among
different products.7 Products deemed bioequivalent may differ
in bioavailability by as much as 25%. Since small changes in
LT4 dose can cause clinically significant changes in a patient’s
TSH,8 it is recommended that a brand name LT4 product be
prescribed to assure that product not be switched at subsequent
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
• There are many products marketed on the Internet and in
health food stores that are claimed to be more effective and
“natural” than LT4 therapy. Many of these products do, in fact,
contain active thyroid hormone products. Patients should be
advised not to use these products since they are unregulated
and have not been tested for safety and efficacy.
Optimal Plan
4.What drug, dosage form, product, dose, schedule, and duration of therapy are best for this patient?
• The standard therapy used for thyroid replacement is LT4. Its
advantages include once-daily dosing, stability, predictable
potency, and a variety of dosage strengths to allow for easy
dosage titration.
• In this patient, brand name LT4 therapy should be initiated
with 50–75 mcg once daily on an empty stomach. Prescribers should be educated to write LT4 prescriptions in mcg
(eg, 50 mcg) doses rather than mg (eg, 0.05 mg) doses to
reduce the chance of a medication error. The TSH should be
reevaluated in 6–8 weeks. If the TSH is not in the target range
(0.5–2.5 mIU/L), the dose should be increased or decreased
by 10–20% and the TSH rechecked in another 6–8 weeks. This
process may be repeated until the patient’s TSH is at target
and she is no longer symptomatic. Some patients have the best
clinical result when the TSH is at a low-normal level. However,
overtreatment with a below normal TSH should be avoided. A
variety of factors can alter LT4 dose requirements over time,
including many drugs, diet, aging, and pregnancy.
• In elderly patients and patients with known cardiac disease, therapy should be initiated with a lower LT4 dose of
12.5–25 mcg daily and titrated slowly upward. Clinical and
biochemical evaluation should be performed 6–8 weeks after
initiation of treatment. If the TSH is not in the target range, the
dose may be titrated as described above. If the patient’s cardiac
condition worsens during the titration phase, the dose should
be reduced, and then retitrated in smaller increments.
• Pharmacologic treatment for her elevated LDL cholesterol
should not be considered until she is/has been euthyroid for at
least several months. If her LDL cholesterol remains elevated,
statin medications should not be used since she is trying to
become pregnant, and these medications are teratogenic.
• Significant drug interactions should be avoided and monitored.
Both iron and calcium have been shown to significantly reduce
the bioavailability of oral LT4. This problem can be avoided by
the patient taking the iron and calcium at least 3–4 hours apart
from the LT4.
Outcome Evaluation
5.What clinical and laboratory parameters are necessary to
evaluate the therapy for achievement of the desired therapeutic
outcome and to detect or prevent adverse effects?
• Perform clinical and biochemical re-evaluation at 6- to 8-week
intervals with dosage increased until the serum TSH is in the
target range and the patient has resolution of symptoms.
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• The patient should obtain relief from her symptoms of fatigue
within 2–3 weeks of beginning therapy. However, dry skin may
take several months to subside.
• Under-replacement with LT4 and long-term mild hypothyroidism has been associated with infertility, elevated serum cholesterol, elevated BP, increased risk of coronary disease, altered
cardiac function, and cognitive impairment.
• If the patient becomes pregnant, monthly TSH monitoring
will be necessary to assure that she is receiving an adequate
LT4 dose. The majority of women who become pregnant while
receiving LT4 will quickly require a dose increase, averaging a
50% increase over the prepregnancy dose. The LT4 dose should
be titrated to a mid- to low-normal TSH level. Undertreatment
and maternal hypothyroidism may result in significant adverse
sequelae to the baby, including an increased risk of obstetrical complications, and impaired development and intellectual
function after birth.
Patient Education
6.What information should be provided to the patient to
enhance adherence, ensure successful therapy, and minimize
adverse effects?
• The reason for taking this medication is to replace the hormone that your thyroid gland is not producing in adequate
amounts. Replacing the thyroid hormone may improve your
chances of becoming pregnant. In doing so, your symptoms
should improve and your abnormal lab values should return
to normal.
• Make sure you receive the same brand of this medication each
time the prescription is filled. While all the brands on the market are good, they are not the same. If the brand is switched,
your blood tests may change and will need to be checked more
often. If the tablets look different when the prescription is
refilled, make sure to ask your pharmacist about it.
• Take this medication once a day exactly as your healthcare
provider directed.
• Space this medicine from the time you take your iron and
calcium tablets by at least 3–4 hours. The iron and calcium
tablets may reduce the amount of thyroid hormone your body
will absorb. If you become pregnant and are taking prenatal
vitamins, the same recommendation applies since those products contain calcium and iron. In addition, you should not take
your thyroid pill with foods that are high in fiber or with fiber
supplements.
• Since taking this medication with food can decrease its absorption, it is best to take it on an empty stomach.
• If you miss a dose, take it as soon as you remember, unless it is
within 12 hours of your next dose. If it is too close to your next
• You should begin to feel better within 2–3 weeks of starting this
medication. You will initially notice an improvement in your
energy and mood. Other symptoms, such as dry skin, may take
longer to disappear.
• Blood tests will need to be checked periodically (every
6–8 weeks) until your healthcare provider determines the best
dose for you. After that, you will only need to have a blood test
once or twice a year unless there is a change in your condition, or if the brand of medication is changed. If you become
pregnant, your TSH test will be checked on a monthly basis,
and your thyroid dose changed to make sure that both you and
your baby are receiving the right amount of medication.
• If the dose of your medication is too high, you may experience diarrhea, sweating, tremors, palpitations, or intolerance
to heat. Call your healthcare provider if you notice these side
effects. Over a long period of time, taking too much of this
medication can cause problems with your bones and heart.
Taking too little of the medication can make you have the same
symptoms you started with, plus you can develop high blood
pressure, high cholesterol levels, and an increased risk of heart
disease. This is a very safe medication, and these problems will
not occur if you take the medication as directed, and if your
thyroid blood tests are checked periodically and stay in the
desired range.
• Call your healthcare provider immediately if you experience
any chest pain, palpitations, or irregular heartbeats.
• Because your thyroid gland is not producing enough thyroid
hormone, you will likely need to take this medication for the
rest of your life.
• It is very important to keep regular appointments with your
healthcare provider(s) to monitor your therapy so that you can
gain the full benefit of this therapy while avoiding potential
side effects.
■■ FOLLOW-UP QUESTIONS
1.How should this patient’s elevated LDL cholesterol be managed now? What if her cholesterol continues to be elevated
after she becomes euthyroid?
• The patient’s elevated LDL may be caused by her hypothyroid
state. Her lipid panel should be rechecked after she has been
euthyroid for several months. Most patients will have a significant reduction on LDL with initiation of LT4 therapy, though
the high-density lipoprotein (HDL) usually is not significantly increased. Pharmacologic lipid-lowering therapy should
only be considered if her LDL remains significantly elevated
after she becomes euthyroid, per evidence-based guidelines.
However, since she is trying to become pregnant, it is best to
withhold any medications that may be harmful to the fetus,
including statins. The patient should be counseled regarding a
healthy diet as part of overall health maintenance.
2.What changes in her thyroid therapy might be necessary if she
does become pregnant?
• Pregnancy increases the need for thyroid hormone, due to
the needs of the developing fetus, increased thyroid hormone
clearance, and protein binding.13–15 The fetus is completely
dependent on maternal thyroid hormone during the first trimester. The majority of women who become pregnant while
receiving LT4 therapy will require a dose increase, averaging
50% above the prepregnancy dose. Since TSH levels normally
drop during pregnancy due to the TSH receptor stimulating
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Hypothyroidism
• Over-replacement of thyroid hormone can lead to signs and
symptoms of hyperthyroidism. Hyperthyroidism is also associated with menstrual problems and infertility. Long-term
over-replacement can lead to reduced bone density, which can
increase the risk of fractures, especially in postmenopausal
women. Mild or subclinical hyperthyroidism also has been
associated with increased rate of atrial fibrillation and cardiovascular mortality.12 Even during maintenance therapy, the
dose of LT4 should be adjusted, if necessary, to keep the TSH
level in the target range.
dose, forget about the dose you missed and continue with your
regular regimen. Do not double doses.
CHAPTER 87
• Once the TSH is at target, evaluate response to therapy with
TSH measurements every 6–12 months, unless there is a
change in the patient’s clinical condition (eg, pregnancy) or the
product is switched.
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SECTION 8
effect of β-HCG, the target TSH during pregnancy is low- to
mid-normal (0.5–1.5 mIU/L). TSH is monitored monthly during pregnancy. Upon delivery, the LT4 dose may be reduced to
the prepregnancy dose.
3.Evaluate this patient’s continued need for iron and calcium.
Should they be discontinued? If not, what potential problems
(if any) might be expected once thyroid replacement therapy is
started?
Endocrinologic Disorders
• It is not clear from the information provided if she has had iron
deficiency anemia since she was a teenager. If she has not and
she has no current risk of iron deficiency (very heavy periods),
it would be reasonable to discontinue the iron. However, if she
becomes pregnant, iron supplementation in the form of a prenatal vitamin will be necessary. If the iron therapy is continued
or restarted, the potential absorption interaction with iron
and LT4 must be addressed. It is not clear why she is taking
calcium, so it would be reasonable to obtain more information
regarding her reasons for using and potential risk factors for
osteoporosis. If she does continue taking calcium, the potential
absorption interaction with LT4 must be addressed.
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Copyright © 2017 by McGraw-Hill Education. All rights reserved.
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