A 23-year-old woman comes to the office due to fatigue, anxiety, and difficulty sleeping over the last several months. The patient has used melatonin as a sleep aid but with no benefit. Medical history is remarkable only for menorrhagia, for which she takes a combination estrogen/progesterone contraceptive pill. Her mother has hypothyroidism and hypertension. The patient occasionally smokes marijuana but does not use tobacco or alcohol. Blood pressure is 120/78 mm Hg and pulse is 82/min. BMI is 18.8 kg/m2. Examination of the neck shows a normal-size thyroid gland without nodules. Serum TSH is 1.5 μU/mL and total T4 is 15 µg/dL. Which of the following is the most likely explanation of this patient's laboratory findings?
Conditions that alter TBG concentration | |
Increased TBG | Decreased TBG |
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HRT = hormone replacement therapy; OCs = oral contraceptives; TBG = thyroxine-binding globulin. | |
This patient has an elevated total T4 concentration but her TSH is normal, suggesting a euthyroid state. Although she has nonspecific symptoms (eg, fatigue, anxiety), her vital signs and thyroid examination are normal. In light of her use of an oral contraceptive, this patient most likely has normal thyroid function with an estrogen-induced increase in T4-binding globulin (TBG).
More than 99% of the circulating thyroid hormone pool is bound to 3 major transport proteins: TBG, transthyretin, and albumin. Only the free (ie, unbound) thyroid hormones are biologically active. Changes in binding protein levels can affect the total circulating pool of thyroid hormones, but if the hypothalamic-pituitary-thyroid axis is intact, free hormone levels are unchanged.
High levels of estrogen (eg, pregnancy, oral contraceptive pills, hormone replacement therapy) increase the level of TBG by decreasing its catabolism and increasing its synthesis in the liver. As the additional TBG binds more thyroid hormone, thyroid hormone production increases to maintain a euthyroid state; this most likely explains this patient's slight elevation in total T4 level (her free T4 level would be expected to be normal).
(Choice A) In patients with normal hypothalamic-pituitary feedback, displacement of T4 from its binding proteins leads to decreased thyroid hormone production and lower total T4 levels (not higher, as seen in this patient) with normal free hormone levels. Medications with this effect include salicylates, furosemide, and heparin.
(Choice B) Graves disease causes hyperthyroidism due to stimulation of TSH receptors by thyrotropin-receptor antibodies. However, pituitary TSH secretion is suppressed and the thyroid gland is palpably enlarged.
(Choice D) In patients with a TSH-secreting pituitary adenoma, TSH is typically elevated, although a subset may have an inappropriately normal TSH. However, patients usually have a goiter and frequently have mass-effect symptoms (eg, headache).
(Choice E) Pregnancy can increase TBG levels but is less likely in a patient taking an oral contraceptive.
(Choice F) Resistance to thyroid hormone is a rare inherited disorder caused by defects in the thyroid hormone receptor. Patients can have elevated T4 levels with a normal or increased TSH, but most have a goiter, and this condition is usually apparent in childhood.
Educational objective:
Estrogen increases the level of T4-binding globulin. This effect is seen in pregnancy and in patients on oral contraceptives or menopausal estrogen replacement. Total thyroid hormone levels are elevated, but patients with normal hypothalamic-pituitary-thyroid function maintain a euthyroid state and normal TSH level.