A 53-year-old woman comes to the office due to insomnia, severe hot flashes, and mood swings for the past several months. Her last menstrual period was a year ago. The patient recently had a wrist fracture that did not require surgery. She has a history of hypothyroidism diagnosed 7 years ago, for which she takes levothyroxine, and the dose has been stable for several years. The patient's last TSH level was 3.5 μU/mL. She has no other chronic medical conditions. She does not use tobacco, alcohol, or illicit drugs. Blood pressure is 120/70 mm Hg and pulse is 75/min. BMI is 24 kg/m². Physical examination shows a nonenlarged thyroid without nodules. Pelvic examination reveals an erythematous, atrophic vulva and vagina without discharge or bleeding. The uterus is small, and the ovaries are not palpable. Initiation of oral estrogen replacement therapy in this patient would most likely result in which of the following changes in thyroid metabolism?

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11ec25c8_d3ca_4cdd_bc81_f1470d760d85_MD0003_00 This patient has common symptoms of menopause, including insomnia, vasomotor symptoms (eg, hot flashes), and mood swings. In the absence of contraindications (eg, history of breast cancer, tobacco use), first-line treatment for severe menopausal vasomotor symptoms is oral estrogen-based hormone therapy. However, estrogen has notable effects on thyroid metabolism. More than 99% of circulating thyroid hormone is bound to plasma proteins, primarily thyroxine-binding globulin (TBG). Estrogen upregulates the production of TBG in the liver; an increase in estrogen activity (eg, pregnancy, oral contraceptive use, menopausal hormone therapy) raises circulating TBG levels, causing a corresponding reduction in free T4 and T3 levels (Choice C). thyroid metabolism In patients with a normal hypothalamic-pituitary-thyroid axis, lower free thyroid hormone levels trigger a transient increase in TSH release, leading to increased thyroid hormone production until the additional TBG becomes saturated with thyroid hormone and free hormone levels are restored. However, patients with hypothyroidism are dependent on exogenous thyroid hormone and are unable to increase production to compensate for the increased TBG. Therefore, patients on thyroid replacement therapy who are prescribed oral estrogens require a compensatory adjustment in levothyroxine dose. (Choice A) Drugs that inhibit deiodination of T4 to T3 include glucocorticoids, beta blockers, and propylthiouracil but not estrogen. (Choice B) In patients taking levothyroxine, increased production of TBG leads to lower free T4 levels, which will result in increased (not decreased) TSH secretion. (Choice D) T4 and T3 are metabolized by the liver via deiodination, glucuronidation, and sulfation. Phenobarbital, rifampin, phenytoin, and carbamazepine increase thyroid hormone clearance by upregulating these enzymes. In contrast, estrogen does not increase hepatic metabolism of thyroid hormones. Educational objective: Oral estrogen use (eg, menopausal hormone therapy) causes an increase in thyroxine-binding globulin, leading to decreased free thyroid hormone levels. Patients with hypothyroidism on levothyroxine therapy are unable to increase endogenous thyroid hormone production to compensate and require an increased levothyroxine dose.

A 53-Year-Old Woman Comes to the Office Due to Insomnia