A healthy 36-year-old woman complains of eye fatigue that worsens as the day wears on, especially in the week before her menses, which are regular. Laboratory evaluations reveal a thyroid-stimulating hormone (TSH) level of 4 µIU/mL, thyroxine 6.2 µg/dL, free thyroxine index 1.8, and triiodothyronine uptake 29.5%. Her TSH, along with a low LDL, has been fairly consistent for the past 18 years. She has no clear-cut signs or symptoms of hypothyroidism but does admit to cold intolerance, dry skin, intermittent, occasional dependent “pins and needle”-type paresthesias, and bradycardia. She is not constipated. Is there any cognitive (i.e., prevention of dementia) or other benefit to therapy with levothyroxine (Synthroid) to achieve a TSH <3? Do any data show that a TSH of 4 may actually be protective against cancer, osteoporosis, or any other diseases?
—Lara Hume, MD, Asheville, N.C.

This woman typifies much of the controversy surrounding clinical management of hypothyroidlike symptoms in patients who are biochemically euthyroid or who are considered to have “subclinical hypothyroidism.” She does not have subclinical hypothyroidism, as defined by an elevated TSH in the context of a normal thyroxine level, but many endocrinologists would argue that the current “normal” levels of TSH are set unacceptably high. The National Academy of Clinical Biochemistry notes that with rigorous testing, more than 90% of euthyroid volunteers will have TSH levels <2.5, and thus a level of 4.0 may actually be too high (Thyroid. 2003;13:3-126).

That information notwithstanding, the effects of thyroid hormone replacement on patients who do meet the current definition of subclinical hypothyroidism remain controversial. Researchers continue to find conflicting results. One study that randomized patients with TSH values of 3.5-10.0 and normal thyroxine levels to a placebo-controlled, double-blind 12-month trial of thyroid supplementation (target TSH 1.0) reported no difference in the main outcome measures of cognitive, emotional, or hypothyroid symptoms (J Clin Endocrinol Metab. 2006;91:145-153).

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One randomized, crossover trial of 22 patients with symptoms of hypothyroidism but normal laboratory thyroid function showed that thyroid hormone replacement was no more effective than placebo in treating cognitive or psychological symptoms (BMJ. 2001;323:891-895).

Authors of many subclinical hypothyroid trials point out that thyroid hormone treatment is not without risk: “Overreplacement” resulting in subclinical or overt hyperthyroidism has potential long-term negative effects, including cardiovascular problems, decreased bone mineral density (BMD), etc. Given the well-known side effects of an overactive thyroid, it is interesting to postulate whether an underactive thyroid will have potential health benefits. As for osteoporosis, while patients with hypothyroidism may have higher BMDs, their risk of fracture may be similar to or even higher than that of a matched euthyroid patient (Calcif Tissue Int. 2003;73:205-209). Conversely, researchers at the MD Anderson Cancer Center in Houston conducted a case-control, retrospective study showing that hypothyroidism may, in fact, decrease a patient’s risk of breast cancer.
—Susan Kashaf, MD, MPH (101-20)