The Challenges and Complexities of Thyroid Hormone Replacement

Shayri M. Kansagra, BS; Christopher R. McCudden, PhD; Monte S. Willis, MD, PhD


Lab Med. 2010;41(6):229-348. 

In This Article

Abstract and Introduction


Hypothyroidism is an endocrine disorder affecting 1%–10% of the population. Symptoms of hypothyroidism include fatigue, lethargy, and decreased cognitive performance. The mainstay therapy for hypothyroidism is synthetic thyroxine (T4) because of its long half-life and conversion to the bioactive form 3-5-3' triiodothyronine (T3). Recently, treatment research has re-emerged from clinicians who found that patients still experienced significant psychological morbidity, such as decreases in cognitive performance, mood, and physical status, despite appropriate standard T4 therapy. It was subsequently reported that patients treated with both T3 and T4 experienced better cognitive functioning compared to patients treated with T4 alone. This review discusses the current literature comparing cognitive improvement in combination T3/T4 therapies to T4 monotherapy in the context of the most recent biological research on thyroid metabolism and signaling in neurons that might help explain the conflicting cognitive results in these studies and help develop new paradigms to test in the future.


Hypothyroidism is an endocrine disorder affecting 1%–10% of the global population.[1–3] Although hypothyroidism can affect any demographic, it is much more common in women older than 60.[1–3] Hypothyroidism is defined as an inadequate production of thyroid hormones by the thyroid gland and can cause numerous symptoms including fatigue, weakness, weight gain, and depression. The thyroid hormones affect every organ and cell type in the body, leading to widespread symptoms when it is lacking. Hypothyroidism can have profound effects on the cardiovascular system,[4] the endocrine system,[5–8] nervous system, and brain.[8–10] Several pituitary hormones are affected by hypothyroidism including prolactin,[11] LH, and FSH,[12] which may underlie abnormalities in libido, erectile dysfunction, and fertility.[13] Symptoms of hypothyroidism relate to the severity of the underlying disease. The disease ranges from sub-clinical hypothyroidism with only subtle biochemical abnormities to overt clinical hypothyroidism where there are several severe symptoms associated with significantly decreased thyroid hormone levels. The most severe forms of hypothyroidism are congenital, leaving newborn children with growth failures and permanent intellectual disability if not treated within the first few weeks of life.[14,15] However, most clinical studies of hormone replacement therapy focus on adult populations with later onset of hypothyroidism.

There are 2 main thyroid hormones produced by the thyroid gland, thyroxine (T4) and triiodothyronine (T3). Both T4 and T3 are synthesized in response to thyroid stimulating hormone (TSH) from the pituitary by follicular cells in the thyroid gland. Thyroid follicles contain a precursor protein called thyroglobulin, which provides a backbone of tyrosine residues that are sequentially iodinated and coupled enzymatically to yield T3 and T4. In healthy individuals, the thyroid gland predominately produces T4, which is released into the circulation and transported by several binding proteins to target tissues for biological effect or further conversion. Both endogenous and synthetic T4 (used in therapy) are converted by peripheral tissues into T3, the most bioactive form of thyroid hormone, by a series of deiodinases. There are 3 types of deiodinases distributed in the body, which convert T4 to T3, and metabolize T3 into other forms such as diiodothyronine (T2) and reverse T3 (rT3). Although these isoforms have been traditionally considered biologically inactive, there is evidence that rT3 is involved in regulating actin polymerization in the brain. In addition, both type I and II deiodinases are expressed in astrocytes and neurons, supporting a specific need for differential thyroid hormone signaling in the brain. Thyroid hormone receptor expression is also highly regulated in both the developing and adult brain. Two types of thyroid hormone receptors (TRα1 and TRβ1) are found in the brain, with differing spatiotemporally expression in neurons. Thyroid hormone receptors act both independently and cooperatively to control brain development, sensory function, and behavior.[16] Collectively, the distribution of the deiodinases, the bioactivity of thyroid hormone metabolites, and the spatiotemporal regulation of receptors in the brain have implications in the treatment of patients with hypothyroidism.

The necessity for biochemical regulation of thyroid hormone action in the brain is exemplified by the neurological manifestations of hypothyroidism. Patients with hypothyroidism commonly display cognitive impairment, depression, and other neurological dysfunctions. Accordingly, many studies of hypothyroidism rely on the measurement of neurological functions such as mood and cognition when comparing treatment efficacy. While there is strong evidence that cognitive impairment and depression are associated with overt clinical hypothyroidism, there is some controversy as to how frequently neurological impairment occurs in sub-clinical hypothyroidism.[17] In a series of studies recently reviewed,[17] only 2 out of 6 reports demonstrated a clear connection between cognitive impairment and hypothyroidism. Collectively, the literature supports that mood and cognitive deficits occur over a range of disease severity. Regardless of the equivocal nature of such measures in sub-clinical disease, neurocognitive tests, such as mood, depression, and quality of life (QOL) remain a mainstay in studies of hypothyroidism pharmacotherapy.

Historically, patients with hypothyroidism were treated with crude thyroid extracts, containing T4, T3, and other compounds. With the discovery of T4, therapy shifted to use of this purified compound. Subsequent synthesis of T3 lead to the introduction of a combination T4 and T3 therapy, which for several decades was considered the acceptable standard. However, it was observed that combination therapy often led to hyperthyroidism due to an excess T3, and as a result, current guidelines from the American Association of Clinical Endocrinologists recommend that clinical hypothyroidism be treated with synthetic T4 (levothyroxine) alone.[18] In addition to the actual therapeutic agent itself, there are many other challenges for thyroid hormone replacement therapy. These range from compliance and dosing to drug interactions and comorbidities. The many different facets of pharmacology should be considered when assessing the efficacy of hypothyroidism treatment.

Recently, there has been a re-emergence of research into the treatment of hypothyroidism as clinicians reported that some patients continued to have symptoms of hypothyroidism despite biochemically appropriate T4 therapy.[19] A series of papers followed providing conflicting evidence regarding the benefits of combination T3/T4 vs T4 monotherapy. This review is focused on comparing combination T3/T4 to T4 monotherapy in the context of new and emerging complexities in thyroid hormone biology.