Drugs That Suppress TSH or Cause Central Hypothyroidism

A small subset of medications including glucocorticoids, dopamine agonists, somatostatin analogs and rexinoids affect thyroid function through suppression of TSH in the thyrotrope or hypothalamus [ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784889/[/ref]. This decrease is less pronounced than the TSH suppression that occurs in hyperthyroidism. These medication effects can be difficult to distinguish from the changes of non-thyroidal illness in the setting of severe illness, where many of these medications are frequently used [ref]Gregory A. Brent. Thyroid Function Testing. 2010; page 261[/ref]. Fortunately, most of these medications do not cause clinically evident central hypothyroidism. However, a newer class of nuclear hormone receptors agonists, called rexinoids, cause clinically significant central hypothyroidism in most patients and dopamine agonists may exacerbate ‘hypothyroidism’ in patients with nonthyroidal illness [ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784889/[/ref].

GLUCOCORTICOIDS

The most common class of steroid hormone used to treat a broad variety of diseases is known as the glucocorticoids. Representative glucocorticoids include cortisone, prednisone, hydrocortisone, dexamethasone, and methylprednisone. These agents are frequently used to treat inflammatory disease such as arthritis, collagen vascular diseases, lung inflammation and asthma, certain types of liver inflammation, some skin diseases and granulomatous diseases [ref]http://www.mythyroid.com/glucocorticoids.html[/ref].

High doses of glucocorticoids have multiple reversible effects on pituitary-thyroid function, including inhibition of TSH secretion, decreased serum thyroxine-binding globulin (TBG) concentrations, inhibition of extrathyroidal conversion of T4 to triiodothyronine (T3), and an increase in the renal clearance of iodide [ref]Lewis E. Braverman, Robert D. Utiger. Werner & Ingbar’s the Thyroid: A Fundamental and Clinical Text. 2005; page 814[/ref].

Inhibition of TSH secretion caused by high doses of glucorticoids

Thyroxine (T4) and triiodothyronine (T3), together referred to as thyroid hormones, play an important role in basal metabolism and the functioning of almost all tissues and systems in the body. In addition to T4 and T3, thyroid stimulating hormone (TSH) secretion typically is maintained within relatively narrow limits via a sensitive negative feedback loop in which TSH stimulates the synthesis and release of thyroid hormones, that in turn negatively feed back to the hypothalamus and anterior pituitary to limit further TSH release [ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520819/#!po=46.8750[/ref]. However, thyroid function in man can be regulated by stimuli other than the circulating levels of thyroid hormone [ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC322682/pdf/jcinvest00226-0168.pdf[/ref]. Physiologic levels of hydrocortisone (cortisol) appear to play an important role in the diurnal variation of serum TSH levels with lower levels of TSH in the morning and higher levels at night [ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784889/[/ref]. These data suggest that normal early morning increase in endogenous serum cortisol levels decreases serum TSH levels and leads to the observed normal circadian variation in TSH [ref]Shlomo Melmed. The Pituitary: Third Edition. 2011; page 183[/ref].

There are probably both positive and negative relationship between TSH and cortisol.

Positive TSH-cortisol relationship

The positive relationship between serum TSH and cortisol levels in a healthy population is a compelling new finding that is consistent with and extends the observation that frankly hypothyroid patients have frankly elevated cortisol levels. Kimberly N Walter examined the relationship between TSH levels and cortisol in a preliminary study of young, healthy adults without known thyroid disease or other underlying health conditions. In their study, they hypothesized that serum TSH levels would be positively associated with serum cortisol levels even in the subclinical hypothyroidism range. They didn’t find out whether this relationship is pathologic or physiologic and what the mechanism(s) involved in this relationship may be. While in frank hypothyroidism, it is hypothyroidism that causes elevation of cortisol by reducing peripheral disposal and blunting feedback of cortisol on the hypothalamic-pituitary-adrenal axis, their cross sectional data do not elucidate whether the same mechanisms hold true for TSH levels in the high normal and low elevated range.  Although limited in sample size, their findings demonstrate that a positive relationship exists between TSH and cortisol that is maintained down to a TSH level of 2.5 uIU/L (but not below). This observation raises the possibility that negative health effects of mild, subclinical hypothyroidism with mild to modest elevations in TSH may begin at levels much lower than those currently considered abnormal based on assigned normal reference range values with an upper reference level of 4.5 uIU/L. Chronic elevations in serum cortisol and hypothyroidism (including subclinical hypothyroidism) have been separately linked with increased rates of depression, anxiety, and poor cognitive functioning. Thus, the association between TSH levels and cortisol suggests at least the possibility of a novel pathway through which hypothyroidism (both clinical and subclinical) may promote poor mental health; or hypothyroidism and an elevated cortisol level could be synergistic on mental health. Their data, that add to what is already known about frank hypothyroidism and cortisol, demonstrate a potentially important relationship between TSH and cortisol in apparently healthy young individuals. The finding that this relationship appears to hold in the controversial TSH range of 2.5-10 uIU/L, but not below, is compelling and requires further scientific and clinical investigation. Another potential explanation for the positive TSH-cortisol relationship is that hypothyroidism – subclinical or clinical – is associated with subtle metabolic stress. Metabolic stress could be imposing an effect on the adrenocorticotropin hormone-adrenal axis leading to an increase in stress hormone (i.e., cortisol) release and production. This hypothesis should be confirmed through the measurement of other stress hormones including the catecholamines, norepinephrine/epinephrine, and/or prolactin [ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520819/#!po=46.8750[/ref].

As already mentioned, in frank hypothyroidism, it is hypothyroidism that causes elevation of cortisol (hypercortisolemia) by reducing peripheral disposal and blunting feedback of cortisol on the hypothalamic-pituitary-adrenal axis [ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520819/#!po=46.8750[/ref]. When replacement doses of a glucocorticoid are given to patients with primary or secondary hypothyroidism (untreated), signs of Cushing’s syndrome may appear because of the hypothyroidism-induced decrease in cortisol clearance. This also explains why patients with hypothyroidism (untreated) are more susceptible than normal subjects to the undesirable effects of glucocorticoid therapy. This clinical state of relative hyperadrenocorticism abates when thyroid hormone is given and the normal rate of metabolism of not only cortisol but also synthetic glucocorticoids is restored [ref]Lewis E. Braverman, Robert D. Utiger. Werner & Ingbar’s the Thyroid: A Fundamental and Clinical Text. 2005;page 814[/ref].

Negative TSH-cortisol relationship

As mentioned above, in the case of primary hypothyroidism (elevated TSH) cortisol is elevated, but in the setting of primarily elevated cortisol TSH is suppressed. Thus when cortisol levels are manipulated through pathologic as well as physiologic ranges, a negative relationship is found between cortisol and TSH. In the negative TSH-cortisol relationship, we are talking about effects of the adrenal axis on thyroid function. Both exogenous and endogenous (i.e. Cushing’s Syndrome, stress) corticosteroids suppress TSH while low cortisol levels elevate TSH [ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520819/#!po=46.8750[/ref].

Let’s talk about more about situation when low cortisol levels elevate TSH. Some patients with adrenal insufficiency (low cortisol) manifest reversible hypothyroidism (elevated TSH). One explanation of elevated TSH levels is that there is impaired sensitivity of the thyroid gland to TSH in hypocortisolemic states that alters thyroid hormone secretion, or perhaps there is a stimulation in deiodination from T₄ to T₃ and reverse T₃. It is also possible that, by lowering the thyroid hormone production, the body might be reducing the metabolism in hypocortisolemic states [ref]http://www.medscape.com/viewarticle/545972[/ref]. In patients with both hypothyroidism and adrenal insufficiency, adrenal crisis can be precipitated if thyroid hormone replacement is instituted before the initiation of corticosteroid therapy [ref]http://www.medscape.com/viewarticle/545972[/ref].  Therefore, in the case of concurrent thyroid insufficiency and primary adrenal insufficiency, acutely ill patients with severe hypothyroidism or myxedema coma should be treated presumptively with cortisol, unless or until their adrenal function is determined to be normal [ref]Lewis E. Braverman, Robert D. Utiger. Werner & Ingbar’s the Thyroid: A Fundamental and Clinical Text. 2005; page 812[/ref]. More interestingly, the thyroid state can normalize solely by treatment of the adrenal insufficiency [ref]http://www.medscape.com/viewarticle/545972[/ref]. In sum, clinicians, when diagnosing hypothyroidism, should pay close attention to the patient’s signs, symptoms, and laboratory values for the possibility of coexisting adrenal insufficiency. Clinicians must also be aware that starting thyroxine replacement therapy can precipitate an adrenal crisis due to the increased clearance of cortisol and need to follow their patients closely for any subtle changes in symptoms. Adrenal insufficiency can be fatal if missed [ref]http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2014.NP.14.MON-0650[/ref].

Let’s go back to a situation when high levels of glucocorticoids suppress TSH levels. Large doses of glucocorticoids given acutely or moderate doses administration of glucocorticoids for a prolonged period suppress the secretion of TSH in euthyroid a hypothyroid individuals (treated hypothyroid patients, in whom TSH levels are not elevated, but they are within a normal range) [ref]Lewis E. Braverman, David S. Cooper. Werner & Ingbar’s The Thyroid a Fundemental and Clinical Text. 2013;page 199[/ref]. Glucocorticoids acutely decrease TSH production [ref]Shlomo Melmed. The Pituitary: Third Edition. 2011; page 188[/ref]. The decrease in serum TSH is not as pronounced as the TSH reduction found in hyperthyroid patients. Within 48 hours of withdrawal of short-term glucocorticoids, TSH levels may transiently increase to above pretreatment levels [ref]Gregory A. Brent. Thyroid Function Testing. 2010; page 262[/ref]. Glucocorticoid suppression of TSH levels may occur directly at the pituitary gland. Animal studies suggest that glucocorticoids exert direct effects on thyrothropes to impair TSH secretion, although these appear to be highly dependent on dose and time-course of administration. Glucocorticoids do not appear to directly affect TSH gene transcription. In humans, TSH pulse frequency is maintained during glucocorticoid administration, while TSH pulse amplitude is reduced, suggesting a direct effect on TSH secretion. In addition to direct pituitary effects, it appears that glucocorticoids may have hypothalamic actions that affect TSH levels [ref]Shlomo Melmed. The Pituitary: Third Edition. 2011; page 183[/ref]. This hypothalamic actions of glucorticoids leads, whether directly or secondarily, to inhibition of the secretion of TRF [ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC297463/pdf/jcinvest00248-0144.pdf[/ref]. For example, dexamethasone 0.5 mg or greater per day, or hydrocortisone 100 mg or greater per day, have been shown to reduce serum TSH levels due to central suppression of TSH secretion [ref]Gregory A. Brent. Thyroid Function Testing. 2010; page 262[/ref]. Patients with Cushing’s syndrome (excessive cortisol) or patients receiving prolonged courses of glucocorticoids may have low serum T4 as well as TSH levels [ref]Shlomo Melmed. The Pituitary: Third Edition. 2011; page 183[/ref]. Although long-term high dose glucocorticoids or Cushing’s syndrome cortisol excess do not appear to cause clinically evident central hypothyroidism requiring thyroid hormone replacement [ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784889/[/ref]. Chronic administration of glucocorticoids usually results in compensatory mechanisms that prevent clinical hypothyroidism from developing [ref]Shlomo Melmed. The Pituitary: Third Edition. 2011; page 188[/ref]. An escape from glucocorticoid suppression was observed to occur in 2 or 3 days with the resumption of a near-normal thyroidal iodine release rate [ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC322682/pdf/jcinvest00226-0168.pdf[/ref]. TSH rebound was observed in high proportion of both hypothyroid (hypothyroid patients receiving thyroid replacement therapy) and euthyroid patients. During glucocorticoid treatment when TRF secretion is presumably impaired, it could accumulate intracellularly in the appropriate hypothalamic centers. Subsequently, this accumulated TRF might be rapidly released and therefore briefly stimulate TSH secretion through its known pituitary action [ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC297463/pdf/jcinvest00248-0144.pdf[/ref]. Furthermore, abnormalities in pituitary-thyroid function in patients Cushing’s syndrome disappear after the Cushing’s syndrome is treated or the exogenous glucocorticoid is discontinued [ref]Lewis E. Braverman, Robert D. Utiger. Werner & Ingbar’s the Thyroid: A Fundamental and Clinical Text. 2005; page 814[/ref].

Other effects of glucocorticoids on Thyroid function

Glucocorticoids are known to have a variety of effects on thyroid function [ref]Gregory A. Brent. Thyroid Function Testing. 2010; page 262[/ref]. In addition to their ability to inhibit TSH secretion, they can decrease serum thyroxine-binding globulin (TBG) concentrations, inhibit extrathyroidal conversion of T4 to triiodothyronine (T3), and cause an increase in the renal clearance of iodide [ref]Lewis E. Braverman, Robert D. Utiger. Werner & Ingbar’s the Thyroid: A Fundamental and Clinical Text. 2005; page 814[/ref]. Dexamethasone is the best-studied glucocorticoid [ref]Gregory A. Brent. Thyroid Function Testing. 2010; page 26[ref].

Clinically the effect of dexamethasone on thyroid hormone metabolism is useful in rapidly and markedly decreasing serum T3 concentrations in the preparation of hyperthyroid patients for thyroid surgery and its anti-inflammatory effect is useful in the subset of patients with amiodarone-induced hyperthyroidism due to destructive thyroiditis [ref]Lewis E. Braverman, David S. Cooper. Werner & Ingbar’s The Thyroid a Fundemental and Clinical Text. 2013;page 199[/ref]. Large doses of dexamethasone (4 mg/day), may cause a decrease in serum T3 concentrations within approximately 3 days in euthyroid and hyperthyroid patients and in hypothyroid patients receiving T4 therapy [ref]Lewis E. Braverman, David S. Cooper. Werner & Ingbar’s The Thyroid a Fundemental and Clinical Text. 2013;page 199[/ref]. Nonthyroidal production of T3 decreases by up to 30% due to inhibition of the T4 5′deiodinase and increased rT3 production [ref]Gregory A. Brent. Thyroid Function Testing. 2010; page 262[/ref]. Effects of dexamethasone, however, are not identical to those of propylthiouracil (PTU); dexamethasone increases serum rT3 levels by increasing rT3 production, whereas PTU increases rT3 by decreasing its plasma clearance. Dexamethasone and other glucocorticoids add to the effects of propylthiouracil.  Williams DE at al. studied the effects of administration of dexamethasone, 2 mg orally every 6 hr for 4 doses, on circulating thyroid hormone levels in hyperthyroid Graves’ disease patients and in normal subjects. Serum triiodothyronine (T3), thyroxine (T4) and thyroglobulin (Tg) fell significantly below baseline values within 24 to 48 h after the first dose of dexamethasone in hyperthyroid patients; the values returned to or toward baseline levels in the subsequent 5 to 6 days. Serum T3 fell transiently in normals but to a much smaller degree than in hyperthyroid patients; T4 and Tg showed no significant change. The fall in serum T3 without a change in serum T4 in normals suggested an effect of dexamethasone on peripheral conversion of T4 to T3. However, the markedly greater, more persistent drop in T3 in the hyperthyroid patients, as well as the associated drop in T4 and Tg, suggested an additional effect of dexamethasone administration on thyroid secretion in these patients [ref]http://www.ncbi.nlm.nih.gov/pubmed/1174132[/ref]. The decrease in T4 secretion can be explained either by a direct thyroidal effect or by decreasing thyroid-stimulating immunoglobulin production.

Adrenal axis dysfunction in the context of thyrotoxicosis of any degree is documented, and responds to exogenous steroid therapy [ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475282/[/ref]. If patients have a cortisol deficiency, glucocorticoid such as dexamethasone (Decadron) or hydrocortisone should be administered [ref]http://www.modernmedicine.com/modern-medicine/content/thyroid-storm-medical-emergency?page=full[/ref].

Long-term glucocorticoid therapy leads to a decrease in TBG concentration, probably due to decreased transcription, although cleavage of the protein also may play a role in increasing the clearance of TBG [ref]Gregory A. Brent. Thyroid Function Testing. 2010; page 262[/ref].

 

These effects of reducing T3, and, to a lesser degree, T4, can be utilized clinically to decrease thyroid hormone concentrations in thyrotoxic patients [ref]Gregory A. Brent. Thyroid Function Testing. 2010; page 262[/ref].

DOPAMIN, SOMATOSTATIN ANALOGS, REXINOIDS

Dopamine infusion, such as used in critical illness, and dopamine agonists like bromocriptine, have also been shown to suppress TSH secretion but have generally not been associated with a clinical syndrome of central hypothyroidism [ref]Edward Laws, Shereen Ezzat, Sylvia Asa, Linda Rio; Pituitary Disorders: Diagnosis and Management; chapter:etiology[/ref].

Dopamine exerts its effect on the hypothalamic-pituitary-thyroid axis through the activation of dopamine D2 receptors (D2R), but appears to have opposite effects on the hypothalamus and the pituitary thyrotrope. Dopamine infusions in healthy volunteers reduces TSH pulse amplitude without significantly altering TSH pulse frequency. Bromocryptine appears to have the same effect on TSH pulse amplitude and is likely occurring through the same D2R mechanism. Interestingly, dopamine stimulates release of TRH from rat hypothalamus through the same D2R, but the overall effect of dopamine is to lower serum TSH so this direct stimulatory effect on the hypothalamus cannot override the inhibitory effect of dopamine on the pituitar. Prolonged treatment with bromocryptine does not appear to cause central hypothyroidism since many patients treated with bromocryptine for macroprolactinomas actually have resolution of central hypothyroidism caused by the adenoma. Long-term use of a dopamine infusion may result in sustained reductions of TSH as well as reduced T4 and T3 secretion from the thyroid [ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784889/[/ref].

Studies using dopamine infusions in critically ill adults and neonates with the nonthyroidal illness (NTI) syndrome suggest that dopamine and NTI have and additive effect of HPT axis suppression. This may lead to iatrogenic central hypothyroidism in these patients. It is not clear whether treatment with levothyroxine is indicated in patients with NTI who are receiving dopamine infusions (21)[ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784889/[/ref].

Somatostatin analogs, such as octreotide and lanreotide, also have the potential to suppress TSH secretion from the pituitary. These analogs bind to somatostatin receptors on the the thyrotrope and inhibit TSH production and secretion and can lead to clinical hypothyroidism. In fact, somatostatin analogs have been used to treat TSH-producing pituitary adenomas and have been shown to reduce tumor size and inhibit TSH secretion [ref]Edward Laws, Shereen Ezzat, Sylvia Asa, Linda Rio; Pituitary Disorders: Diagnosis and Management; chapter:etiology[/ref]. They are also an effective medical therapy in patients with the symdrome of pituitary resistance to thyroid hormone [ref]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784889/[/ref]. Thyroid hormone inhibits thyrotropin (TSH) production and thyrotrope growth. Somatostatin has been implicated as a synergistic factor in the inhibition of thyrotrope function. Octreotide (Sandostatin LAR) required a euthyroid status to alter thyrotrope parameters. Physiological LT4 replacement therapy resulted in tumor shrinkage, while Sandostatin LAR alone had no effect. However, Sandostatin LAR combined with LT4 synergistically reduced final tumor weights to a greater degree [ref]http://www.ncbi.nlm.nih.gov/pubmed/10958305[/ref].

Rexinoids are another class of drugs that have been demonstrated to cause TSH suppression and clinically significant central hypothyroidism. Rexinoids are subclass of drugs known as retinoids (derived from vitamin A) that specifically interact with the retinoid X nuclear hormone receptor (RXR) and are known to play an important role in regulation of cellular proliferation and development. Consequently, rexinoids have been investigated as antineoplastic agents and the first rexinoid approved for clinical use was Bexarotene for cutaneous T cell lymphoma. Bexarotene is a potent inhibitor of TSH release as even a single dose can cause TSH suppression that persist at least 48 hours [ref]Edward Laws, Shereen Ezzat, Sylvia Asa, Linda Rio; Pituitary Disorders: Diagnosis and Management; chapter:etiology[/ref]. Treatment of patients with bexarotene-induced hypothyroidism commonly requires high doses of thyroid hormone for replacement therapy, often twice the typical doses used to treat more common etiologies of hypothyroidism. These observations suggest that bexarotene probably has two fundamental effects on thyroid function: to suppress TSH production and to increase thyroid hormone metabolic clearance [ref]http://www.ncbi.nlm.nih.gov/pubmed/12672276[/ref].