Effects of commonly prescribed nonsteroidal anti-inflammatory drugs on thyroid hormone measurements

doi:10.1016/0002-9343(94)90148-1

The American Journal of Medicine

Volume 96, Issue 3, March 1994, Pages 235-238

https://doi.org/10.1016/0002-9343(94)90148-1 Get rights and content

Abstract

purpose: To assess the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on thyroid function tests.

patients and methods: Eighty-nine patients receiving NSAIDs and 22 control subjects not taking NSAIDs were studied in a cross-sectional survey at Veterans Affairs and University hospitals. Measurements of serum thyroxine (T₄), free T₄ index, triiodothyronine (T₃), and thyrotropin (thyroid-stimulating hormone [TSH]) were obtained for all subjects.

results: Serum T₄ measurements were lowered only in salsalate-treated patients, while serum T₃ was depressed in patients receiving salsalate, diclofenac sodium, and naproxen. Serum T₄ and T₃ were unchanged in patients treated with diflunisal, ibuprofen, indomethacin, piroxicam, or sulindac. Serum TSH was normal in all subjects.

conclusions: Several NSAIDs can lower serum thyroid hormone concentrations, principally by interfering with the binding of T₄ and T₃ to serum carrier proteins; patients taking these drugs remain euthyroid. Awareness of these interactions may prevent unnecessary diagnostic or therapeutic interventions.

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Cited by (37)

Naproxen affects multiple organs in fish but is still an environmentally better alternative to diclofenac
2020, Aquatic Toxicology
Citation Excerpt :
The authors motivate their study by referring to Bishnoi et al. (1994), a non-randomized clinical study in humans with NSAID-treated disease. Bishnoi et al. (1994) provide circumstantial, inconclusive evidence for effects of NSAIDs on the thyroid system in humans. Samuels et al. (2003), on the other hand, performed a randomized clinical study in healthy humans and found no evidence that naproxen affect thyroid hormone levels.
The presence of diclofenac in the aquatic environment and the risks for aquatic wildlife, especially fish, have been raised in several studies. One way to manage risks without enforcing improved wastewater treatment would be to substitute diclofenac (when suitable from a clinical perspective) with another non-steroidal anti-inflammatory drug (NSAID) associated with less environmental risk. While there are many ecotoxicity-studies of different NSAIDs, they vary extensively in set-up, species studied, endpoints and reporting format, making direct comparisons difficult. We previously published a comprehensive study on the effects of diclofenac in the three-spined stickleback (Gasterosteus aculeatus). Our present aim was to generate relevant effect data for another NSAID (naproxen) using a very similar setup, which also allowed direct comparisons with diclofenac regarding hazards and risks. Sticklebacks were therefore exposed to naproxen in flow-through systems for 27 days. Triplicate aquaria with 20 fish per aquarium were used for each concentration (0, 18, 70, 299 or 1232 μg/L). We investigated bioconcentration, hepatic gene expression, jaw lesions, kidney and liver histology. On day 21, mortalities in the highest exposure concentration group unexpectedly reached ≥ 25 % in all three replicate aquaria, leading us to terminate and sample that group the same day. On the last day (day 27), the mortality was also significantly increased in the second highest exposure concentration group. Increased renal hematopoietic hyperplasia was observed in fish exposed to 299 and 1232 μg/L. This represents considerably higher concentrations than those expected in surface waters as a result of naproxen use. Such effects were observed already at 4.6 μg/L in the experiment with diclofenac (lowest tested concentration). Similar to the responses to diclofenac, a concentration-dependent increase in both relative hepatic gene expression of c7 (complement component 7) and jaw lesions were observed, again at concentrations considerably higher than expected in surface waters. Naproxen bioconcentrated less than diclofenac, in line with the observed effect data. An analysis of recent sales data and reported concentrations in treated sewage effluent in Sweden suggest that despite higher dosages used for naproxen, a complete substitution would only be expected to double naproxen emissions. In summary, naproxen and diclofenac produce highly similar effects in fish but the environmental hazards and risks are clearly lower for naproxen. Hence, if there are concerns for environmental risks to fish with diclofenac, a substitution would be advisable when naproxen presents an adequate alternative from a clinical point-of-view.
Long-term exposure to the non-steroidal anti-inflammatory drug (NSAID)naproxen causes thyroid disruption in zebrafish at environmentally relevant concentrations
2019, Science of the Total Environment
Citation Excerpt :
Although numerous xenobiotics have been shown to have a thyroid-disrupting effect on fish, the current understanding of the effects of NSAIDs on aquatic organisms is limited. However, clinical studies have reported that several NSAIDs influence thyroid homeostasis in humans (Bishnoi et al., 1994), and recent in silico research indicated that NSAIDs have the potential to bind to thyroid receptors (Zloh et al., 2016). Aquatic vertebrates have enzymes and receptors of the thyroid system that are very similar to those of humans (Evans, 1993; Huggett et al., 2003).
The presence of trace levels of pharmaceuticals is an emerging issue impacting the aquatic ecosystem. Naproxen (NPX) is a nonsteroidal anti-inflammatory drug (NSAID) that has been frequently detected in aquatic environments worldwide. Recently, concerns regarding endocrine disruption by NSAIDs have increased; however, their effects on the thyroid system have yet to be understood. In this study, zebrafish were utilized to evaluate the thyroid-disrupting effects of NPX. After a 60-day exposure to various concentrations of NPX (0.1, 1, 10 and 100 μg/L), the body length and weight of the zebrafish were significantly decreased. The decrease of cytochrome P450 gene expression and enzyme activity might inhibit the metabolism of NPX, which might result in the significant bioconcentration in zebrafish. Thyroid hormone (TH) analysis showed that both triiodothyronine (T3) and thyroxine (T4) levels were substantially decreased. Gene transcription expressions along the hypothalamic-pituitary-thyroid (HPT) axis were also markedly affected. Significant downregulation of dio1, dio2, nis, nkx2.1, pax8, tg, tpo, trβ and ttr levels, along with the stimulation of the tshβ gene, were also observed in exposed fish compared to controls. Western blot analysis indicated that expression of the TTR protein was significantly decreased, which coincides with the results of the gene expression analysis. Collectively, our observations show that NPX increases the risk of bioconcentration and thyroid disruption in zebrafish. Given the continued increasing consumption and emission of pharmaceuticals, thyroid disruption should be considered when assessing the aquatic risk of long-term exposure to environmentally relevant concentrations of pharmaceuticals.
Evidence that diclofenac and celecoxib are thyroid hormone receptor beta antagonists
2016, Life Sciences
Citation Excerpt :
As proof of concept we chose the potential interaction between celecoxib and diclofenac with TRβ, and show for the first time that both celecoxib and diclofenac have the potential to directly bind to and inactivate TRβ signalling. Previous reports have indicated a link between NSAIDs and the lowering of serum thyroid hormone concentrations [29], although this is the first report that indicates a potential for diclofenac and celecoxib to interfere with the TRβ receptor at physiological concentrations. Alterations in thyroid hormone activity is linked to cardiac function, in particular hypothyroidism leads to impaired systolic and diastolic function [30], as well as increased vascular stiffness and endothelial dysfunction [31], symptoms often associated with NSAID usage.
Long term use of NSAIDs is linked to side effects such as gastric bleeding and myocardial infarction.
Use of in silico methods and pharmacology to investigate the potential for NSAIDs diclofenac, celecoxib and naproxen to bind to nuclear receptors.
In silico screening predicted that both diclofenac and celecoxib has the potential to bind to a number of different nuclear receptors; docking analysis confirmed a theoretical ability for diclofenac and celecoxib but not naproxen to bind to TRβ.
Results from TRβ luciferase reporter assays confirmed that both diclofenac and celecoxib display TRβ antagonistic properties; celecoxib, IC₅₀ 3.6 × 10^− 6 M, and diclofenac IC₅₀ 5.3 × 10^− 6 M, comparable to the TRβ antagonist MLS (IC₅₀ 3.1 × 10^− 6 M). In contrast naproxen, a cardio-sparing NSAID, lacked TRβ antagonist effects. In order to determine the effects of NSAIDs in whole organ in vitro, we used isometric wire myography to measure the changes to Triiodothyronine (T3) induced vasodilation of rat mesenteric arteries. Incubation of arteries in the presence of the TRβ antagonist MLS000389544 (10^− 5 M), as well as diclofenac (10^− 5 M) and celecoxib (10^− 5 M) but not naproxen significantly inhibited T3 induced vasodilation compared to controls.
These results highlight the benefits of computational chemistry methods used to retrospectively analyse well known drugs for side effects. Using in silico and in vitro methods we have shown that both celecoxib and diclofenac but not naproxen exhibit off-target TRβ antagonist behaviour, which may be linked to their detrimental side effects.
Thyroid Function Testing
2015, Endocrinology: Adult and Pediatric
Hypothyroidism
2015, Canine and Feline Endocrinology: Fourth Edition
net Non thyroidal illnesses (NTIS)
2010, Annales d'Endocrinologie
Toutes les maladies générales peuvent s’accompagner de perturbations des concentrations plasmatiques des hormones thyroïdiennes et de la TSH. Ces dyshormonémies des affections non thyroïdiennes résultent de mécanismes complexes qui associent effets de certains médicaments, de cytokines, de facteurs endocriniens et nutritionnels à tous les niveaux de l’axe thyréotrope, de l’hypothalamus au transport cellulaire des hormones thyroïdiennes et à la liaison avec leur récepteur nucléaire. Les profils observés dépendent de la maladie causale et de sa sévérité. Trente-cinq ans après leur description initiale, la signification physiopathologique des ces anomalies reste controversée : processus d’adaptation visant à protéger l’organisme d’un état d’hypercatabolisme en cas d’agression, ou défaillance thyroïdienne élément d’un cercle vicieux entretenant l’incapacité de cet organisme à faire face à un stress majeur ? Le débat ne se limite pas à une question théorique car dans le premier cas ce processus doit être respecté, dans l’autre une substitution thyroïdienne serait justifiée. Les essais cliniques, peu nombreux, n’ont pour l’instant montré aucun bénéfice d’une substitution. Mais les situations cliniques, le choix de la molécule, de la dose et de la voie d’administration n’étaient pas forcément les plus pertinents. Sur un plan théorique, dans certains états prolongés d’agression, une stimulation de l’axe thyréotrope par le TRH serait susceptible d’apporter un bénéfice clinique. En attendant que la démonstration par des essais cliniques en soit faite, la question risque de rester sans réponse pendant quelques années encore.
Abnormalities in the circulating levels of thyroid hormones, without evidence of coexisting thyroid or pituitary gland disease can be observed in all general diseases. These nonthyroidal illnesses (NTIS) are the result of complex mechanisms that combine the effect of some drugs, cytokines, nutritional and endocrine factors at all levels of the thyrotropic axis, from the hypothalamus to the cellular transporters and nuclear receptors of thyroid hormones. The patterns of NTIS depend on the underlying disease and its severity. Thirtyfive years after the initial description, the pathophysiological significance of these anomalies remains controversial. One of the dilemma of NTIS is whether the hormone responses represent an adaptive and normal, physiologic response to conserve energy and protect against hypercatabolism in case of aggression, or whether it is a maladaptive response contributing to a worsening of the disease. This debate is not just a theoretical question, because in the first case the process must be respected, in the other case a vigorous treatment to restore circulating thyroid hormone levels is justified. There have been very few clinical studies designed to address whether the substitution with thyroid hormone is advantageous, and there is at current time no permissive evidence for the use of thyroid hormone replacement in patients with NTIS. But the clinical context, the choice of the molecule or of the dose and the way of administration were not necessarily the most relevant. Theoretically, stimulation of thyreotrope axis used a continuous infusion of TRH seems to provide clinical benefit. With the expectation that randomized clinical trials will provide demonstration of NTIS treatment efficiency, the question might remain unanswered for several more years.

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: Supported by funds from the Research Service of the Department of Veterans Affairs.

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Effects of commonly prescribed nonsteroidal anti-inflammatory drugs on thyroid hormone measurements

Abstract

Am J Med Sci

J Pharm Sci

Clin Chim Acta

Drug and fatty acid effects on serum thyroid hormone binding

J Clin Endocrinol Metab

Drug competition for thyroxine binding to transthyretin (pre-albumin): comparison with the effects on thyroxine-binding globulin

J Clin Endocrinol Metab

Misleading thyroid function tests and several homeostatic abnormalities induced by Disalcid therapy

J Am Geriatr Soc

Salsalate alters thyroid function test results

Arthritis Rheum