![]() ![]() However, a drawback of this type of study is that different points in time are compared with one another, and thus results may be influenced by fluctuations that occur within an individual over time ( 8). In a N-of-1 trial, each individual receives several treatments in a multiple crossover design, allowing determination of the best intervention for an individual patient. As a promising strategy toward personalized medicine, N-of-1 studies have been proposed as a design to determine the best treatment for individual patients ( 7). As it is becoming increasingly clear that patients are a heterogeneous group, in current practice and guidelines, there is increasing recognition of the need to individualize management of a patient’s disease. Consequently, evidence on how such vulnerable patients respond to treatment is lacking ( 6). Especially vulnerable patients, which include older patients with comorbidities and polypharmacy, are underrepresented in clinical trials. Medical practice and guidelines have been traditionally based on the “average” patient and how the “average” patient responds to various treatments, as informed by randomized clinical trials. Independent of time, within-person variation in TSH is also caused by effects of among others medication, illness, TPO antibody positivity, and iodine intake. Furthermore, TSH levels change with age, with in general higher levels with increasing age ( 5). Within-person variation in TSH levels is caused by rhythms ranging from minutes to years, including pulsatile secretion, circadian rhythm, monthly changes, and seasonality ( 3, 4). In the current review we focus on biological variation, in particular on within-person biological variation. Variation in TSH levels can be caused by biological and non-biological variation, the latter includes pre-analytical and analytical variations, and has been reviewed by others ( 3). In this review, we discuss the magnitude of the variation in TSH levels and the potential sources (internal and external) that may contribute. Consequently, the influence of variation in TSH levels on diagnosis and study outcomes might be underestimated. However, the magnitude and the importance of variation in TSH levels within a person over time are not completely clear yet. Indeed, it is known that TSH levels can vary over time within a person.Īmong other, TSH levels are influenced by drugs, acute and chronic illness, undernutrition, the biological clock, seasonality, pregnancy, and by other hormones, e.g., cortisol. By adapting the level of TSH, circulating levels of thyroxine (T4) and partly triiodothyronine (T3) are controlled and kept within a normal range ( 1, 2). Thyroid stimulating hormone (TSH) is a key player in this system, which is designed to respond quickly to changes in the environment aiming to maintain homeostasis in the human body. ![]() Hormones of the hypothalamus-pituitary-thyroid (HPT) axis are part of a feedforward and feedback system. In clinical practice, the season for thyroid testing can influence a patient’s test result and it occurs frequently that subclinical hypothyroid patients normalize to euthyroid levels over time without intervention. The observed increase in TSH level with ageing can be explained at a population level and at an organism level. Such cues include the biological clock, environmental temperature, and length of day. Potential underlying biological mechanisms of within-person variation in TSH levels can be safely concluded from the ability of TSH to respond quickly to changes in cues from the internal or external environment in order to maintain homeostasis. Other factors that affect TSH levels include thyroid peroxidase (TPO)-antibody positivity, BMI, obesity, smoking, critical illness, and many xenobiotics, including environmental pollutants and drugs. Furthermore, elevated TSH levels have been observed with ageing. ![]() Since TSH is secreted in a pulsatile manner, TSH levels also fluctuate over minutes. Another source of within-person variation in TSH levels is seasonality, with generally higher levels during the cold winter months. In euthyroid individuals, the circadian rhythm, with a nocturnal surge around 02:00–04:00 h and a nadir during daytime has the greatest impact on variations in serum TSH concentrations. ![]()
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