Ocena częstości występowania działań niepożądanych po zastosowaniu rekombinowanego TSH (rhTSH)

Introduction

In recent years the frequency of differentiated thyroid cancer (DTC) diagnosis has significantly increased. This was influenced by, among other things, widespread access to ultrasound examination of the thyroid and more frequent verification concerning visualised cytological lesions [1, 2]. The majority of new cases of DTC are characterised by a low degree of clinical advancement and a very promising prognosis for a 5-year survival of 97.3% [3]. Applicable recommendations advocating a lifetime of oncology supervision, with the ever-increasing number of new cases, mean that the number of patients for diagnostic control increases significantly every year. Sensitivity check-ups increase significantly if you perform them employing thyroid-stimulating hormone (TSH) stimulation, which until recently could only be achieved through the discontinuation of thyroxine use. However, interruption of the treatment with thyroxine is usually associated with severe hypothyroidism and deterioration in the quality of life, causing exacerbation of comorbid conditions and the inability to maintain employment.
The introduction of recombinant human thyroid stimulating hormone (rhTSH), in 2000, is considered to be a landmark event in the treatment and monitoring of patients with DTC. rhTSH is a glycoprotein consisting of two non-covalently associated sub-units. The  sub-unit is composed by 92 amino acids containing two N-glycosylation sites, and the β sub-unit by 118 amino acids containing one N-glycosylation site [4]. This structure of rhTSH presents its biochemical properties as comparable to the endogenous TSH. Thyroid-stimulating hormone biological activity is dependent on the degree of saturation of the components of the carbohydrate sialic acid residues. To continue, in the state of over hypothyroidism the degree of saturation is greater than in steady-state hormone conditions; therefore, it results in slower biodegradation of TSH, giving similar chemical characteristics as the ones exhibited by rhTSH. rhTSH when binding to the receptor for TSH on thyroid follicular cells or DTC cells leads to the activation of sodium iodine symporter (NIS), and an increased uptake of ¹³¹I as well as production of thyroglobulin.

Aim of the research

The widespread use of rhTSH has significantly improved patients’ comfort with DTC during the treatment and diagnostic follow-up. However, parenteral use of the protein formulation can cause various side effects. The aim of the study was the evaluation of the tolerability and adverse side effects associated with the administration of rhTSH in preparation for medical follow-ups for patients with DTC.

Material and methods

The study was conducted at the Department of Endocrinology of Holycross Cancer Centre in Kielce on patients with DTC, after a complete thyroidectomy and adjuvant therapy of ¹³¹I, who reported for the planned follow-up diagnostic controls. The study group consisted of 113 patients (average age: 53.7 ±14.8 years), including 95 (84%) women and 18 (16%) men. The test was performed in the period from January to May 2015.
The research tool was an original questionnaire concerning the occurrence of adverse side effects resulting from using rhTSH, such us hot flushes, headache, weakness, palpitations, musculoskeletal pain, rash, discomfort after administration, diarrhoea, dizziness, nausea, vomiting, and others (high blood pressure, swelling of the lower limbs, dry skin, abdominal bloating, and difficulty falling asleep). In addition, the questionnaire contained the request to make a comparison of tolerance regarding endogenous TSH stimulation with the use of rhTSH (for patients who underwent check-ups employing both methods for stimulating TSH). rhTSH was administered according to the recommended schedule, involving two doses of 0.9 mg intramuscularly at 24-hour intervals. An anonymous survey was carried out 24 h after the second injection. Patients were interviewed and examined before rhTSH administration. The study involved patients who, prior to the administration of rhTSH, did not exhibit the symptoms listed in the questionnaire. The study was approved by local Ethics Committee.

Results

Seventy-five (66.4%) patients reported adverse side effects relating to administered treatment (Table 1). Amongst the respondents, the most commonly reported side effects following the use of rhTSH included: hot flushes, 32 (28.3%) patients; headache, 30 (26.5%) patients; weakness, 19 (16.8%) patients; and palpitations, 13 (11.5%) patients. What is more, women most often complained of the following: hot flushes, 28 (29.4%) women; headache, 25 (26.3%) women; and asthenia, 13 (13.7%) women. In contrast, men with the highest frequency enumerated the following: weakness, 6 (33.3%) men; headache, 5 (27.7%) men; and hot flushes, 4 (22.2%) men. Taking into consideration particular surveyed patients, the reported symptoms were summed up: 37 (32.7%) patients reported one side effect, 23 (20.3%) patients reported two side effects, while 15 (13.3%) patients reported three or more. To continue, 38 (33.6%) patients did not list any side effects. The side effects other than those listed in the questionnaire, such as high blood pressure, swelling of the lower limbs, dry skin, abdominal bloating. and difficulty falling asleep, after the use of rhTSH, were noticed by 8 (7.1%) patients.
Among the respondents, 27 (24%) patients had previous control diagnosis performed under thyroid hormone withdrawal. As far as those two methods are concerned, the majority of patients (21 (77.8%)) indicated the administration of rhTSH as the preferred method; one patient chose (3.7%) stimulation of endogenous TSH, while 5 (18.5%) patients did not experience any difference between implementing compared methods.

Discussion

In the frequency of adverse side effects described in the Summary of Product Characteristics, Thyrogen [4] differs from the results of a survey conducted among the patients of our Endocrinology Department. The data gathered by the manufacturer came from 481 patients with six prospective studies and the reported cases of adverse reactions after releasing the product. They show that the side effects seen as very common are nausea (12%) and headache (7%). In their study, Menzel et al. observed 2 (3.1%) cases of headaches accompanied by nausea [5]. Additionally, Bryan et al. described headaches (9.2%), nausea (6.1%), and weakness (3.5%) [6] as the most common side effects. The results of the above-mentioned work, compared to the study of our patients, show a different distribution of reported discomfort and their reduced incidence. Differences may result from individual sensitivity and tolerance of patients undergoing diagnostic controls. Furthermore, perceived symptoms, although appearing often, were usually short term and not harmful to patients. Their severities in all cases were minor and never resulted in the need for medical intervention.
Moreover, 21 of 27 patients (77.8%) who had earlier undergone diagnostic control performed with the endogenous TSH stimulation, comparing the two methods, preferred the administration of rhTSH. Similar results were presented by Dietlein et al., where as much as 97% of respondents chose rhTSH [7].
The benefits of using rhTSH are multidimensional. First of all, it allows avoidance of the symptoms associated with hypothyroidism, such as sluggishness, sleepiness, swelling, weight gain, coldness, and constipation, and therefore it improves the quality of life of the patients, as pointed out in the works of Lee et al., Szymonek et al., and Taïeb et al. [8–10]. This is of particular importance for the elderly, with a number of cardiac workload, wherein withdrawal of thyroxine could lead to symptoms of heart failure and ischaemic heart disease. Moreover, in the conditions of hypothyroidism impaired renal function and a reduction in glomerular filtration rate occur, which lead to slower removal of ¹³¹I. Therefore, the maintenance of normal creatinine clearance through the use of rhTSH reduces the toxicity of ¹³¹I, decreasing the time of its expulsion, as highlighted by Luster et al. and Pacini et al. [11, 12]. It is worth noting that the use of rhTSH shortens the period of inability to work with patients undergoing diagnostic standard control as well as their relatives [7, 10], positively affecting the socioeconomic status of the society in which the patient functions [13, 14].
There is no doubt that the introduction of rhTSH was a major breakthrough in the treatment of patients with DTC. It allows the same results in ¹³¹I treatment and diagnostics control that is obtained during endogenous TSH stimulation [6, 15], without exposing the patients to severe symptoms of hypothyroidism. Although the observed adverse side effects associated with the use of rhTSH were quite common, their severity was minor and short term, which does not detract from the advantages of rhTSH and does not affect the limitation of its usage.

Conflict of interest

The authors declare no conflict of interest.

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Address for correspondence:

Agnieszka Suligowska
Department of Endocrinology
Holy Cross Cancer Center
ul. Artwińskiego 3, 25-734 Kielce, Poland
Phone: +48 507 756 268
E-mail: a.suligowska@wp.pl