Thyroid hormone therapy or minimally invasive treatments for benign thyroid nodules

Review question

What are the effects of thyroid hormone treatment (levothyroxine) and minimally invasive procedures on benign thyroid nodules?


Nodules (lumps) within the thyroid gland are common and usually benign. They are more frequent in women, the elderly and in iodine-deficient areas. Thyroid nodules are often observed as an incidental finding in the course of ultrasonography of the thyroid, nodules of more than 1 cm in size are usually detected by palpation of the thyroid gland during a physical examination. Thyroid nodules may occur as a single nodule or as multiple nodules and may contain fluid (cyst). About 5 in 100 palpable thyroid nodules have a risk of becoming malignant (thyroid cancer). Thyroid nodules are often treated with thyroid hormones in order to reduce the size of the nodule. If thyroid nodules cause problems such as pressure symptoms or cosmetic complaints, surgery may be performed. Other therapies try to destroy the thyroid nodule by means of minimally invasive procedures (techniques which are less invasive than open surgery) and are usually performed on an outpatient basis.

Study characteristics

We identified 31 randomised controlled trials for this systematic review. Altogether 2952 participants were allocated to the various intervention and comparator groups. In total, 16 studies lasting six months to five years investigated the effects of levothyroxine therapy. Eight studies lasting 1 to 12 months investigated the efficacy of injections, mostly of ethanol, into thyroid nodules from which fluid had been slowly removed. Laser therapy (one or up to three sessions) was applied to nodules in five studies lasting 6 to 12 months. Two studies investigated the application of one or two radiofrequency (high-frequency radiowaves) sessions over 6 to 12 months.

Key results

None of the interventions investigated death from any cause, the development of thyroid cancer or health-related quality of life. Nodule volume reductions were achieved by all therapies; however, the clinical relevance of this outcome is doubtful. Minimally invasive treatments resulted in improvements in pressure symptoms and cosmetic complaints. Some side effects such as light-to-moderate pain were observed after minimally invasive procedures.

Quality of the evidence

Most study results were of overall low quality, mainly because only a few people were investigated, findings were imprecise or measurements were prone to bias. Future studies should investigate more patient-important outcomes, such as health-related quality of life, and should compare minimally invasive therapies with surgery. Studies with longer follow-up periods are needed to provide evidence on the development of thyroid cancer, death from any cause and long-term side effects of treatments.

Currentness of data

This evidence is up to date as of April 2014.

Authors' conclusions: 

No study evaluated all-cause mortality, health-related quality of life or provided systematic data on the development of thyroid cancer. Longest follow-up was five years and median follow-up was 12 months. Nodule volume reductions were achieved by PEI, LP and RF, and to a lesser extent, by LT4. However, the clinical relevance of this outcome measure is doubtful. PEI, LP and RF led to improvements in pressure symptoms and cosmetic complaints. Adverse events such as light-to-moderate periprocedural pain were seen after PEI, LP and RF. Future studies should focus on patient-important outcome measures, especially health-related quality of life, and compare minimally invasive procedures with surgery. RCTs with follow-up periods of several years and good-quality observational studies are needed to provide evidence on the development of thyroid cancer, all-cause mortality and long-term adverse events.

Read the full abstract...

Thyroid nodules (TN) are common in the adult population. Some physicians use suppressive levothyroxine (LT4) therapy to achieve a reduction in the number and volume of TN. In addition, minimally invasive treatments, such as percutaneous ethanol injection (PEI) sclerotherapy, laser photocoagulation (LP), and microwave (MW), radiofrequency (RF) and high-intensity focused ultrasound (HIFU) ablation, have been proposed, especially for pressure symptoms and cosmetic complaints, as an alternative to surgery. However, the risk to benefit ratio of all treatments for benign TN is currently unknown.


To assess the effects of LT4 or minimally invasive therapies (PEI, LP, and RF/HIFU/MW ablation) on benign TN.

Search strategy: 

We identified studies from computerised searches of The Cochrane Library, MEDLINE, EMBASE and LILACS (all performed up to April 2014). We also searched trial registers, examined reference lists of included randomised controlled trials (RCTs) and systematic reviews, and contacted study authors.

Selection criteria: 

We included studies if they were RCTs of LT4, PEI, LP, RF, HIFU or MW therapy in participants with an established diagnosis of benign TN. We excluded trials investigating the prevention of recurrence of thyroid disease after surgery, irradiation or treatment with radioiodine.

Data collection and analysis: 

Two review authors independently extracted data, assessed studies for risk of bias and evaluated overall study quality utilising the GRADE instrument. We assessed the statistical heterogeneity of included studies by visually inspecting forest plots and quantifying the diversity using the I²statistic. We synthesised data using random-effects model meta-analysis or descriptive analysis, as appropriate.

Main results: 

Thirty-one studies randomised 2952 outpatients to investigate the effects of different therapies on benign TN. Studies on LT4, PEI, LP and RF ablation therapy randomised 2083, 607, 192 and 70 participants, respectively. We found no RCTs of HIFU or MW ablation therapy in benign TN. The duration of treatment varied according to the applied therapies: up to five years for LT4 and one to three PEI ablations, one to three LP sessions and one or two RF sessions. Median follow-up was 12 months for LT4 and six months for minimally invasive therapies. Evidence was of low-to-moderate quality, and risk of performance and detection bias for subjective outcomes was high in most trials.

No study evaluated all-cause mortality or health-related quality of life. Only one LT4 study provided some data on the development of thyroid cancer, reporting no abnormal cytological findings. One LP study provided limited information on costs of treatment.

LT4 compared with no treatment or placebo was associated with a nodule volume reduction of 50% or more in 16% compared with 10% of participants after 6 to 24 months of follow-up (risk ratio (RR) 1.57 (95% confidence interval (CI) 1.04 to 2.38); P = 0.03; 958 participants; 10 studies; moderate-quality evidence). Pressure symptoms or cosmetic complaints were not investigated in LT4 studies. LT4 therapy was generally well tolerated: three studies provided quantitative data on signs and symptoms of hyperthyroidism, which were observed in 25% of LT4-treated versus 7% of placebo-treated participants at 12 to 18 months of follow-up (269 participants; 3 trials; low-quality evidence).

PEI compared with cyst aspiration only was associated with a nodule volume reduction of 50% or more in 83% compared with 44% of participants after 1 to 24 months of follow-up (RR 1.83 (95% CI 1.32 to 2.54); P = 0.0003; 105 participants; 3 studies; low-quality evidence). Improvements in neck compression symptoms after 6 to 12 months of follow-up were seen in 78% of participants receiving PEI versus 38% of those in comparator groups. No reliable summary effect estimate could be established, RR ranged from 1.0 to 3.06 in favour of PEI (370 participants; 3 trials; low-quality evidence). In all trials, participants experienced periprocedural cervical tenderness and light-to-moderate pain usually lasting from minutes to several hours. As a result of the PEI procedure, 26% of participants reported slight-to-moderate pain compared with 12% of those receiving cyst aspiration only (RR 1.78 (95% CI 0.62 to 5.12); P = 0.28; 104 participants; 3 studies; low-quality evidence).

One study comparing LP with LT4 showed a nodule volume reduction of 50% or more in favour of LP after 12 months of follow-up in 33% of LP participants versus 0% of LT4 participants, respectively (62 participants; 1 trial; low-quality evidence). A total of 82% of LP-treated versus 0% of untreated participants showed improvements in pressure symptoms after 6 to 12 months of follow-up (RR 26.65 (95% CI 5.47 to 129.72); P < 0.0001; 92 participants; 3 trials; low-quality evidence). Around 20% of LP-treated participants reported light-to-moderate cervical pain lasting 48 hours or more (97 participants; 3 trials; low-quality evidence).

One trial with 40 participants, comparing RF with no treatment, resulted in a mean nodule volume reduction of 76% in the RF group compared with 0% of those in the no-treatment group at six months of follow-up (low-quality evidence). These RF-treated participants had fewer pressure symptoms and cosmetic complaints after 12 months of follow-up compared with untreated participants (a 2.8 decrease versus a 1.1 increase on a six-point scale, respectively, with higher values indicating more severe symptoms; low-quality evidence). All participants complained of pain and discomfort during RF, which disappeared when the energy was reduced or turned off (low-quality evidence).