From how radioiodine therapy for Graves’ disease impacts cancer occurrence and the potential usefulness of pharmacologic treatment for benign thyroid nodules to how a minimally invasive procedure could be the preferred treatment option, recent studies from The Journal of Clinical Endocrinology & Metabolism further demonstrate how endocrine science is benefiting patients around the world.
As Thyroid Awareness Month begins, three studies offer new insights into the management of common thyroid conditions, from the promise of noninvasive drug therapies to reassurance about the safety of established treatments.
The management of thyroid nodules and thyroid dysfunction represents a substantial clinical challenge given the high prevalence of these conditions in clinical practice. Three recent studies published in The Journal of Clinical Endocrinology & Metabolism address complementary aspects of this clinical backdrop. Two studies sought to answer similar questions about less-invasive treatment for benign thyroid nodules (BTNs), which have an extremely high prevalence.
BTNs are found in about half of adults on autopsy and in up to two-thirds of patients when evaluated with high-frequency ultrasound. While most BTNs can be safely observed, some affect patient quality of life, and treatments that balance patient preferences with the benign nature of the disease and minimize procedural risk represent an important unmet clinical need. The third study looks at the purported risk of developing thyroid cancer after treatment for Graves disease.
Together, these studies shed light on both established and emerging therapeutic strategies for thyroid disorders, while addressing fundamental safety concerns that will influence clinical decision-making and patient counseling.
Pharmacologic Treatment for Benign Thyroid Nodules
In “Drug Repurposing for Reducing the Size of Benign Thyroid Nodules: A Systematic 1 Review,” Cristian Soto Jacome, MD, and Juan P. Brito, MD, MSc, both of the Mayo Clinic in Rochester, Minn., and team cite a gap in available treatments as the impetus for their investigation. When treatment for BTNs becomes desirable, current treatment options are either invasive or minimally invasive.
“This project grew out of a very common clinical tension in thyroid care. Surgery or ablation are effective but invasive and not always aligned with patient preferences for a benign condition,” explains Brito. “At the same time, a number of small studies have explored whether existing medications used for other indications might influence BTN size.” These heterogenous studies, however, involved different drug classes, populations, and study designs, and they often reported mixed or “difficult-to-interpret” results. Without a clear synthesis of the literature, whether any of these findings were meaningful or whether they justified further investigation was unclear. “We undertook this systematic review to consolidate the available evidence, assess whether there was any consistent signal across studies, and identify where the real gaps in knowledge remain,” says Brito.
For the subset of patients with BTNs experiencing a negative impact on their quality of life, treatment becomes important when BTNs interfere with their daily comfort (e.g., by causing neck pressure, discomfort, or swallowing difficulties), body image (e.g., from visible neck asymmetry), or peace of mind (e.g., when progressive nodule growth raises concern about future symptoms or the need for surgery). Even when nodules are asymptomatic, repeated imaging, biopsies, and follow-up visits can cause patient anxiety and distress despite reassurance that the condition is benign. “Because current effective treatments are invasive,” says Brito, “identifying safe, noninvasive ways to reduce nodule size could meaningfully improve quality of life by relieving symptoms, reducing anxiety, and potentially avoiding procedures in patients with otherwise benign disease.”
Twenty studies met the team’s inclusion criteria for their systematic review: six randomized controlled trials (RCTs), six prospective cohorts, three retrospective observational studies, three case reports, one cross-sectional study, and one preclinical study. “We did not start with a predefined list of medications or specific drug classes,” explains Brito. “Instead, our approach was intentionally broad and driven by what has already been studied in the literature. We searched systematically for any pharmacologic agent that had been evaluated for an effect on BTNs, regardless of the original indication of the drug.”
Overall, metformin presents the strongest case for pharmacologic management of BTN, particularly when metabolic dysfunction coexists, but this finding comes with caveats. It was the most extensively studied drug (n=7), with five reports — including two RCTs — showing statistically meaningful volume reductions in dominant nodules. One prospective trial noted diameter reduction without statistical significance, and one RCT found no effect. Results for statins (n=4) and somatostatin analogues (n=4) were variable. Limited evidence from isolated studies suggests possible efficacy for myo-inositol-selenium combinations, botanical formulations, and immune checkpoint inhibitors.
As the authors are quick to point out, however, the evidence base remains incomplete and inconsistent, necessitating rigorous, adequately powered trials before clinical implementation can be recommended.
To dig into metformin’s particular efficacy in the setting of metabolic dysfunction a bit, observational studies have reported an association between obesity, insulin resistance, or other metabolic conditions and the presence of BTNs. But, says, Brito: “These findings need to be interpreted with caution. One important consideration is detection bias. Patients with obesity or metabolic diseases are often more engaged with the healthcare system and may undergo more frequent laboratory testing and thyroid imaging, particularly ultrasound. This increased surveillance can create an apparent association between metabolic conditions and thyroid nodules that does not necessarily reflect a true biological relationship.” He further explains that plausible biological mechanisms nevertheless link metabolic dysfunction and thyroid tissue growth, and the repeated observation of this association across studies suggests a genuine signal may be present. The current evidence supports an association rather than a causal relationship, however.
“From a clinical standpoint, this review does not support the routine use of metformin or any other medication as a treatment to shrink [benign thyroid nodules]. Although some studies, particularly those evaluating metformin, reported statistically significant changes in nodule size, the evidence is heterogeneous, often based on small samples, and in many cases the magnitude of change is unlikely to be clinically meaningful. As a result, these findings should not be interpreted as practice changing.” — Juan P. Brito, MD, MSc, Professor of Medicine, Mayo Clinic in Rochester, Minn.
Those caveats mentioned above? “From a clinical standpoint, this review does not support the routine use of metformin or any other medication as a treatment to shrink BTNs. Although some studies, particularly those evaluating metformin, reported statistically significant changes in nodule size, the evidence is heterogeneous, often based on small samples, and in many cases the magnitude of change is unlikely to be clinically meaningful. As a result, these findings should not be interpreted as practice changing,” cautions Brito.
He says the primary value of the work he, Jacome, and team undertook is in guiding future research. “By assembling and critically appraising the existing literature, the review identifies early signals, clarifies their limitations, and helps define where more rigorous investigation is needed.” Larger, well-designed RCTs are needed to confirm whether any repurposed medications can achieve clinically meaningful reductions in BTN size, not just statistically significant changes. According to Brito and team, these studies should use standardized outcome measures, include clear thresholds for meaningful response, and follow patients long enough to assess durability.
He says their work also aims to stimulate a research agenda in which traditional clinical studies are complemented by newer approaches, including the use of large datasets and artificial intelligence methods, tools that may allow the field to better identify patterns, generate hypotheses, and uncover new candidate medications that influence thyroid nodule growth. “Together, these efforts could help move the field from scattered early signals toward evidence that is strong enough to inform future noninvasive treatment strategies.”
“For now, the takeaway for clinicians is that observation and procedural treatments remain the standard, while pharmacologic approaches should be viewed as an emerging research opportunity rather than a ready-to-use therapy,” says Brito.
Long-Term Ablation Efficacy
The search for less-invasive alternatives to surgery for BTNs has also driven advances in procedural techniques. In “Percutaneous Laser Ablation for Thyroid Nodules: Efficacy and Safety in 1,492 Patients With Median Follow-up of 10 Years or More,” Giovanni Gambelunghe, MD, PhD, of the Clinica Liotti in Perugia, Italy, and team adopted percutaneous, ultrasound-guided laser ablation in 2004 and progressively refined the technique during the following years.
“From the outset, we recognized the importance of this approach in minimizing surgical trauma in patients with thyroid nodular disease,” says Gambelunghe. “This awareness led us to perform a retrospective evaluation of all treated patients, which confirmed what we observed in daily clinical practice — namely, the method’s safety and effectiveness.” The patients he refers to underwent one session of laser ablation at various sites in Taormina and Perugia between May 2009 and July 2024.
Gambelunghe explains that thermoablative techniques are now a well-established alternative to surgery for BTN, multiple studies having demonstrated significant improvements in quality of life among patients treated with these approaches: “The principal benefits include reduction in nodule volume — often 50% to 80% within six to 12 months — which leads to decreased sensation of a foreign body in the throat, reduced dysphagia, improvement in dysphonia or cervical pressure, and better breathing in cases associated with compressive symptoms,” he says. These overall improvements in daily functioning, including speaking, eating, and sleeping, are complemented by improved cosmetic outcomes; avoidance of hormone replacement therapy, as the energy delivery is confined to the nodule and spares the healthy thyroid tissue; and rapid recovery and absence of scarring, since the procedure is outpatient, and patients can typically resume work almost immediately,” he continues.
“The study confirms that laser thermoablation is both safe and effective not only in the short term but also over long-term follow-up, which is one of its most noteworthy findings. What impressed me most, however, was that the overwhelming majority of patients reported they would willingly undergo the procedure again — strong evidence of the technique’s truly minimally invasive nature. Clinicians should feel confident in adopting this technique as part of their therapeutic armamentarium.” — Giovanni Gambelunghe, MD, PhD, Endocrine Unit, Clinica Liotti, Perugia, Italy
Notably, laser ablation is the only ablative technique that does not require sedation or even local anesthesia. Says Gambelunghe: “Laser ablation demonstrates efficacy and safety comparable to other thermal ablation techniques, while offering lower procedural complexity, smaller applicators, lower energy delivery, improved safety in critical areas, and a shorter learning curve.” Its minimal invasiveness also has cost implications. “Although a formal economic evaluation was beyond the scope of this study, a recent Italian cost-analysis showed that thermal ablation is less expensive than both hemithyroidectomy and total thyroidectomy, mainly due to the avoidance of the operating room, shorter hospital stay, and reduced productivity loss,” explains Gambelunghe. “Accordingly, laser ablation is expected to be cost-competitive or potentially more economical than other treatment options, particularly because it is performed in an outpatient setting without anesthesia and requires low-cost disposable devices.”
The sole remaining issue for Gambelunghe and team to investigate was whether all of these benefits would persist for the long term, with patients with nontoxic nodules followed for a median of 10.4 years. “The study confirms that laser thermoablation is both safe and effective not only in the short term but also over long-term follow-up, which is one of its most noteworthy findings,” he says. “What impressed me most, however, was that the overwhelming majority of patients reported they would willingly undergo the procedure again — strong evidence of the technique’s truly minimally invasive nature. Clinicians should feel confident in adopting this technique as part of their therapeutic armamentarium.”
Safety of Radioactive Iodine Therapy for Graves Disease
In “Occurrence of Newly Diagnosed Thyroid Cancer Is Not Increased After Radioactive Iodine Therapy for Graves’ Disease,” Natsuko Watanabe, MD, of the Ito Hospital in Tokyo, Japan, and team took on the controversial question of whether radioactive iodine therapy (RAIT) for Graves disease could be a risk factor for the development of thyroid cancer and secondarily whether specific characteristics of thyroid cancer develop after RAIT, considering the patient background, histology, and genotype.
Their study was prompted by ongoing debates about cancer risks associated with RAIT. Study authors note that recent reports indicate that the number of patients opting for RAIT has decreased, with more than half of patients in the United States instead choosing antithyroid drugs because of concerns about possible worsening of thyroid eye disease or even developing cancer.
Indeed, previous research has yielded conflicting results. A 2021 meta-analysis suggested that RAIT might increase thyroid cancer incidence and mortality, finding a linear dose–response relationship between radiation dose and solid cancer mortality. However, the patient populations in those studies were highly varied, including not only Graves’ disease but also functional thyroid nodules, and some studies used the general population rather than patients with hyperthyroidism as controls. As the authors point out, “hyperthyroidism itself and possibly anti–thyroid receptor autoantibodies may also be associated with developing thyroid cancer,” making appropriate control groups essential.
To address these limitations, Watanabe and team conducted two parallel analyses using their institution’s extensive database. First, they retrospectively analyzed 13,874 patients diagnosed with untreated Graves’ disease from January 2007 to December 2016, comparing thyroid cancer incidence rates across three treatment groups: RAIT (n=2,273), surgery (n=287), and medication (n=11,314). New-onset thyroid cancer was identified in eight patients in the RAIT group and 39 in the medication group, with no cases in the surgery group. Using person-years (107,218) to compare treatment groups, they found no significant difference in cancer incidence rates.
Second, they analyzed all 23,179 patients who underwent RAIT for Graves’ disease at their institution from April 1997 to December 2022. Of the 17 cases that developed thyroid cancer after RAIT, only one was anaplastic thyroid cancer, while the remaining 16 were papillary thyroid carcinoma (PTC), of which 15 were microcarcinomas. Notably, four of these were incidental findings discovered during thyroidectomy performed for other indications, primarily recurrent Graves’ disease.
Logistic regression analysis failed to identify any significant risk factors for thyroid cancer development after RAIT. Parameters including thyroid size, administered radiation dose, absorbed radiation dose, and cumulative number of RAIT procedures showed no significant associations with cancer development. “Despite previous studies’ concern about a dose–response relationship between the administered radiation dose and cancer development,” the authors report, their analysis “did not identify any significant risk factors for thyroid cancer development.”
The team also investigated whether thyroid cancers developing after RAIT exhibited concerning histologic or genetic features. Reassuringly, “no instances of overlapping TERT promoter and BRAF mutations, which is considered to suggest a poor prognosis, were found” in cancers that developed after RAIT.
The authors acknowledge important study limitations, including its retrospective design at a specialized institution and the possibility that strict inclusion criteria resulted in a relatively small number of confirmed cancer cases. They also note that geographic and clinical practice differences may limit generalizability, particularly as Japan is an iodine-excess area and Japanese practice patterns for RAIT differ from those in other countries. “In Japan, there is not always a goal to achieve early hypothyroidism in all cases, and there is a tendency to monitor patients for several years after RAIT,” they explain, whereas American Thyroid Association guidelines recommend considering additional RAIT if hypothyroidism has not occurred within six months. Future studies should include extended observation periods and further follow-up.
Their findings nevertheless provide important reassurance: “This study demonstrated that the incidence of new thyroid cancer cases did not increase following RAIT. When cancer did develop, most cases were micro-PTCs, with no evidence of a particularly poor prognosis.” These results, drawn from one of the largest and longest-followed cohorts of patients with Graves’ disease treated with RAIT, may help inform more confident clinical decision making and patient counseling regarding this effective treatment option.
______________________________________________________________________________
These three studies collectively advance our understanding of thyroid disorders and illustrate how contemporary research is expanding treatment options while addressing longstanding safety concerns. Drug repurposing, although as yet unproven, represents a plausible pathway for developing noninvasive treatments for BTNs; laser ablation demonstrates proven long-term efficacy as a minimally invasive option; and concerns about carcinogenic effects of RAIT appear unsubstantiated, potentially removing a barrier to this effective treatment for hyperthyroidism.
Future research should continue to build on these foundations, with the ultimate goal of providing patients with thyroid disease a spectrum of evidence-based treatment options that align with their values, minimize risk, and optimize quality of life.
Horvath is a freelance writer based in Baltimore, Md. For the eleventh year running, she undertook the December issue’s “Eureka!” article where she spoke with Endocrine Society journal editors about the top endocrine science discoveries of 2025.
Loading ...