The combination of liothyronine (LT3) with levothyroxine (LT4) for the treatment of hypothyroidism shows no evidence of any increased risk of breast cancer in a large, long-term study, contrary to concerns raised in some prior trials.
“An increasing number of patients ask their physicians for a prescription of combination therapy, often causing tensions. Thus, the question of whether combination therapy does any harm to patients is crucial,” say Tereza Planck, MD, PhD, of Skane University Hospital, Malmo, Sweden, and colleagues, in their article published online January 5 in Thyroid.
“Our data provide reassuring evidence regarding the risk of cancer and mortality,” they stress.
Asked to comment, Caroline T. Nguyen, MD, agrees that the study results are welcome in light of some previous evidence.
“The findings of these [prior] studies were concerning as they suggested an association between T3 and breast cancer, breast cancer-specific mortality, and poorer prognosis with potential estrogen-like activity of T3 on the estrogen-receptor,” Nguyen, of the Division of Endocrinology, Diabetes & Metabolism, Keck Medical Center of USC, in Los Angeles, told Medscape Medical News.
“Therefore, the findings of this paper provide some reassurance, which is important because as the paper states, the use of T3 is becoming increasingly common.”
Many Patients With Hypothyroidism Opt to Add Liothyronine
Although the standard treatment for hypothyroidism, levothyroxine, increases free thyroxine (T4) to high-normal levels, it may potentially lower triiodothyronine (T3) to relatively low levels. There is speculation that the imbalance in a subset of patients could explain why some fail to have an adequate reduction of symptoms with levothyroxine alone.
To offset the effect, some add liothyronine (a synthetic version of T3) to levothyroxine treatment as so-called “combination therapy.” However, a long-term study conducted in Scotland showed a borderline significant increase in breast cancer risk with the combination, raising concern.
To further investigate, Planck and coauthors used Swedish adult population data, identifying 575,461 individuals who had made at least three purchases of thyroid hormone therapy between July 2005 and December 2017, and had no history of breast cancer at the time of their first prescription.
Among the individuals, 11,147 had made at least three purchases of LT3, including combinations with LT4. LT4-only users were an average age of 54.4 years, and the average age of those who also took LT3 was 44.7 years.
Over a median follow-up of 8.1 years, there was no significantly increased risk of breast cancer among women treated with LT3 plus LT4 versus LT4 alone (hazard ratio [HR], 0.93), after adjusting for differences in age, sex, previous thyroid cancer, previous other cancer, use of antithyroid preparations, use of sex hormones, and dose.
Further evaluation of women as well as men showed those treated with LT3 also had no increased incidence of any cancer (HR, 0.97).
In dose-adjusted models, LT3 treatment did, surprisingly, appear to have a protective effect in terms of all-cause mortality (HR, 0.69) and any cancer mortality (HR, 0.78) for men and women.
However, the implications of these latter results remain uncertain, first author Planck told Medscape Medical News.
“We think the data on reduced mortality should be interpreted with caution, as we only observe the differences in the models adjusting for dose,” she noted.
LT3 Treatment Still Considered “Experimental”
Despite the dramatic increase in LT3 prescribing in recent years noted by the authors, as many as five systematic reviews/meta-analyses have shown no superiority of combination therapy over LT4 alone in terms of hypothyroid symptoms, quality of life, or patient preference.
As a result, many international guidelines still consider the combination treatment approach to be experimental.
Other trials that have raised concerns about the combination include previous large, prospective Swedish studies that have linked higher endogenous T3 levels to breast cancer in postmenopausal women.
As for the mechanism, some small experimental studies have suggested an estrogen-like effect whereby T3 could enhance the proliferation of breast cancer cells.
On a broader level, thyroid hormones, in general, have been extensively studied in cancer research as possibly promoting cancer cell proliferation in a variety of cancer types.
However, the current findings should lay some of those concerns to rest, Planck reiterated: “Our data provide reassuring evidence regarding the risk of cancer and mortality.”
“We did not identify any increase in breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, or breast cancer mortality between individuals using LT3 and LT4 treatment.”
The authors and Nguyen have reported no relevant financial relationships.
Thyroid. Published online January 5, 2021. Abstract