Endocrinology and Metabolism

Review Article

Thyroid
T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity: Wilmar M. Wiersinga; Endocrinol Metab. 2021;36(5):938-951. Published online September 30, 2021; DOI: https://doi.org/10.3803/EnM.2021.501

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Thyroxine (T4)+triiodothyronine (T3) combination therapy can be considered in case of persistent symptoms despite normal serum thyroid stimulating hormone in levothyroxine (LT4)-treated hypothyroid patients. Combination therapy has gained popularity in the last two decades, especially in countries with a relatively high gross domestic product. The prevalence of persistent symptoms has also increased; most frequent are complaints about energy levels and fatigue (80% to 90%), weight management (70% to 75%), memory (60% to 80%), and mood (40% to 50%). Pathophysiological explanations for persistent problems are unrealistic patient expectations, comorbidities, somatic symptoms, related disorders (Diagnostic and Statistical Manual of Mental Disorders [DSM-5]), autoimmune neuroinflammation, and low tissue T3. There is fair circumstantial evidence for the latter cause (tissue and specifically brain T3 content is normalized by T4+T3, not by T4 alone), but the other causes are viewed as more relevant in current practice. This might be related to the ‘hype’ that has emerged surrounding T4+T3 therapy. Although more and better-designed trials are needed to validate the efficacy of T4+T3 combination, the management of persistent symptoms should also be directed towards alternative causes. Improving the doctor-patient relationship and including more and better information is crucial. For example, dissatisfaction with the outcomes of T4 treatment for subclinical hypothyroidism can be anticipated as recent trials have demonstrated that LT4 is hardly effective in improving symptoms associated with subclinical hypothyroidism.

Citations

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Thyroid.2022;[Epub] CrossRef

Original Articles

Thyroid
Combined Effects of Baicalein and Docetaxel on Apoptosis in 8505c Anaplastic Thyroid Cancer Cells via Downregulation of the ERK and Akt/mTOR Pathways: Chan Ho Park, Se Eun Han, Il Seong Nam-Goong, Young Il Kim, Eun Sook Kim; Endocrinol Metab. 2018;33(1):121-132. Published online March 21, 2018; DOI: https://doi.org/10.3803/EnM.2018.33.1.121

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Abstract PDF Supplementary Material PubReader ePub

Background

Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies. Docetaxel, a microtubule stabilizer, is a common chemotherapeutic agent used to treat various metastatic cancers. However, prolonged use results in various side effects and drug resistance. Flavonoids, such as baicalein, are accepted chemotherapeutic and dietary chemopreventive agents with many advantages, such as greater accessibility, affordability, and lower toxicity, compared with traditional chemotherapy agents. In this study, we evaluated whether baicalein enhances the effects of docetaxel on apoptosis and metastasis in 8505c ATC cells.

Methods

The 8505c cells were treated with baicalein or docetaxel individually and in combination. Cell viability was measured by MTT (thiazolyl blue tetrazolium bromide) assay, and apoptosis was detected by fluorescence microscopy of Hoechst-stained cells. The expression of apoptotic (Bax and caspase-3), anti-apoptotic (Bcl-2), angiogenic (vascular endothelial growth factor [VEGF], transforming growth factor β [TGF-β], E-cadherin, and N-cadherin), and signaling (extracellular signal-regulated kinase [ERK] mitogen activated protein kinase [MAPK], Akt, and mammalian target of rapamycin [mTOR]) proteins was determined by Western blot analysis.

Results

The combination of baicalein (50 or 100 µM) and docetaxel (10 nM) significantly inhibited proliferation and induced apoptosis compared with monotherapies. The combination treatment significantly inhibited the expression of Bax, caspase-3, VEGF, TGF-β1, E-cadherin, N-cadherin, and mTOR, but decreased the expression of Bcl-2 and significantly decreased the phosphorylation of ERK and Akt.

Conclusion

The combination of baicalein and docetaxel effectively induced apoptosis and inhibited metastasis in 8505c cells through downregulation of apoptotic and angiogenic protein expression and blocking of the ERK and Akt/mTOR pathways in 8505c cells. These results suggest that baicalein enhances the anticancer effects of docetaxel in ATC.

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The Effects of Combination Therapy of Cathepsin K Inhibitor and PTH on Change in Bone Mineral Density in an Animal Model of Osteoporosis.: Seung Hun Lee, Jung Min Koh, Young Sun Lee, Beom Jun Kim, Je Yong Choi, Ghi Su Kim; Endocrinol Metab. 2011;26(4):303-309. Published online December 1, 2011; DOI: https://doi.org/10.3803/EnM.2011.26.4.303

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Abstract PDF

BACKGROUND
We hypothesized that combination therapy of cathepsin K inhibitor (CTKi) and human parathyroid hormone (1-34) (teriparatide, PTH) would overcome the coupling phenomenon of bone resorption and formation and thus may rapidly increase bone mass. METHODS: We selected a dose of zoledronic acid (ZA) that had shown similar effects with CTKi on body bone mineral density (BMD) change during the preliminary experiment. Female mice were subjected to ovariectomized (OVX control) or a sham operation (SHAM group). The mice were treated with CTKi (CTKi group), ZA (ZA group), PTH (PTH group) or with a combination of PTH with ZA (ZA + PTH group) or CTKi (CTKi + PTH group) for 8 weeks. Total BMD was measured before the operation and at 4 and 8 weeks. RESULTS: In the preliminary results, 10 microg/kg of ZA showed similar BMD changes with CTKi. Compared with the OVX control, BMD in the SHAM, ZA, CTKi, PTH, ZA + PTH, and CTKi + PTH groups was significantly increased after treatment. BMD in the CTKi + PTH group, but not in the ZA + PTH group increased more significantly than in the PTH group at the end of treatment. Compared with the OVX control, changes in BMD in the SHAM, ZA, CTKi, PTH, ZA + PTH, and CTKi + PTH groups increased significantly after 8 weeks of treatment. The change in BMD in the CTKi + PTH group, but not in the ZA + PTH group was more significantly increased than the change in BMD in the PTH group. CONCLUSION: When combined with PTH, CTKi augmented the anabolic action of PTH. Therefore, combination therapy with CTKi and PTH might be a new therapeutic modality capable of overcoming the coupling phenomenon, thereby markedly and rapidly increasing bone mass.

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The Effects of Combination Therapy of Cathepsin K Inhibitor and PTH on Change of Bone Mineral Density in Animal Model of Osteoporosis
Yumie Rhee
Endocrinology and Metabolism.2011; 26(4): 295. CrossRef

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