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Hypothalamic-Pituitary-Thyroid Axis Perturbations in Male Mice by CNS-Penetrating Thyromimetics

Skylar J Ferrara1, Dennis Bourdette2, Thomas S Scanlan1

  • 1Program in Chemical Biology, Department of Physiology & Pharmacology, Oregon Health and Science University, Portland, Oregon.

Endocrinology
|May 31, 2018
PubMed

Insights

Thyromimetics like sobetirome and Sob-AM2 impact the hypothalamic-pituitary-thyroid (HPT) axis, causing central hypothyroidism in mice. However, these mice do not exhibit hypothyroidism symptoms due to the drug

Area of Science:

  • Endocrinology
  • Pharmacology
  • Molecular Biology

Background:

  • Thyromimetics offer tissue-selective thyroid hormone action.
  • The effects of thyromimetics on the hypothalamic-pituitary-thyroid (HPT) axis and systemic thyroid hormone levels are not well understood.
  • Understanding these effects is crucial for developing novel therapeutic strategies.

Purpose of the Study:

  • To investigate and compare the HPT-axis effects of sobetirome and its CNS-targeted prodrug, Sob-AM2.
  • To elucidate the impact of tissue distribution on thyromimetic-induced HPT-axis modulation.
  • To characterize the systemic thyroid hormone profile and potential hypothyroidism in response to these drugs.

Main Methods:

  • Male C57BL/6 mice were administered sobetirome and Sob-AM2 at concentrations ≥10 μg/kg/d for 29 days.
  • Gene transcript levels of the HPT axis were analyzed.
  • Circulating levels of thyroxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone (TSH) were measured.

Main Results:

  • Both sobetirome and Sob-AM2 suppressed HPT-axis gene transcript levels, correlating with their distribution properties (periphery vs. CNS).
  • Mice treated with ≥10 μg/kg/d of either drug exhibited depleted circulating T4 and T3 with normal TSH levels, mimicking central hypothyroidism.
  • Despite systemic thyroid hormone depletion, treated mice did not display overt signs of hypothyroidism.

Conclusions:

  • Thyromimetics significantly modulate the HPT axis, with effects dependent on their tissue distribution.
  • Sobetirome and Sob-AM2 can induce a state resembling central hypothyroidism in mice.
  • The absence of hypothyroidism symptoms may be attributed to the presence of the thyromimetic in a thyroid hormone-depleted environment.

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