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3.26.2013

New Miller School Study Points to Importance of Overlooked Hormone Indicator in Thyroid Health

A new Miller School study points to the importance of an overlooked indicator of thyroid health. “Better monitoring of a key hormone could lead to new treatment approaches with beneficial results for patients,” said Antonio Bianco, M.D., Ph.D., Chief of the Division of Endocrinology, Diabetes and Metabolism, who led the scientific study. Bianco, who has studied the thyroid gland for more than 30 years, recently received the Rosalind Pitt-Rivers Medal from the British Thyroid Association for his career achievements.

The Miller School study, “Coordination of hypothalamic and pituitary T3 production regulates TSH expression,” was published recently in the prestigious Journal of Clinical Investigation. Other Miller School authors were post-doctoral associates Tatiana Fonseca, Ph.D., and Mayrin Correa-Medina, M.D., Ph.D.; Maira P.O. Campos, M.D., resident; Rafael Arrojo e Drigo, Ph.D., post-doctoral fellow; Magda Mora-Garzon, M.D., resident; Cintia Bagne Ueta, Ph.D., graduate student; and Alejandro Caicedo, Ph.D., research associate professor of medicine.

One of the key endocrine glands, the thyroid produces hormones – primarily thyroxine (T4) and triiodothyronine (T3) – that regulate important processes in the body, such as growth, cardiovascular function, cognition and metabolism. An underactive thyroid can lead to sluggishness, weight gain, and mental fatigue, a condition called hypothyroidism. In contrast, an overactive thyroid can result in hyperthyroidism, with symptoms that may include weight loss, rapid heartbeat, anxiety and agitation. While patients with hypothyroidism are treated with levothyroxine (the pharmaceutical form of T4), hyperthyroid patients can be treated with anti-thyroid medication, radioactive iodide or surgery.

Clinicians typically evaluate the health of a thyroid by measuring the levels of T4 and thyroid-stimulating hormone (TSH), which is produced by the pituitary gland under the control of the thyrotropin-releasing hormone (TRH) made by the hypothalamus. “When you have a thyroid that doesn’t work as much as it should, the thyroid hormone levels in the plasma go down and the TSH levels go up; the opposite happens when you have an excess of thyroid hormones, and the TSH levels will be very low and the thyroid hormones will be high,” said Bianco. “Although we understand the overall principles of this hormone feedback mechanism, many details that have clinical significance are still missing.”

In the laboratory study, the Miller School research team focused on the role of an enzyme called Type II deiodinase (D2) produced in the hypothalamus and pituitary that converts the less active T4 to the highly active T3 hormone. “The question is important for clinicians, because plasma T4 must be converted to T3 in order to be detected by the pituitary gland and decrease TSH secretion,” Bianco said. “We wanted to understand the relative roles played by pituitary versus hypothalamic D2 in the thyroid hormone-mediated feedback mechanism.”

Using new mouse strains developed at the Miller School as an experimental model, Bianco and his team found that inactivating the D2 enzyme in the pituitary gland produced major changes in TRH, TSH and T4 levels, but did not affect T3 levels in the plasma. “This finding clearly shows that the body’s endocrine system is wired to keep plasma T3 in the normal range,” he said. “It also points to the importance of T3 as a clinical indicator in the follow-up of hypothyroid patients who are being treated with levothyroxine.”

Bianco noted that clinicians today, following guidelines set by the American Thyroid Association, use TSH and T4 levels in the blood as the key indicators of thyroid health of hypothyroid patients treated with levothyroxine. “Only rarely will physicians obtain T3 levels directly in the diagnosis or treatment of hypothyroid patients,” he said.

But Bianco believes that paying closer attention to plasma T3 could lead to better quality of life for patients with lower-functioning thyroids – a finding supported by his previous studies, as well as work by other researchers. Bianco believes a focus on plasma T3 as a diagnostic indicator could also stimulate pharmaceutical companies to develop better drug delivery systems to normalize plasma levels of T3. This will be one of the topics discussed at the American Thyroid Association Spring Symposium and Research Summit 2013 to be held April 25-26 in Washington, D.C. The conference is co-chaired by Bianco, with the overall theme of “Treatment of Hypothyroidism: Exploring the Possibilities.”

“We know that about 20 percent of hypothyroid patients treated with levothyroxine are not happy despite having normal plasma T4 and TSH levels,” Bianco said, “and many of these patients exhibit lower plasma levels of T3. Other hypothyroid patients don’t complain to their doctors, but could potentially benefit as well from more effective treatments that normalize plasma T3, potentially making it easier to lose weight or maintain their mental focus.”

Other study co-authors were Gabor Wittmann, Ph.D., and Ronald Lechan, M.D. Ph.D., of Tufts Medical Center, Boston; Joao Werneck-de-Castro, Ph.D., Federal University of Rio de Janeiro; and Gereben Balazs, Ph.D., and Csaba Fekete, Ph.D., Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.

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