The facts: Severe hypothyroidism with normal blood hormone levels and an intact hypothalamic pituitary thyroid axis. Peripheral tissue response was restored by supraphysiological doses of exogenous thyroid hormone with a suppressed TSH indicating peripheral resistance to thyroid hormone. Onset was in adulthood and varied over time, the condition was acquired and not genetic. This confirms Acquired Resistance to Thyroid Hormone (ARTH).
TSH can a sensitive marker for thyroid failure. However, the pituitary differs from peripheral tissues in many ways: –
- The pituitary has a negative TRE, activity is reduced by thyroid hormone.
- The hypothalamus and pituitary uniquely express TRβ2 receptors (except for small amounts in the eye and developing ear).
- Peripheral tissues utilize heterodimer binding, the pituitary is also able to use homodimer binding.
- In peripheral tissues type-2 deiodinase (D2: T4 to T3 conversion) is regulated by ubiquitin and other factors, expression of D2 is reduced as T4 increases, so as T4 rises conversion of T4 to T3 by D2 reduces. Conversion of T4 to T3 is not regulated in this way by the hypothalamus and pituitary.
Some of my signs and symptoms such as elevated cholesterol, impaired working memory (hippocampus) and a tendency to
Attention deficit hyperactivity disorder (ADHD) with otherwise normal brain function suggested my resistance was greater in TRβ1 receptors. A PubMed search ‘thyroid hormone receptor beta-1 heterodimer’ returned a study ‘Polychlorinated biphenyls suppress thyroid hormone receptor-mediated transcription through a novel mechanism‘ which showed that PCBs suppress transcription in TR/RXR heterodimer binding but not in TR/TR homodimer binding. This was a possible explanation for a form of RTH that is restricted to peripheral tissues. Substances such as PCBs are called Endocrine Disrupting Chemicals (EDCs).
On reflection I’m not sure the heterodimer binding point is backed up by strong evidence. It describes my reasoning at the time, with a damaged brain. It may be that my later advances were a result of luck rather than skill!
PCBs were used in electrical equipment such as transformers. The risk of exposure to the general population is low. However, I worked on a large manufacturing site with its own electricity generation, so I had my PCB levels assessed by an expensive blood test. My PCB levels were low, so I discounted this possibility. It’s possible that another EDC could cause my hypothyroidism.
RTH is caused by genetic mutations to thyroid hormone receptors. These mutated receptors are almost but not quite identical to healthy receptors. EDCs are an environmental equivalent, almost but not quite identical to thyroid hormone. EDCs are widespread and in susceptible individuals they disrupt hormone action in similar ways to mutated receptors.
Before identifying the problem EDC it is worth getting better aquanted with EDCs in general. The above video is from the Endocrine Society’s information on EDCs. The Endocrine Society is the United States’ learned body for endocrinologists. It’s ironic that endocrinologists worldwide have so little knowledge of EDCs and their effects. A good time to take a closer look at Endocrine Disrupting Chemicals (EDCs).