I was reading through a post by Cigana which is about 3 years old and it got me thinking about hypothyroid symptoms and how they manifest even when numbers are in range and all blood work comes back normal. In this post, I'm not going to focus on obvious causes, like high estrogen, high TBG, or RT3. Although RT3 does show a metabolic down regulation consistent with high levels of cortisol. The two people I consistently keep coming back to on this issue are Chris Kresser, and David J Clark. Chris Kresser has authored a number of insightful articles about hypothyroid conditions. Of particular interest is his detailed article about how adrenal issues cause hypothyroid symptoms. ADRENALS In this article he lists 5 ways in which the adrenals will cause hypothyroidism. The first two directly lower t3, but since we're assuming numbers are at least in the normal range, will throw those out. Number 3 addresses the auto immune factor, so we'll throw that out too, however we'll come back to autoimmune, because it's possible you have an autoimmune condition without testing positive for any antibodies. "4) Adrenal stress causes thyroid hormone resistance In order for thyroid hormone circulating in blood to have a physiological effect, it must first activate receptors on cells. Inflammatory cytokines have been shown to suppress thyroid receptor site sensitivity. If you’re familiar with insulin resistance, where the cells gradually lose their sensitivity to insulin, this is a similar pattern. It’s as if the thyroid hormone is knocking on the cell’s door, but the cells don’t answer. While there’s no practical way to measure receptor site sensitivity in a clinical setting, the research above suggests it is decreased in autoimmune and other inflammatory conditions. A perfect example of this in practice is the Hashimoto’s patient who is taking replacement hormones but still suffers from hypothyroid symptoms – often in spite of repeated changes in the dose and type of medication. In these patients, inflammation is depressing thyroid receptor site sensitivity and producing hypothyroid symptoms, even though lab markers like TSH, T4 and T3 may be normal." But the $64,000 question, is: What's causing the adrenal dysfunction? Let's throw out the notion that they get "fatigued." They are doing what they are told, and something is telling them to do that. You figure out the cause of this, and you fix everything, if you can treat it. "Balancing the adrenals Here’s the tricky thing about adrenal stress: it’s almost always caused – at least in part – by something else. These causes include anemia, blood sugar swings, gut inflammation, food intolerances (especially gluten), essential fatty acid deficiencies, environmental toxins, and of course, chronic emotional and psychological stress." High cortisol causes T3 receptors to shutdown. You can have super physiological amounts of t3 floating around from taking high doses of cytomel, but it has no affect because it can't dock with the receptor: AUTO IMMUNE Most are familar with Hashimoto's, and we're assuming you did not test positive for the antibodies. However, that doesn't mean you don't have Hashimoto's. Say what? According to David J Clark: "You're lucky if you were tested and you actually showed elevated antibodies. Scientific research shows that about 15 percent of Hashimoto's victims are seronegative---they don't make enough antibodies to be detected. Even though they really do have Hashimoto's and have got all the symptoms" Also, You can have positive TSH antibodies for Grave's, but it actually causes Hashitmotos: INFLAMATION (Cytokines) Chris Kresser gives us an example for our adrenals in how cytokines can disrupt the HPA axis, however this event would show up in thyroid blood work, so it doesn't really count: "Studies have shown that the inflammatory cytokines IL-1 beta, IL-6 and TNF-alpha, which are released during the stress response, down-regulate the HPA axis and reduce levels of thyroid stimulating hormone (TSH)." However, these same cytokines do something else, which just like as we saw with high levels of cortisol, high levels of cytokines shutdown t3 receptors, and lab numbers look normal. HOMOCYSTEINE Those with MTHFR should keep an eye on this one. With poor methylation and high homocysteine, you could become hypothyroid, and all your other lab numbers could appear normal. "Homocysteine can dock on a cell and have it stop having a response to thyroid hormone." VITAMIN A DEFFICIENCY This is a bit of an odd ball, but still a potential cause, and not caught on normal blood work labs. The one thing that jumps out at me after going through this material is how the adrenal glands can cause hypothyroidism via multiple mechanisms at the same time. High cortisol can: Shut down t3 receptors Cause high rt3, which could block receptors that aren't shut down Interfere with pituitary and hypothalamus signaling (lowering TSH) Cause auto immune conditions (Hashimoto's --- you can have it even if you tested negative to antibiodies) HPA-axis disruption causes high cytokines which shutdown t3 receptors (but bloodwork looks normal!) Raises TBG which lowers free t3 ALL AT THE SAME TIME!