A Primer on Thyroid Dysfunction
This blog post accompanies the 6th episode of my BioBros Podcast, featuring Derek of More Plates More Dates and Vigorous Steve. During the episode, I discuss thyroid function because (1) both Dallas the alleged growth hormone abusers Dallas McCarver and Dave Palumbo developed it, and (2) GH use lowers TSH levels in most people. Until now, it is my impression that no one in the PED or biohacking community has ever explained how growth hormone lowers TSH, and whether it is dangerous for the thyroid.
Without knowing anything about thyroid function, I assumed that pro-growth forces could accelerate cancer development, leading me to conclude upregulating TSH chronically could produce hyperplasia. It turns out that I was right, but the situation is much worse than that. And who knew that cabergoline/pramipexole are potent growth hormone inhibitors?
1. Hypothalamus releases thyrotropin-releasing hormone (TRH).
a. Binds to the thyrotropin-releasing hormone receptor (TRHR) in the anterior pituitary.
2. Pituitary releases thyroid-stimulating hormone (TSH) into the bloodstream.
3. TSH stimulates the thyroid to produce thyroxine (T4) and triiodothyronine (T3), which stimulates the metabolism.
4. T3 and T4 act via somatostatin to inhibit hypothalamic TRH in a negative feedback loop.
MECHANISMS OF THYROID HYPERPLASIA
1. Chronic TSH stimulation can produce hyperplasia of the thyroid gland.
2. Catecholamines: not fully understood, except at the dopamine receptor.
a. Norepinephrine stimulates the release of TRH from the hypothalamus, which is likely how the cold speeds up our metabolism faster.
b. Dopamine regulates TSH.
i. Dopamine and dopamine receptor agonists suppress TSH synthesis while dopamine antagonists minorly enhance TSH synthesis.
1. Schizophrenics have higher T3 and T4 levels.
ii. Note that dopamine may lower GH pulses.
1. Dopamine agonists are used to treat gigantism, inhibiting GH more effectively than IGF-1 - think of using nandrolone sans GH now!
2. Acutely, they cause growth hormone release in healthy people.
a. Type 1 IGF-1 receptor is mostly expressed in the thyroid gland.
b. IGF-1R overexpression in the thyroid increases gland weight, decreases TSH, increases serum T4, suggesting that IGF-1 and the IGF-1R stimulate thyroid function.
c. Epidemiologic studies reveal IGF-1 levels are associated with goiter.
d. In acromegaly:
i. Acromegalic people have increased thyroid vascularity.
ii. In a study of 62 Italian acromegalics: thyroid volume is associated with the duration of acromegaly, 78% of patients had thyroid disorders (particularly non-toxic nodular disorder), and thyroid carcinoma was more common.
iii. A study of 37 acromegalics found goiters to be common.
1. Early in the course of the disease, a diffuse goiter develops.
2. Thyroid autonomy and nodule formation begin – growth can continue without TSH.
3. Attenuating GH secretion can reduce thyroid size, but this is limited by the extent of nodularity.
e. In hypopituitary patients given GH, IGF-1 does not independently stimulate thyroid growth but enhanced proliferation of thyroid cells by potentiation the mitogenic effects of TSH.
f. In women but not obese people, GH administration suppresses TSH.
g. IGF-1 levels are dose-dependently associated with the risk of thyroid enlargement and nodule formation in non-acromegalic people.
1. When iodine sufficient, about 5% of people have thyroid nodules, though 68% harbor occult nodules.
2. 65% with ultrasound, 15% with CT or fMRI, and 1-2% with positron emission tomography (PET).
3. Solitary in 50% of cases.
4. More nodules in older people, females, and larger people.
5. 16 million Americans have a palpable nodule: about 10% have cancer, 5% cause compressive problems, and 5% cause thyroid dysfunction.
THYROID CANCER INCIDENCE
1. 211% increase from 1975-2013, 3% annually.
2. Most new diagnoses are of papillary thyroid cancer (PTC), the least aggressive and most common type.
3. Doctors hypothesized that over-surveillance of small tumors that would not cause pathologies may be responsible.
4. This meta-analysis finds a true increase in both the thyroid cancer rate and mortality from advanced-stage papillary thyroid cancers.
POTENTIAL CAUSES OF INCREASED CANCER INCIDENCE
1. Nitrate exposure:
a. Nitrates compete with iodide for the sodium-iodide symporter on thyroid follicles, reducing T3 and T4 and increasing TSH.
b. Due to TSH elevation, thyroid hypertrophies (even from nitrate in drinking water).
c. This is aside from the N-nitroso carcinogens.
2. Polychlorinated biphenyls (PCBs): synthetic, lipophilic compounds mainly found in large fish and they disrupt the thyroid function.
a. Phthalates in cosmetics, food packaging, cleaning agents, medical equipment.
i. They don’t accumulate but are excreted through urine.
ii. They can activate the estrogen receptor and upregulate VEGF.
b. Bisphenol A (BPA):
i. Structurally similar to 17-B-estradiol, competes with endogenous estrogens at the ER.
ii. Inhibits thrombopoietin (TPO) activity.
iii. Binds to the thyroid hormone receptor (TR) weakly, antagonizing the activity of T3.
4. Radiation, particularly for papillary thyroid cancers.
5. Perfluorinated compounds (PFCs): Stain repellent products (usually used to resist stains or oils) associated with thyroid disease.
a. Cadmium most strongly (chocolate); lead.
AUTOIMMUNE THYROID DISEASE (AITD)
1. Excess iodine intake increases AITD prevalence.
2. Autoimmune disease sufferers are 85+% female; only early childhood incidence of T1D is nearly equalin both sexes.
a. Males have greater immune suppression than females in most species.
b. Females have more immunoreactivity to insult (antigens).
i. Over half of the immune genes that are overexpressed in them have estrogen response elements, compared to less than 10% of the men’s immune genes that are overexpressed following a challenge.
3. Grave’s disease (GD) and Hashimoto’s thyroiditis (HT) are the most common.
a. Grave’s has a sudden onset and is usually controlled within 2 years.
b. Hashimoto’s has a slower onset and titers of antibodies can be very high.
i. Even with levothyroxine treatment, titers of anti-TSPO antibodies decrease slowly (i.e. over 5 years) and remain within the pathological range.
4. Primary antibodies:
i. Anti-TSHR > 1.75 U/mL
ii. Anti-TPO > 35 U/l
iii. Anti-Tg > 20 U/l
b. Anti-thyroid-stimulating hormone receptor (TSHR):
i. The first anti-TSHR antibody to be identified was later called immunoglobulin G (IgG).
ii. Anti-TSHR antibodies found in 90% of GD, 0-20% of HT, and 10-75% of atrophic thyroiditis patients.
1. Autoantigen initiation in GD to the TSHR seems to occur when A-subunits are shed during the normal function of the receptor on the thyrocyte.
2. Stimulating antibodies are found in 73-100% of GD patients, while blocking antibodies are found in 25-75% - always more stimulatory antibodies.
3. High anti-TSHR antibodies at diagnoses or cessation of therapy is an indication for recurrence of GD and more severe therapy (i.e. surgery/radioiodine).
c. Anti-thyroid peroxidase (TPO):
i. More common and critical than Anti-Tg antibodies.
ii. Detected in 90-95% of AITD, 80% of GD, and only 10-15% of healthy people.
iii. They can be of any class of immunoglobulin G (IgG), though IgG1 and IgG4 are more common, and low levels of IgAs have also been reported.
iv. Anti-TPO antibodies increase oxidative stress, but cause less damage to the thyroid than T-cell of cytokine-mediated apoptosis.
1. While cytotoxic to thyrocytes in GD, that has not been shown in HT.
d. Anti-thyroglobulin (Tg):
i. Tg is a heterogenous glycoprotein made of dimers (two attached molecules), usually with 2-4 T4 and 0.3 T3 molecules.
ii. Anti-Tg antibodies in GD are mostly IgG4, with low levels of IgA.
iii. In HT, the IgG2 class may be dominant.
iv. Anti-Tg antibodies are found in 10% of healthy people, 15% of people over 60, 50-60% in GD, and 60-80% in HT (CITATION)
v. They do not cause thyrocyte destruction.
5. Antibodies against thyroid antigens (rarely detected):
a. Anhydrase 2, megalin, T3 and T4, sodium iodide symporter (NIS), and pendrin.
i. Smoking is protective for HT but increases likelihood of GD by 3.3x.
1. Lowers anti-Tg and anti-TPO antibody levels.
2. (Similar to how it helps colitis but worsens Crohn’s).
ii. Stress increases the prevalence of GD but not HT.
i. Teetotalers are 2.17x more likely to develop AITD.
1. High alcohol consumption suppresses the immune system.
i. Infection with viruses and bacteria (e.g. H. Pylori) increases AITD prevalence.
ii. Interferon gamma (IFN-y), IL-2, and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels.
iii. Polyaromatic hydrocarbon exposure elevates circulating antibodies against TPO and Tg.
iv. The use of lithium:
1. It becomes concentrated in thyrocytes and either reduces or increases iodine uptake to the thyroid.
a. Reduction: Lithium causes more iodide retention and competes for the iodide transport in the thyroid.
b. Increase: Due to decreased thyroid function and consequent increased TSH secretion.
2. Reduces thyroid hormone synthesis via inhibiting the action of TSH on cyclic adenosine monophosphate (cAMP) and via other mechanisms.
v. Therapeutic or environmental radiation.
d. Iodine supplementation:
i. Humans contain 25-50 mg of iodine, 50-70% stored outside the thyroid, mostly in the gastrosalivary pool.
ii. Iodine can be attached to sodium, potassium, lipids, or proteins (i.e. iodotyrosin, idiolactone).
iii. Iodine intake of 400-600 mcg/day or more can induce or worsen autoantibody formation, increasing the immunogenicity of Tg.
iv. Higher iodine concentrations can induce oxidative stress via TPO activation.
v. Iodinization increases anti-TPO antibodies from 14-24% and anti-Tg antibodies from 14-20% in epidemiological studies.
vi. Increased iodine supplementation also increases cytokine secretion, T cells, and antibody production by B cells.
vii. Iodine has 10x the antioxidant potential of vitamin C and 50x that of iodide.
1. Most supplements either contain iodide alone or a combination of the two.
2. Breast cancer cells can take up iodine by facilitated diffusion, and Lugol’s solution (5% iodine, 10% kalium iodide) has a net anti-estrogenic effect.
a. 79% of GD manifestation can be explained by genetics; antibody formation among twins is 73% positively correlated.
b. It around 55% for HT and AT, with antibody formation among monozygotic twins at 80% and among dizygotic twins at 40%.
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