If you wish to discuss the below document by Perseverance, please visit the original discussion thread:
http://www.benzobuddies.org/forum/index.php?topic=74474.0Benzodiazepines and thyroid conditions- is there a relation?
Looking back in history, I found a paper written in 1971 authored in part by a Pfizer Research Fellow noting a possible connection between benzodiazepines and thyrotoxicosis. The paper begins with this introduction:
“Increasing numbers of patients are receiving treatment with the tranquillizing drugs, and patients referred to hospital with suspected thyrotoxicosis are often taking such drugs. It is important to know what effects these drugs have on tests of thyroid function if diagnostic confusion is to be avoided.”(1)
And another article written in 1967 said:
“...this department agrees with his finding of a depressed thyroid uptake of "'I in patients on chlordiazepoxide [Librium]. In addition, we have found that the related drug diazepam (Valium) has a similar effect. As these two drugs are now very popular in the treatment of anxiety and emotional disorders, it is often found that patients referred with suspected thyrotoxicosis are taking one or other.” (13)
Medical inquiries such as these seemed to have vanished after the early 1970’s. So what happened to this line of inquiry? Did the number of cases decline? Did researchers after the 1970’s determine there was no relation- no basis? One researcher of that era commented on the scarcity of medical literature drawing associations between benzodiazepines and thyroid conditions. Unfortunately I too have found this subject to be sorely lacking in the medical literature.
However, due to the inordinate number of members on this forum who have been diagnosed with thyroid conditions I decided to look into the matter and this paper is a compilation of what I was able to find.
Here is an outline of what this paper will cover. In Part I – I give a run down on the function of the Hypothalamus-Pituitary-Thyroid (HPT) Axis function, thyroid conditions, and related items. In Part II – I go into possible involvement of benzodiazepines in thyroid related issues.
PART 1 - BACKGROUND
I HPT AXIS
A.THYROID NEGATIVE FEEDBACK LOOP
II IODINE
III THYROID HORMONES
IV THYROID CONDITIONS
A. HYPERTHYROIDISM
B. HYPERFUNCTIONING THYROID NODULES
C. HYPOTHYROIDISM
1.PRIMARY HYPOTHYROIDISM
2.SECONDARY HYPOTHYROIDISM
3.TERTIARY HYPOTHYROIDISM
D. THYROIDITIS
E. THYROTOXICOSIS
F. ANTI-THYROID ANTIBODIES ASSOCIATED WITH GRAVES’ AND HASHIMOTO’S
V THYROID MEDICATIONS
PART 2 - HOW BENZODIAZEPINES MIGHT INFLUENCE THYROID FUNCTION
A.THE HYPOTHALAMIC LEVEL
1. NUCLEAR THYROID HORMONE RECEPTORS
2. CRH AND TSH
3. GABA
4. SUPRACHIASMATIC NUCLEUS
5. DOPAMINE
6. CCK, NPY, AND AVP
B. PITUITARY GLAND
1. GABA
2. STEROID HORMONES
3. PBRs
C. THYROID GLAND
1. GABA
2.PBRs
D. THYROID HORMONE TRANSPORT
1. MITOCHONDRIA
2. STRESS
3. REVERSE T3 TEST
PART 1 - BACKGROUND
Thyroid Hormone (TH) affects nearly every type of tissue in the body at cellular level. TH functions as a controller of the pace of all of the processes in the body. This pace is called the metabolic rate. If there is too much TH, every function of the body tends to speed up.(3) Reservoirs of TH in the thyroid gland and blood provide constant thyroid availability to the body.(2)
I HPT AXIS
The HPT axis is sensitive to small changes in circulating TH concentrations.(2)
Here is an illustration depicting the HPT axis:
A. THYROID NEGATIVE FEEDBACK LOOP
This system is self-regulating, keeping TH levels steady through something called negative feedback. In negative feedback, the hypothalamus senses low circulating levels of TH (T3 and T4) and responds by releasing thyrotropin-releasing hormone (TRH) from the paraventricular nucleus (PVN) of the hypothalamus(4,36). Hypophysiotropic TRH neurons (hypophysiotropic means they act on the pituitary gland) in the PVN project their axons to the median eminence, this is where the TRH is released and drained to the anterior pituitary through the long portal veins of the hypophyseal portal system.(22) The TRH stimulates the pituitary to produce thyroid-stimulating hormone (TSH). The TSH, in turn, stimulates the thyroid to produce TH until levels in the blood return to normal.(4)
TH exerts negative feedback control over the hypothalamus as well as anterior pituitary, thus controlling the release of both TRH from the hypothalamus and TSH from the anterior pituitary gland.(4) TH receptors have been identified on TRH neurons in the PVN of the Hypothalamus(35); and at the pituitary level, T3 acts by binding to the thyrotroph (a cell in the anterior pituitary which produces TSH) nuclear T3 receptor. T4 mainly acts through intra-pituitary or intra-hypothalamic conversion to T3.(22)
II IODINE
The thyroid gland uses iodine to make THs.(2) The recommended daily allowance (RDA) for adults, 18 years or older, is 150 mcg.(15) High levels of iodine can increase the incidence of iodine-induced hyperthyroidism, autoimmune thyroid disease and maybe even thyroid cancer in certain individuals, and too little iodine may cause goiter and hypothyroidism.(14) In normal situations, the thyroid gland is equipped to handle iodine excess and scarcity. However in certain conditions and circumstances high or low levels of iodine intake can have these types of effects.(18,19)
For example, Euthyroid patients (‘Euthyroid’ means patients with normal thyroid gland function) previously treated with antithyroid drugs for Graves' disease are more prone to develop iodine-induced hyperthyroidism.(17,18,19) Also, excess iodine in hyperthyroid Graves' disease patients may reduce the effectiveness of the antithyroid drugs.(17)
Iodinated contrast medium solutions used in radiography contain small amounts of iodine that may be of significance for patients at risk. However in general, contrast medium induced thyrotoxicosis is rare and contrast medium injection does not affect thyroid function tests (e.g., T3, T4, TSH) in patients with a normal thyroid.(14,19)
III THYROID HORMONES
The two most important THs are thyroxine (T4) which has four iodine molecules attached to its chemical structure, and triiodothyronine (T3), which has three.(2)
The major form of TH in the blood is T4. About 80% of circulating T3 is actually produced outside the thyroid gland from T4; only 20% is directly secreted by the thyroid gland. T4 is converted to the biologically active T3 within the target cells, as required by the tissues. T4 is mainly a prohormone that becomes activated upon its conversion to T3. In this way, T4 is believed to be a reservoir for T3. Most TH actions are initiated by binding of T3 to its nuclear receptors in target cells.(5,44)
99 percent of all the TH circulating in the blood is bound to transport proteins. Only a very small fraction of the circulating hormone is free (unbound) and biologically active, meaning they directly interact with body cells to help regulate metabolism.(2,5) There are three main transport proteins responsible for carrying THs in the bloodstream: thyroxine-binding globulin [(TBG) or thyropexin], transthyretin [(TTR) or thyroxine-binding prealbumin (TBPA)], and albumin [human serum albumin (HAS)].(16)
IV THYROID CONDITIONS
A. Hyperthyroidism, often referred to as an 'overactive thyroid', is a condition in which the thyroid gland produces and secretes excessive amounts of the free (not protein bound) THs; T3 and/or T4. Graves’ disease is the most common form of hyperthyroidism.(3) High levels of T-4, T-3, or both and low or nonexistent amounts of TSH indicate an overactive thyroid.(9,10) Also, a high Radioactive iodine uptake test result would indicate that your thyroid gland is producing too much T-4.(10)
B. Hyperthyroidism can also occur from hyperfunctioning thyroid nodules (aka- toxic adenoma, toxic multinodular goiter, Plummer's disease). This form of hyperthyroidism occurs when one or more adenomas of your thyroid produce too much T-4. An adenoma is a part of the gland that has walled itself off from the rest of the gland, forming noncancerous (benign) lumps that may cause an enlargement of the thyroid. Not all adenomas produce excess T-4, however the ones that do don’t require TSH stimulation to release T-4. Here again, a high Radioactive iodine uptake test result would indicate that your thyroid gland is producing too much T-4.(10,11)
C. Hypothyroidism ('sluggish thyroid') is the reduced production and secretion of T3 and/or T4. The most common form is Hashimoto's thyroiditis (an autoimmune disease). Another common cause of hypothyroidism is radioiodine therapy which is used for hyperthyroidism. This therapy severely restricts, or altogether destroys the function of a hyperactive thyroid gland.(3,7)
Hypothyroidism is classified into 3 categories, depending on where the cause originates on the HPT Axis:
1. Primary hypothyroidism - the inability of the thyroid gland to produce hormone.
2. Secondary hypothyroidism - problems with the pituitary cause decreased synthesis and release of TSH.
3. Tertiary hypothyroidism - problems within the hypothalamus cause decreased synthesis of TRH and subsequent decreased stimulation of the pituitary.(12)
D. Sometimes your thyroid gland can become inflamed for unknown reasons. This is referred to as Thyroiditis. The inflammation can cause excess TH stored in the gland to leak into your bloodstream. One rare type of thyroiditis, known as subacute thyroiditis, causes pain in the thyroid gland. Other types are painless and may sometimes occur after pregnancy (postpartum thyroiditis). If you have hyperthyroidism and your radioiodine uptake test comes back low, you may have thyroiditis.(10)
E. Thyrotoxicosis is a condition resulting from excessive concentrations of unbound THs in the body, whether or not the thyroid gland is the primary source. It can be a result from hyperthyroidism.(6,9)
F. Graves’ disease and Hashimoto's Thyroiditis are commonly associated with the presence of anti-thyroid autoantibodies. Although there is overlap, anti-thyroid-peroxidase (anti-TPO) antibodies are most commonly associated with Hashimoto's Thyroiditis and activating TSH-receptor antibodies (TRAbs) are most commonly associated with Graves' Disease.(8 )
V THYROID MEDICATIONS
Antithyroid drugs are medications that treat an overactive thyroid (hyperthyroidism) by blocking the thyroid gland's ability to produce TH (TH synthesis). The major inhibitory drugs used are the thionamides: propylthiouracil and methimazole.(14)
PART 2 - HOW BENZODIAZEPINES MIGHT INFLUENCE HPT AXIS FUNCTION
A. THE HYPOTHALAMIC LEVEL
An intricate set of relationships within and outside the central nervous system controls the TRH-producing neurones in the medial basal hypothalamus. Alterations in any of these mechanisms can influence TRH and consequently TSH release.(22)
1. A single intraperitoneal injection of diazepam (Valium) into rats within 24 hours affected the density of the nuclear Thyroid Hormone Receptors (TRs) and their expression pattern in the adult rat brain.(34)
2. Benzodiazepines are known to inhibit CRH (20,21). In animal models, TSH secretion has been shown to be stimulated by CRH.(22,23,24) So there may be a connection between CRH levels and TSH in humans.
3. In humans, GABA inhibits thyroid stimulating hormone (TSH) release from the pituitary, possibly by action directly on the pituitary or on hypothalamic thyrotropin-releasing hormone neurons.(25)
4. The suprachiasmatic nucleus (SCN) is responsible for controlling circadian rhythms in the body. The classical inhibitory neurotransmitter γ-aminobutyric acid (GABA), its receptors, synthesis enzymes, and transporters are in nearly every cell in the SCN. GABAA receptor agonists act in the SCN to reset circadian rhythms during the day but inhibit the ability of light to reset rhythms during the night.(26) Neuro-endocrine hormone secretion, including TRH, has a circadian rhythmicity- and therefore may be indirectly affected by benzodiazepine usage. Benzodiazepine induced cortisol irregularities, outside of the normal cortisol circadian rhythmic pattern, may affect HPT axis function. Cortisol circadian rhythmicity has been associated with modulating HPT axis function.(27)
5. Dopamine is involved in TSH synthesis and release.(22) Benzodiazepines have been shown to decrease Dopamine levels.(28)
6. The Neuropeptides Colecistokinin (CCK), neuropeptide Y (NPY); and arginin-vasopressin (AVP) may exert inhibitory and stimulatory effects on TSH secretion respectively.(22) Benzodiazepine treatment interferes with the release of NPY and CCK(21)- and is able to inhibit hypothalamic AVP release.(32)
B. PITUITARY GLAND
The Greek word for Pituitary gland is hypophysis, which is important to know when reading medical literature pertaining to this subject. Structures related to the Pituitary gland contain this term in one form or another- for example- hypophysiotropic neurons are neurons which act on the Pituitary Gland and TRH travels from the brain to the Pituitary gland via the hypophyseal portal system.
The following factors related to GABA and/or benzodiazepines may possibly exert an influence over the Pituitary output of TSH.
1. As previously stated, in humans, GABA inhibits thyroid stimulating hormone (TSH) release from the pituitary, possibly by action directly on the pituitary or on hypothalamic thyrotropin-releasing hormone neurons.(25)
2. Steroid hormones including corticosteroids, estrogen, and testosterone modulate TSH β gene expression.(22) Benzodiazepines can affect steroid hormone levels via suppression of the Hypothalamus-Pituitary-Adrenal (HPA) axis(29); there can be fluctuations in cortisol due to inter-dose withdrawal during chronic treatment(30); and there can be a rebound elevation in cortisol upon discontinuation.(31)
3. Peripheral benzodiazepine receptors (PBR) are expressed in the pituitary gland.(20,38)
C. THYROID GLAND
1. In mice, GABA inhibits TSH-stimulated TH release from the thyroid gland.(25)
2. PBRs are expressed in the thyroid gland.(38)
D. THYROID HORMONE TRANSPORT
Serum thyroid levels are commonly used as an indication of cellular thyroid activity. However, in order to have biological activity T4 and T3 must cross the cellular membrane from the serum into the target cells. It follows that the activity of these transport processes may have an important influence on the regulation of biological activity of the thyroid hormones.(39)
1. Transport of thyroid hormones into the cell is energy dependent; therefore any condition associated with reduced production of the cellular energy (mitochondrial dysfunction) will also be associated with reduced transport of thyroid into the cell, resulting in cellular hypothyroidism despite having standard blood tests in the “normal” range. Even slight reductions in cellular energy (mitochondrial function) results in dramatic declines in the uptake of T4 while the uptake of T3 is much less affected. An impaired transport of T4 can results in cellular hypothyroidism. This cellular hypothyroidism is not detected by blood tests for T4 because the less T4 transported into the cell and the lower the cellular level of T4, the higher the serum T4 level.(39)
Benzodiazepines are known to damage mitochondria,(42) plus benzodiazepines such as diazepam (Valium), lorazapam (Ativan) and alprazolam (Xanax), have been shown to inhibit T3 uptake into the cells of the body.(39,43,44) Also, PBRs may play a role in regulating mitochondrial function and apoptosis.(40,41)
2. There are a number of substances that are produced by the body in response to physiologic stress that negatively affect thyroid hormone transport. Studies have shown a direct correlation between degrees of physiological stress and reduction of the uptake of T4 by the cells. These changes would not be reflected by TSH testing because thyroid uptake in the pituitary cells is not effected as previously stated.(39) Since virtually every stress mechanism can be effected by benzodiazepine usage or withdrawal, benzodiazepines may have an indirect effect on cellular thyroid transport in any tissue other than the pituitary.
3. The reverse T3 (rT3) test is an excellent marker for reduced cellular T4 and T3 levels not detected by TSH or serum T4 and T3 levels because increased rT3 indicates reduced uptake of T4 and reduced T4 to T3 conversion.(39)
REFERENCES
1) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2466912/pdf/postmedj00342-0018.pdf
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5) http://en.wikipedia.org/wiki/Thyroid_hormone
6) http://www.thefreedictionary.com/thyrotoxicosis
7) http://en.wikipedia.org/wiki/Hypothyroidism
8 ) http://en.wikipedia.org/wiki/Anti-thyroid_autoantibodies
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11) http://en.wikipedia.org/wiki/Toxic_multinodular_goitre
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15) http://ods.od.nih.gov/factsheets/Iodine-HealthProfessional/
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journal_id=1&archive=0&issue_id=22&article_id=704
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