Charles Matthews M.D.
Director, the North Carolina Comprehensive Headache Clinic
Raleigh, N.C.
Prior to 1980, when the protein bound iodine test for thyroid status was introduced, the assessment of thyroid function utilized clinical criteria and, when available, determination of basal metabolic rate (1). At that time dessicated thyroid preparations were commonly administered for a variety of functional disorders (2). The definition of hypothyroidism historically shifted from the physical examination and became based on normative data for the TSH, but was never correlated with the previously accepted clinical criteria for hypothyroidism and clinical practice in the use of thyroid supplementation (3). The sole reliance on blood tests for defining thyroid function has met with controversy is recent years, some of which is directed at the question of optimum rather than normal TSH, and some of which questions the status of the TSH itself when clinical markers diverge (4).
Migraine and thyroid:
Migraine is a systemic disease involving the brain, as well as the autonomic, cardiovascular, endocrine, gastrointestinal, and immune systems (5). In addition to the manifestations of head pain, there is a substantial overlap between chronic headache and other functional disorders, such as chronic fatigue, weight gain, irritable bowel syndrome, mood disorders, sleep disturbance, fibromyalgia, and menstrual irregularities. The overlap between headache and each functional disorder reaches 70% in the refractory headache population, raising the question of whether these conditions have entirely distinct etiologies (6). Many patients presenting at headache clinics are on multiple medications of the antidepressant, anticonvulsant, and antihypertensive classes, often with side effects which exacerbate one of the other functional disorders (common examples include weight gain and fatigue with antidepressants, depression with beta blockers, constipation and exacerbation of IBS with tricyclics, and menstrual irregularities and precipitation of PCOS with anticonvulsant medication.
Migraine may appear as a slowly traveling cortical metabolic defect called the Spreading Depression of Leao on functional imaging. The etiology of this metabolic defect is unknown, but may be a manifestation of mitochondrial dysfunction (7). Migraine has been linked with mitochondrial disorders; the evidence is strongest in migraine with aura and hemiplegic migraine (8). Some known mitochondrial abnormalities cause migraine (for example, MELAS). Ubiquinone, a mitochondrial co-factor, has been used successfully to treat migraine in limited clinical trials (9). Migraine is associated with hypocapnia in the presence of elevated serum lactate and other Krebs Cycle acids, , suggesting respiratory compensation for an underlying metabolic acidosis, possibly explained by a diffuse mitochondrial dysfunction; migraine is also associated with interictal and ictal hypothermia(10).
Mitochondrial output and number, and by extension basal body temperature and CO2 production, are under the primary control of the thyroid gland. It has been demonstrated that environmental agents such as insecticides, processed fats, plasticizers, and food additives interfere with the effect of thyroid on mitochondria (12). It has been speculated that this effect may be passed up through the food chain and concentrated ("biological lensing") causing endocrine disruption in humans (13). It is likely that environmental endocrine disruptors, as well as individual variability in central nervous system local uptake and utilization of liothyronine, plays a role in the development of migraine, even in patients with normal laboratory functions.
Experience to date:
There are multiple anecdotal references to the successful treatment of migraine with thyroid augmentation prior to 1980, and one published trial of 100 patients with headache reporting 95 responders and no significant side effects (14). At that time, dessicated (whole) thyroid was used, which contains T4, T3, T2, calcitonin, and selenium. No negative studies were published to account for the lapse of the use of thyroid augmentation for headache, and the practice of thyroid supplementation declined as the more narrow definition of hypothyroidism became adopted with the advent of the TSH and the popularity of synthetic L-thyroxine (T4) as sole therapy for hypothyroidism.
In an initial series of fifty patients referred to the Headache Clinic, refractory to multiple medications and other therapeutic modalities, thyroid augmentation appears to be effective in relieving symptoms of headache, and in many instances, of multiple other functional disorders, as well as correcting hypocapnia and basal hypothermia. Thyroid augmentation appears to be well tolerated. Other practitioners have described similar positive experiences (Marcelo Bigal M.D., Ray Peat Ph.D., Broda Barnes foundation members, the Belgian endocrinologist Thierry Hertzoghe M.D., personal communications).
Endocrinologists have extensive clinical experience in thyroid augmentation (TSH suppression) for thyroid cancer, and there is a long tradition in psychiatry in treating refractory depression with thyroid augmentation. The combined clinical experience suggests that thyroid augmentation, and TSH suppression, is well tolerated (15). Recent studies further support the safety of maintaining higher thyroid hormone levels (and a low TSH) as a therapeutic option (16)(17).
Standards of Care Concerns:
During thyroid augmentation, TSH is expected to fall to "hyperthyroid" levels and may become undetectable. Except for management of thyroid cancer, and for treatment of certain types of depression, maintaining a low or undetectable TSH for therapeutic purposes in treating headache is not a current standard of care.
Risks:
Excess thyroid administration may be associated with cardiac arrhythmias, myocardial infarction, anxiety or panic attacks, and weight loss. Some, but not all, authors raise concerns about osteoporosis. Suppression of endogenous thyroid function may occur. There is insufficient information on the practical relevance of such risks under supervised thyroid augmentation for headache, and there may be side effects which are not presently known. These potential risks will be monitored carefully, and must be balanced against the risks of lack of treatment and of their current treatment. Since thyroid augmentation increases the clearance of cortisol, in patients with adrenal compromise, thyroid augmentation may precipitate symptoms of adrenal insufficiency.
References:
1) Thyroid Diseases: Basic Science, Pathology, Clinical and Laboratory Diagnoses by Luigi Troncone, Brahm Shapiro, Maria A. Satta, and Fabrizio Monaco
2) Hypothyroidism: The Unsuspected Illness by Broda Barnes M.D. Ph.D.
This book was written by a clinician and researcher during the active years of thyroid supplementation and contains extensive information on his years of clinical experience in thyroid augmentation.
3) Raymond Peat Ph.D. in "Thyroid Therapy" article posted on Raypeat.com.
Ray Peat is an endocrine physiologist who has written a number of books and articles which are conveniently posted on his web site.
4) This viewpoint and literature is summarized in this article posted on thyroid.com, a patient advocate site.
The TSH Reference Wars: What's "Normal?", Who is Wrong, Who is Right...And What does it all Mean for You and Your Health? by Mary Shomon
2) Hypothyroidism: The Unsuspected Illness by Broda Barnes M.D. PhD.
This article discusses migraine from a systemic disease point of view.
6) Cole JA, Rothman KJ, Cabral HJ, Zhang Y, Farraye FA (2006). "Migraine, fibromyalgia, and depression among people with IBS: a prevalence study". BMC gastroenterology 6: 26. doi:10.1186/1471-230X-6-26. PMID 17007634.
7) "Mechanisms of migraine aura revealed by functional MRI in human visual cortex", Hadjikhani et al., PNAS 98 (2001), pages 4687-4692
8) Mitochondrial dysfunction and migraine: evidence and hypotheses.
Review
Cephalalgia. 26(4):361-372, April 2006.
Sparaco, M 1; Feleppa, M 1; Lipton, R B 2,3,4; Rapoport, A M 5,6; Bigal, M E
9) Open label trial of coenzyme Q10 as a migraine preventive.
TD Rozen, ML Oshinsky, CA Gebeline, KC
Cephalalgia:Volume 22(2)March 2002p 137-141
10) Personal observation unpublished data
11) Studies on the rapid stimulation of mitochondrial respiration by thyroid hormones. O'Reilly and Murphy. Acta Endocrinologica, Vol 127, Issue 6, 542-546
12) Unsaturated Vegetable Oils: Toxic. An article posted by Ray Peat Ph.D. at
raypeat.com/articles/articles/unsaturated-oils.shtml
13) ibid.
14) Hypothyroidism: the Unsuspected Illness by Broda Barnes M.D. Ph.D.
15) Thyroid dysfunction in refractory depression: implications for pathophysiology and treatment. Howland, R H J-Clin-Psychiatry. 1993 Feb; 54(2):47-54
16) Leese, Graham & Flynn, Robert. "Is it safe for patients taking thyroxine to have a low but not suppressed serumTSH concentration?," Endocrine Abstracts (2010) 21 OC5.6, Society for Endocrinology BES 2010, 15 March 2010 - 18 March 2010, British Endocrine Societies. Online
17) "Low TSH levels may be safe for patients taking thyroxine replacement." Endocrine Today. Posted on March 22, 2010, Online
Thyroid hormone utilization requires enzyme participation, and recent work on deiodinase polymorphisms reflect a rapidly emerging understanding of the potential role of brain thyroid utilization in the genesis of common functional disorders such as chronic pain, depression, and fatigue.
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