Ionizing radiation damages DNA and other proteins directly, but does most of its dirty work through oxidative damage when a storm of free radicals are generated by the effect of radiation on water molecules inside the cells. That makes the best protection from ionizing radiation a comprehensive approach that optimizes intrinsic resources for ameliorating oxidative and mutagenic damage. Additionally, it is well known that iodine (potassium iodide) can help to protect the thyroid gland by displacing radioactive forms of the element, but should it be taken preventively? In fact, there is a substantial amount of scientific evidence that great care must be taken when recommending iodine for any health concern. Most clinicians that practice according the functional model are aware that the widespread surge in autoimmune disease presents a specific risk because iodine supplementation can trigger latent or aggravate pre-existing autoimmune thyroiditis (Hashimoto’s disease), as illustrated by a paper published recently in the journal Hormones. The authors state:

“Epidemiological studies have linked increased iodide intake from dietary or other sources to the development of hypothyroidism, and it appears that in several—though not all—cases, this phenomenon has an autoimmune basis.”

They further note:

“Within an immunological context, iodine may mediate thyroiditis induction via at least two mechanisms: a) by increased post-translational modification of thyroglobulin (Tg), an event which may enhance the immunopathogenicity of this molecule as detailed further in this review; and b) via apoptotic/necrotic effects of thyrocytes, a step that could initiate presentation of thyroid antigens at immunostimulatory levels.”

All clinicians who manage conditions for which supplemental iodine therapy is contemplated should bear in mind the authors’ conclusion:

“High dietary iodide intake may lead to the development of thyroid autoimmunity via at least two pathways. First, iodide may epigenetically modify the Tg molecule and create iodinated neoantigenic determinants to which immune tolerance has not been established or alter the processing of Tg to facilitate generation of pathogenic but cryptic Tg determinants that may not contain iodine. Second, iodine may precipitate apoptotic/necrotic effects on thyrocytes, thus releasing increased amounts of thyroid antigens that can activate autoreactive T cells in situ or in thyroid-draining lymph nodes. The genetic background of the host may be permissive to one or both of these pathways that may act in synergy or independently of each other.”

The authors of a study published in the Journal of Clinical Endocrinology & Metabolism also weigh in on the subject of hypothyroid due to thyroiditis from high iodine intake:

“Twenty-two patients with spontaneously occurring primary hypothyroidism were studied to evaluate the spontaneous reversibility of the hypothyroid state. Twelve (54.5%) became euthyroid [normal thyroid] after restriction of iodine intake for 3 weeks (reversible type).”

Of particular interest is the finding that:

“Seven patients with the reversible type were given 25 mg iodine daily for 2–4 weeks; all became hypothyroid again...The patients with reversible hypothyroidism had focal lymphocytic thyroiditis changes in the thyroid biopsy specimen, whereas those with irreversible hypothyroidism had more severe destruction of the thyroid gland.”

Their conclusion is consonant with those of the previously mentioned study, and implies that milder forms of thyroiditis may recover if iodine is discontinued:

“These results indicate the existence of a reversible type of hypothyroidism sensitive to iodine restriction and characterized by relatively minor changes in lymphocytic thyroiditis histologically. Attention should be directed to this type of hypothyroidism, because thyroid function may revert to normal with iodine restriction alone.”

Another study published in the journal Biological Trace Element Research finds more evidence for the role of iodine in promoting hypothyroidism. The authors first state:

“Excessive iodine intake is known to induce hypothyroidism in people who have underlying thyroid disorders. However, few studies have been performed on subjects with normal thyroid function without a history of autoimmune thyroid disease. We hypothesized that high iodine intake may cause a subtle change in thyroid function even in subjects with normal thyroid function.“

They examined 337 subjects with normal levels of thyroid antibodies for urinary iodine excretion, free T4 (FT4), and thyroid-stimulating hormone (TSH).

“The results showed urinary iodine excretion had negative correlation with FT4 and showed a positive trend with TSH. We found that 61.7% of subjects had circulating TPO-Ab within normal reference range. In all subjects, TPO-Ab levels were negatively correlated with FT4 and positively with TSH.”

In other words, as iodine went up the thyroid hormone free T4 went down and TSH (thyroid stimulating hormone)—bother markers for hypothyroid disease. Additionally, while 38.3% had high levels of thyroid peroxidase antibody (proof of autoimmune thyroiditis), for everyone higher levels of TPO-Ab correlated with lower free T4 and higher TSH. (Personally, I have observed that the standard reference ranges for thyroid antibodies are too ‘generous’.) They authors summarize the implications of their data:

“In conclusion, high iodine intake can negatively affect thyroid hormone levels in subjects with normal thyroid function.”

I have heard the Japanese consumption of seaweed cited as evidence for allowing higher levels of iodine intake, but a study published in the Endocrine Journal (of the Japanese Endocrine Society) contradicts this assumption.

“The effect of ingesting seaweed “Kombu” (Laminaria japonica) on thyroid function was studied in normal Japanese adults. Ingesting 15 and 30 g of Kombu (iodine contents: 35 and 70 mg) daily for a short term (7-10 days) significantly increased serum thyrotropin (TSH) concentrations, exceeding the normal limits in some subjects…During long term daily ingestion of 15 g of Kombu (55-87 days), the TSH levels were elevated and sustained while the FT4 and FT3 levels were almost unchanged. Urinary excretion of iodine significantly increased during ingestion of Kombu. These abnormal values returned to the initial levels 7 to 40 days after discontinuing the ingestion of Kombu.”

In other words, a diet  heavy on the seaweed Kombu can introduce enough iodine to suppress thyroid function. The authors conclude by recommending:

“Based on these findings that thyroid function was suppressed during ingestion of Kombu, though the effect was reversible, we recommend Japanese people avoid ingesting excessive amounts of seaweed.”

Their findings are echoed in a paper published recently in The Medical Journal of Australia which reports…

“…a series of cases of thyroid dysfunction in adults associated with ingestion of a brand of soy milk manufactured with kombu (seaweed), and a case of hypothyroidism in a neonate whose mother had been drinking this milk. We also report two cases of neonatal hypothyroidism linked to maternal ingestion of seaweed made into soup. These products were found to contain high levels of iodine.”

Happily, in both cases the TSH returned and the patients recovered after discontinuing the seaweed enriched soy milk. The conclude with this alert:

“Despite increasing awareness of iodine deficiency, the potential for iodine toxicity, particularly from sources such as seaweed, is less well recognised.“

Another paper just published in the Journal of Paediatrics and Child Health reports a similar phenomenon and offers a balanced conclusion:

“Mild iodine deficiency is a recognised problem in Australia and New Zealand. However, iodine excess can cause hypothyroidism in some infants. We highlight two cases which illustrate the risks of excess dietary iodine intake during pregnancy and breastfeeding. They also describe a cultural practice of consuming seaweed soup to promote breast milk supply. Although most attention recently has been on the inadequacy of iodine in Australian diets, the reverse situation should not be overlooked. Neither feast nor famine is desirable.“

Caution should be used even when applying topical iodine as an antiseptic as reported in a paper published in the journal Anales española de pediatría. They note that iodine-containing antiseptics are still common in obstetrics and neonatology, and that…

“Topical iodine given both to the mother before delivery and to the neonate causes iodine overload. The absorption of maternal iodine through the skin is so fast that iodine in the blood of the umbilical cord increases by 50% a few minutes before delivery. Iodine overload also occurs in the mother. Urinary and breast-milk iodine are increased more than 10-fold in the days after delivery if providone-iodine is used in episiotomy. The overload in the neonate is even higher if breast-fed….this overload can produce thyroid blockade…”

The effects of thyroid blockade in the infant are potentially very serious, especially considering the importance of thyroid function for brain development. The authors conclude with a warning:

“Attention should be drawn to the undesirable effects of iodine antiseptics and their use in the perinatal period should be avoided.“

Of course there is a place for iodine supplementation in cases of deficiency conditions (which can manifest in a variety of ways) along with prophylaxis for disastrous exposure to ionizing radiation, but generally speaking, how much is enough? A very nice study on a chronically iodine-deficient population was recently published in the journal Endokrynologia Polska (Polish Journal of Endocrinology):

“Until 1997, Poland was one of the European countries suffering from mild/moderate iodine deficiency. In 1997, a national iodine prophylaxis programme was implemented based on mandatory iodisation of household salt with 30 ± 10 mg KI/kg salt, obligatory iodisation of neonatal formula with 10 μg KI/100 mL and voluntary supplementation of pregnant and breast-feeding women with additional 100-150 μg of iodine. Our aim in this study was to evaluate the iodine status of pregnant women ten years after iodine prophylaxis was introduced.“

They examined 100 healthy pregnant women between the fifth and the 38th week of pregnancy for serum TSH, fT(4), fT(3), thyroglobulin (TG), anti-peroxidase antibodies (TPO-Ab), anti-thyroglobulin antibodies (TGAb), urinary iodine concentration (UIC) and thyroid volume and structure by ultrasonography. This really was an iodine-deficient population—28% of the subjects had a goiter. What did their data show?

“Median UIC was significantly higher in the group receiving iodine supplements than in the group without iodine supplements…Serum TSH, fT(3) and fT(3)/fT(4) molar ratio increased significantly during pregnancy while fT(4) declined. Median serum TG was normal: 18.3 ng/mL (range 0.4-300.0 ng/mL) and did not differ between trimesters. Neonatal TSH performed on the third day of life as a neonatal screening test for hypothyroidism was normal.”

Thus the authors concluded:

“Iodine supplements with 150 μg of iodine should be prescribed for each healthy pregnant [Polish] woman according to the assumptions of Polish iodine prophylaxis programme to obtain adequate iodine supply.”

Here is a point worth noting for those who are aware of a recent trend for prescribing extremely high doses of supplemental iodine, as high as 50 mg per day and sometimes more: 50 mg = 50,000 μg (micrograms). That’s 333 times the amount recommended by the Polish study. This is not to say that there are never cases where megadoses of iodine may be indicated, but clinicians should maintain a biological perspective and exercise caution.

Regarding tools to support the practitioner’s thoughtful efforts to structure a careful approach to thyroid case management and iodine supplementation, can we rely on urinary iodine concentration (UIC) as a metric? A study published in Clinical Endocrinology suggests that we can’t. The authors set out to…

“…measure breast milk iodine (MI) and urinary iodine (UI) concentrations in healthy newborns and their nursing mothers from an iodine-sufficient region to determine adequacy and to relate these parameters to thyroid function tests in mothers and infants.”

Their study cohort included 48 healthy neonates of 37 to 42 weeks’ gestation and their mothers. Serum thyroid function tests and urinary iodine excretion were measured for infants and mothers, and maternal milk iodine concentration were measured. What did their data show?

“Neonatal and maternal UI did not correlate with serum thyroid function tests…Among euthyroid neonates, UI was adequate despite low median maternal UI and MI concentrations. There were no significant correlations between UI or MI and thyroid function tests in the mothers and infants.“

What about in cases where there is documented thyroid dysfunction? Is urinary iodine a correlative marker in this patient population. An interesting study published in the journal Endocrine implies that it is not. The authors state:

“The prevalence of thyroid dysfunction varies in different populations. The aim of this cross-sectional study was to analyze the prevalence of undiagnosed thyroid dysfunction and thyroid antibodies and their relationship with urine iodine excretion in a representative sample of 1,124 (55.5% women; mean age: 44.8 ± 15.2 years) non-hospitalized Mediterranean adults, in Catalonia (Spain).”

They measured free thyroxine (fT4), thyroid-stimulating hormone (TSH), thyroperoxidase and thyroglobulin antibodies, and urine iodine. Interestingly, they found thyroid dysfunction in 8.9% of their subjects with 5.3% previously undiagnosed (13.61% and 9.8% in those over age 60). Rough indicators of autoimmune thyroiditis were present: thyroperoxidase antibodies in 2.4% of men and 9.4% of women and thyroglobulin antibodies in 1.3% of men and 3.8% of women. What about the correlation with urine iodine?

“No differences were observed in urine iodine between groups with thyroid dysfunction and euthyroidism, or between subjects with positive or negative antibodies.“

In other words, urine iodine completely failed to discriminate between those with normal and abnormal thyroid function.

Here’s what the evidence boils down to: iodine supplementation has its place when used with sound clinical judgment and a biological perspective in the hands of a practitioner with the knowledge and experience to assess the need and tolerance of each individual patient with care. As for protection from harmful doses of ionizing radiation, clinicians who employ a functional medicine perspective are well equipped to evaluate your resources for ameliorating oxidative and mutagenic stresses.

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A study just published in the Archives of Internal Medicine presents evidence that taking levothyroxine (T4, thyroid hormone) before bed raises levels more effectively. But it also illustrates the important practical point that it still doesn’t help most patients to feel better anyway (because of the autoimmune dynamics of most hypothyroid cases). The authors state:

“There is consensus that levothyroxine should be taken in the morning on an empty stomach. A pilot study showed that levothyroxine intake at bedtime significantly decreased thyrotropin levels and increased free thyroxine and total triiodothyronine levels…To ascertain if levothyroxine intake at bedtime instead of in the morning improves thyroid hormone levels, a randomized double-blind crossover trial was performed.”

Patients at Maasstad Hospital Rotterdam in the Netherlands took a capsule in the morning and at bedtime. One was levothyroxine and the other placebo. After three months the capsules were ‘reversed’. The authors followed thyroid hormone levels, creatinine, lipids, body mass index, heart rate, and quality of life. What did the data show?

“Ninety patients completed the trial and were available for analysis. Compared with morning intake, direct treatment effects when levothyroxine was taken at bedtime were a decrease in thyrotropin [TSH, due to increase thyroxine] level of 1.25 mIU/L, an increase in free thyroxine level of 0.07 ng/dL, and an increase in total triiodothyronine level of 6.5 ng/dL.”

BUT…

“Secondary outcomes, including quality-of-life questionnaires (36-Item Short Form Health Survey, Hospital Anxiety and Depression Scale, 20-Item Multidimensional Fatigue Inventory, and a symptoms questionnaire), showed no significant changes between morning vs bedtime intake of levothyroxine.”

The authors concluded:

“Levothyroxine taken at bedtime significantly improved thyroid hormone levels. Quality-of-life variables and plasma lipid levels showed no significant changes with bedtime vs morning intake.“

Why? Because most hypothyroid in developed countries is autoimmune in nature. The background inflammatory activity impairs thyroid receptor function and upregulation of the relevant genes. For those interested in the functional medicine approach to thyroid conditions see Dr. Kharrazian’s Why Do I Still Have Thyroid Symptoms under Useful Links on the right.

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Thyroid dysfunction is not to be overlooked as a possible contributing cause to problems with learning, behavior and brain development. It can be expressed in a variety of ways, often requiring a nuanced functional analysis to detect and solve the problem. A study published in the journal Brain Research discusses an often overlooked type of thyroid dysregulation that can contribute to ADHD. The authors state:

“Attention deficit disorders are a frequent manifestation of resistance to thyroid hormone (RTH), a disorder caused by mutations in the hormone-binding domain of the human thyroid hormone receptor β gene.”

They used PET scans to measure cerebral glucose metabolism in regions of the brain involved in attention, comparing normal subjects to those with RTH. A clear-cut difference was observed:

“Compared to the control group, performance on a continuous auditory discrimination task was severely impaired in the RTH subjects, while metabolism was higher both in the right parietal cortex and the anterior cingulate gyrus. Abnormally high functional activity of the anterior cingulate during sustained attention may be associated with a decreased signal-to-noise ratio for the neural processing of task stimuli in subjects with RTH.“

In other words, resistance to thyroid hormone was associated with impaired function in the parts of the brain that are active in paying attention to and processing what we are trying to listen to. Other parts of the brain went into ‘hyperdrive’ in an attempt to compensate. Remember that this type of thyroid dysfunction, peripheral resistance to thyroid hormone, will appear normal on the usual lab tests.

A paper published in Pediatric Neurology directs our attention to the disruption of learning and behavior caused by subclinical hyperthyroidism—’subclinical’ meaning that no other overt signs of hyperthyroid are clinically apparent. The authors…

“…report three children who exhibited developmental learning disabilities (DLDs) associated with behavioral disturbances, such as attention deficit, hyperactivity, and autistic features. The thyroid function tests performed as a part of routine endocrinologic evaluation of children with DLDs revealed a hormonal profile consistent with hyperthyroidism. These children had no systemic signs of hyperthyroidism.”

Though it may not be the most sustainable long-term therapy from a functional perspective, they treated with medication to suppress thyroid hormone synthesis and reported that it…

“…resulted in good control of their hyperkinetic behavior and subsequent improvement in language function attributable to an increased attention span, thereby facilitating speech therapy.”

Although only a subset of children with learning and behavioral disorders will be found to found to have subclinical hyperthyroidism, it is a possibility that should be borne in mind and ‘crossed off the list’. The authors state:

“Although routine screening of all children with DLDs for thyroid dysfunction may not be cost-effective, selective screening of children with familial attention-deficit hyperactivity disorder and those with attention-deficit and hyperactivity in association with DLDs and pervasive developmental disorders appears to be justified.”

Another study published in the journal Psychoneuroendocrinology draws our attention to functional disturbances in thyroid hormone regulation from a different perspective. The authors state:

“Thyroid abnormalities have been associated with attention deficit/hyperactivity disorder (ADHD) and with other childhood psychiatric disorders. The goal of this study was to determine the relationships between thyroid hormone concentrations, neurocognitive functioning, and psychiatric diagnosis in children.”

They examined 338 children referred to a clinic for learning and behavior problems, measuring their thyroid stimulating hormone (TSH) levels and free thyroxine index (FT4I) and correlating them with diagnostic and descriptive information. Not surprisingly, the data showed that it was the more subtle functional abnormalities rather than gross pathologic ones that discriminated different types of ADHD:

“Thyroid abnormalities were uncommon in children referred for ADHD. After excluding children with thyroid disease, there was a greater proportion with low concentrations of normal FT4I for ADHD–Predominantly Inattentive type, but not for ADHD–Combined Type. High concentrations of normal FT4I were associated with mood lability, preoccupations, and lower ratings of attention problems. Thyroxine concentrations within the normal range were differentially associated with ADHD–Combined Type compared to ADHD–Predominantly Inattentive, mood disorders, and pervasive developmental disorders.”

The authors sum up their findings for this group of children with subtle disturbances in thyroxine regulation:

“Thyroxine concentrations were associated with mood symptoms and unusual behaviors, and were less strongly related to attentional functioning. Thyroxine concentrations were not related to hyperactivity.”

We can gain additional insight into the issue of thyroid hormone resistance and ADHD from a case report published in the journal Deutsche Medizinische Wochenschrift (German Medical Weekly). The authors state:

“Two siblings with goiter and attention deficit-hyperactivity disorder were presented. Earlier laboratory tests showed increased serum levels of thyroid hormones in association with non-suppressed serum levels of thyrotropin (TSH) in both children.”

Review for lay readers: as in the first paper cited, elevation of thyroid hormones in hyperthyroidism is accompanied by low levels of TSH (thyroid stimulating hormone ‘aka’ thyrotropin, which is  produced in the pituitary; it stimulates thyroid hormone production in the thyroid gland on a feedback loop). Resistance to thyroid hormone by its receptors in the rest of the body can cause TSH to be high even when thyroid hormones are elevated. Peripheral resistance can also cause a low thyroid state with labs that look normal. The doctors in this case did what was necessary to rule out hyperthyroid disease:

“Because hyperthyroidism caused by inappropriate secretion of thyrotropin was suspected, a cerebral MRI was performed. A pituitary adenoma was excluded in both children. Before antithyroid drug treatment was initiated, both patients were referred to our hospital. Careful medical history, clinical examination of the patients and careful interpretation of the laboratory results finally led to the diagnosis resistance to thyroid hormone (RTH).”

This spared the children inappropriate aggressive thyrostatic treatment (thyroid suppression or destruction). Moreover, there are functional therapies for RTH. I certainly concur with the authors’ conclusion:

“Careful medical history, correct interpretation of laboratory results, comprehensive clinical examination and molecular genetic analysis are important in the diagnosis of RTH.”

A paper recently published in the Journal of Affective Disorders sheds more light on how profound thyroid dysregulation evidenced by an increase TSH can be. The authors begin by observing:

“The relationship of bipolar disorder (BD) and altered thyroid function is increasingly recognized. Recently, a behavioral phenotype of co-occurring deviance on the Anxious/Depressed (A/D), Attention Problems (AP), and Aggressive Behavior (AB) syndrome scales has been identified as the Child Behavior Checklist Dysregulation Profile (CBCL-DP), which itself has been linked to BD. This study tested for differences in thyroid function within a sample of psychiatric children and adolescents with and without the CBCL-DP.”

They correlated the CBCL-DP scores according to each behavioral phenotype with serum levels of TSH, fT3 (free T3) and fT4 (free T4). What did their data show?

“In participants showing the CBCL-DP, basal serum TSH was elevated compared to controls. More CBCL-DP subjects than controls showed subclinical hypothyroidism. No differences were observed for serum fT3 and fT4 levels.“

Here again we see the manifestation of resistance to thyroid hormone, this time with elevated TSH and normal fT3 and fT4. It is likely, in our experience, that the chronic microinflammation resulting in peripheral resistance to thyroid hormone (RTH) is due to autoimmune/allergic phenomena that are simultaneously activating microglial cells (immune cells in the brain) to produce neuroinflammation. In this case the brain gets a ‘double whammy’—RTH and brain inflammation.

Bringing the matter even more up to date, an excellent and important paper recently published in the journal Clinical Endocrinology clearly articulates why it is mandatory for clinicians to be alert to functional changes in thyroid hormone measurements that are usually within the ‘normal’ laboratory reference range.The authors stated their initial objective:

“Thyroid hormone concentrations outside the normal range affect brain development, but their specific influence on behaviour and mental abilities within normal values is unknown. The objective of this study was to investigate whether thyroid hormone concentrations are related to neurodevelopment and ADHD (attention deficit and hyperactivity disorder) symptoms in healthy preschoolers.”

They assessed mental and motor development with McCarthy’s scales for neuropsychological outcomes and ADHD-DSM-IV for ADHD symptoms, correlating them with thyroid hormones TSH, free T4 and T3. What did the data show?

“Children with TSH concentrations in the upper quartile of the normal range performed lower on McCarthy’s scales and were at higher risk for attention deficit and hyperactivity/impulsivity symptoms. In the Menorca cohort, a decrease of 5·8 and 6·9 points was observed in memory and quantitative skills, respectively. In contrast, high T4 concentrations were associated with decreased risk of having 1–5 attention deficit symptoms…No associations were observed with T3.”

Bottom line: when there are symptoms of learning, behavioral or developmental disorders, the astute parent or clinician must ask “Is there any indication that thyroid function needs to be investigated in this case?” If so, it must be borne in mind that there are types of thyroid dysfunction that occur in the presence of ‘normal’ values for TSH, T3 and T4. The authors emphasize this in their conclusion:

“Despite being within the normal range, high TSH concentrations are associated with a lower cognitive function and high TSH and low free T4 with ADHD symptoms in healthy preschoolers. Statistically significant differences were observed in the highest quartiles of TSH, suggesting a need for re-evaluation of the upper limit of the normal TSH range.“

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There is a large body of evidence that compels us not to overlook hormonal dysregulation in ADHD and other disorders of learning, behavior and brain development. A paper published not long ago in the journal European Neuropsychopharmacology addresses the broad topic of neurosteroids. The authors state in regard to the steroid hormones active in the nervous system:

“Neurosteroids play a significant role in neurodevelopment and are involved in a wide variety of psychopathological processes…there is increasing evidence for their critical role from the early stages of brain development until adolescence.“

They proceed to review the involvement of neurosteroids in neurodevelopment and mental disorders in children and adolescents, noting in particular:

“Adequate physiological levels protect the developing neural system from insult and contribute to the regulation of brain organization and function. Neurosteroids may be involved in the pathophysiology and pharmacotherapy of a variety of disorders in children and adolescents, including schizophrenia, depression, eating disorders, aggressive behavior and attention deficit.”

A paper published in the journal Neuropediatrics examines the association of hypothalamo-pituitary-adrenal (HPA) axis dysfunction and intelligence performance:

“The aim of the present study was to examine the effects of hypothalamo-pituitary-adrenal (HPA) axis reactivity on intelligence test performance in subjects with attention-deficit/hyperactivity disorder (ADHD). We investigated the extent to which an increase or decrease in cortisol after stress was associated with the intelligence test performance in 68 clinic-referred children with ADHD.”

They administered a battery of tests for both assessment and stressor applications, plus…

“A saliva sample was collected from each subject before and after psychological testing in order to measure the level of cortisol in the saliva.”

Salivary cortisol is the most reliable and necessarily non-invasive way to measure functional cortisol levels as we know here from extensive clinical experience. Their data painted a striking picture:

“Decreases in the level of cortisol after the test were correlated with poor intelligence performance and the decrease of cortisol in respect to baseline significantly affected the verbal, performance and total IQ in subjects who showed blunted responses to stress.”

A fine study published recently in the Chinese Journal of Contemporary Pediatrics further investigates…

“…the function of the hypothalamus-pituitary-adrenal (HPA) axis in children with attention deficit hyperactivity disorder (ADHD).”

128 boys with ADHD at ages of 6 to 14 years were diagnosed and grouped according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV): ADHD-predominantly inattention type, ADHD-predominantly hyperactive impulsive type and ADHD-combined type. 30 healthy boys served as the control group. They tested cortisol and assessed intelligence level with Raven′s standard progressive matrices. What did the data show?

“The mean plasma cortisol level in the ADHD group was significantly lower than that in the control group. The three ADHD subgroups showed significantly decreased plasma cortisol level compared with the control group. The plasma level of cortisol was the lowest in the ADHD-HI group, followed by the ADHD-I group and the ADHD-C group.”

Their conclusion should be borne in mind by both clinicians and parents:

“In the non-stress state, the HPA axis may be dysfunctional in children with ADHD, which may be attributed to the under reactivity of the HPA axis. Lower plasma cortisol…may closely be related to attention deficit, hyperactivity and impulsive behaviors.“

More valuable research was published in the Yonsei Medical Journal (Korea) in which the authors state:

“Children with attention-deficit/hyperactivity disorder (ADHD) often perform poorly during cognitive tests. We sought to evaluate cortisol as potential moderator of performance in mentally challenging tasks in children with ADHD.”

They measured salivary cortisol in 90 children with ADHD before and after administration of a continuous performance test (CPT). Their data adds evidence that cortisol dysregulation in association with poorer performance can be either abnormally high or low:

“Children whose cortisol level increased after testing displayed a significantly longer response time and increased response time variability scores as compared to children who did not display increase of cortisol after the CPT test.”

Since activation of α1 adrenergic receptor mediates both cortisol level increase and attention impairment, they also conclude that in association with cortisol:

“The result of the current study suggests that stress-induced high norepinephrine (NE) release may accompany poorer attention performance in patients with ADHD.”

The authors of a paper published in European Child & Adolescent Psychiatry offer additional evidence that children with ADHD must be evaluated as individuals for varying patterns of cortisol dysregulation:

“The aim of this study was to investigate whether a different pattern of HPA axis activity is found between the inattentive (I) and combined (C) subtypes of ADHD, in comparison with healthy control children.”

They studied the effects of stress by comparing cortisol responses to a psychosocial stressor (a public speaking task). Their data revealed interesting differences:

“Children with ADHD-I showed an elevated cortisol response to the psychosocial stressor, in contrast to children with ADHD-C who showed a blunted cortisol response to the psychosocial stressor…hyperactivity symptoms were clearly related to a lower cortisol reactivity to stress. The results indicate that a low-cortisol responsivity to stress may be a neurobiological marker for children with ADHD-C, but not for those with ADHD-I.”

The authors of a paper published in the Journal of Attention Disorders draw our attention to the link between sensory hyperarousal and HPA axis dysregulation with their investigation of salivary cortisol levels:

“To determine if sensory overresponsivity (SOR) is a moderating condition impacting the activity of the Hypothalamic Pituitary Adrenal (HPA) Axis in children with ADHD.”

Children with ADHD and known SOR were compared with those with ADHD but without SOR and normal children, all of whom participated in a Sensory Challenge Protocol. Salivary cortisol was used as a measure of HPA activity with two prechallenge and seven postchallenge samples taken. Interestingly, their data showed…

“…a borderline significant difference found between the ADHDt [without SOR] and ADHDs [with SOR] group and a significant difference between ADHDt and the typical [normal] group.”

In other words, salivary cortisol measurements distinguished both ADHD groups from the normal group.

Clarification of the different patterns of HPA axis dysregulation in ADHD was reported in the Journal of Abnormal Child Psychology:

“Disruptions to hypothalamic-pituitary-adrenal (HPA) axis function have been associated with varying forms of psychopathology in children. Studies suggesting children with ADHD have blunted HPA function have been complicated by the prevalence of comorbid diagnoses and heterogeneity of ADHD. The goals of this research were to assess the relations between waking and stress–response salivary cortisol levels and comorbid disruptive behavior (DBD) and anxiety (AnxD) disorders and problems in boys with ADHD, and to examine whether cortisol levels varied across ADHD subtypes.”

The authors examined salivary cortisol on waking and in reaction to venipuncture (to determine stress-response levels), psychiatric symptoms and behavioral problems in 170 elementary school-age boys. The data left no doubt that there are dysfunctional subtypes of ADHD, emphasizing the importance of evaluating each child as an individual:

“Boys’ comorbid AnxD and anxiety problems were associated with greater cortisol reactivity, whereas boys’ comorbid DBD and oppositional problems predicted diminished adrenocortical activity. Reactive cortisol increases were greatest in boys with ADHD and comorbid AnxD, but without DBD…comorbid DBD predicted decreased cortisol reactivity in boys with inattentive and hyperactive subtypes of ADHD, but not in boys with combined subtype of ADHD. The results clarify previous patterns of distinct and divergent dysregulations of HPA function associated with boys’ varying kinds of psychopathology.”

By the way, note that venipuncture (drawing blood) was used elicit a cortisol-modifying stress response. This is one reason why we use saliva instead of blood tests for cortisol.

We can add to this a study published in the journal Child Psychiatry & Human Development that further examines HPA axis dysregulation in a specific subtype of ADHD. The authors set out…

“To investigate the hypothalamic pituitary adrenal (HPA) axis response to a stressor in adolescents with inattentive type attention-deficit hyperactivity disorder symptoms (ADHD-I).”

They too used salivary cortisol measurements as a metric in response to a social/cognitive stressor for threshold inattentive (TI), moderately inattentive (MI) and no symptom groups of healthy adolescents. A distinction was present in this study as well:

“The TI group displayed a significant decrease in cortisol post stressor whereas both the MI and comparison groups showed an increase in cortisol.”

We can also appreciate a study published in the journal Psychiatry Research that looks specifically at aggressive behavior and cortisol. The authors state:

“We examined the relationship between the cortisol response to stress and aggression in patients with attention deficit hyperactivity disorder (ADHD). Based on a report stating that only some of the patients with ADHD retain their hypothalamic-pituitary-adrenal axis reactivity to stress, we separately analyzed the relationship between aggression and the cortisol response to stress in two groups according to their reactivity to stress.”

Their data included psychological testing as a stress indicator with salivary cortisol measurements made before and after psychological test administration. Behavioral problems and aggression were assessed with the local (Korean) version of the Child Behavior Checklist. Their findings also showed the connection:

“The increase of the cortisol level was inversely correlated with aggression in patients who retained their reactivity to stress. The absolute value of the decrease was negatively correlated with the attention score of the CBCL for the patients who showed decreases in cortisol after stress. For the patients who showed increases in their concentration of cortisol in reaction to stress, cortisol may play a protective role against aggression.”

In other words, when cortisol went down aggression went up and attention scored worse. As we can see, there is a large body of evidence showing that we must consider the possibility of hypothalamic-pituitary-adrenal dysregulation in pediatric disorders of learning and behavior. This is best assessed by the functional approach that encompasses the multiple factors such as blood sugar dysregulation, inflammation from allergy or autoimmunity, etc. that can be contributing causes to HPA axis dysfunction, along with experienced assessment of salivary cortisol levels together with associated laboratory findings.

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This paper published in the medical journal Menopause International touches on the huge topic of thyroid dysfunction before, during and after menopause. As the author states, “Thyroid dysfunction is common, especially among women over the age of 50. In caring for peri- and post-menopausal women, it is important to recognize the changing clinical manifestations of thyroid disease with age.” Subclinical hypo and hyperthyroidism (thyroid dysfunction in the presence of normal TSH levels), an extremely important topic that you will see more about here, is noted in particular. The author notes, “…caution is required in diagnosing and treating thyroid dysfunction in women who are taking oral estrogens or selective estrogen receptor modulators.” The functional approach that fully examines and treats the two dozen underlying patterns of thyroid dysfunction with appropriate tests and therapies is far more extensive than indicated here. See Dr. Kharrazian’s book for an overview for the layperson.

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Numerous studies have noted the association of autoimmune thyroid disease and celiac disease (not to mention the more widespread non-celiac gluten sensitivity). This recent paper in Nature Reviews Endocrinology asserts that “Clinicians should screen for autoimmune thyroiditis in all patients with celiac disease.”

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Thyroid function is critical during every stage of life  but is especially vulnerable at menopause. As this paper from the journal of the International Society of Gynecological Endocrinology states: “The symptoms of thyroid disease can be similar to postmenopausal complaints and are clinically difficult to differentiate…It is of importance that even mild thyroid failure can have a number of clinical effects such as depression, memory loss, cognitive impairment and a variety of neuromuscular complaints…There is also an increased cardiovascular risk.” Inadequate assessment and calibration of estrogen support is another menopausal hazard for the thyroid as this research concludes: “Low estrogen level may lead to mild thyroidal hypofunction while estradiol treatment may lead to hyperactivity so it should be used very cautiously in the treatment of postmenopausal symptoms to avoid its undesirable stimulatory effect on the thyroid.”

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