CHAPTER 6 Endocrine Disorders and Adrenal Support
THYROID DISORDERS: HYPOTHYROIDISM AND HYPERTHYROIDISM
Thyroid disease is a disorder in women that, left untreated, can exact pronounced consequences on health and quality of life.1,2 Thyroid dysfunction in women can alter menstrual regularity, affect reproduction, and lead to infertility, miscarriage, and affect intelligence in children born to women with untreated thyroid disorders during pregnancy. 3 4 5 6 7 Long-term, untreated thyroid conditions significantly increase the risk of cardiovascular disease, osteoporosis, reproductive cancer, and multisystem failure. Approximately 5% of Americans report having thyroid disease or taking thyroid medication, and numerous individuals have undiagnosed thyroid disorders.2 The most common thyroid disorders are hypothyroidism, both clinical and subclinical, and hyperthyroidism. Detection and treatment of most thyroid disorders is straightforward and can prevent long-term and potentially disastrous sequelae that may occur in the absence of appropriate care.
HYPOTHYROIDISM
Hypothyroidism is a persistent insufficiency in thyroid hormone production leading to a generalized decrease in metabolic functions (Box 6-1). It is the most prevalent of the pathologic hormone deficiencies, and can reduce physical and mental functional ability, quality of life, and long-term health.2,8 Hypothyroidism is classified on the basis of onset (congenital or acquired), endocrine dysfunction level (primary, secondary, or tertiary), and severity, which is classified as overt (clinical) or mild (subclinical) hypothyroidism.8 The total frequency of hypothyroidism, including subclinical cases, among adult females from all age groups, ranges from 3.0% to 7.5%, with significantly higher rates in women over 60 years old.1 Hypothyroidism occurs at a rate approximately 10 times higher in women than men.9
Pathophysiology
Hypothyroidism is classified as primary, secondary, or tertiary. Primary hypothyroidism is significantly more common than secondary, occurring at a rate of approximately 1000:1, and tertiary hypothyroidism, resulting from disease in the hypothalamus, is rare.8,10 Myxoedema refers to severe or complicated cases of overt hypothyroidism with cretinism syndrome, and is extremely rare.8 Those at increased risk of developing hypothyroidism include:9
The following biological activities are particularly impaired by hypothyroidism:8
The clinical manifestations of hypothyroidism (see Symptoms) are the result of effects occurring at the molecular level because of the impact of thyroid hormone insufficiency.8
Primary Hypothyroidism
Primary hypothyroidism is the most common form of hypothyroid disorder. It may be either congenital or acquired. Globally, the most common cause of congenital hypothyroidism is endemic iodine deficiency; however, it may also result from thyroid gland agenesis, defective thyroid hormone biosynthesis, or rarely, hemangiomas, which also may occur in young children.8,9 (Congenital hypothyroidism is not discussed in the remainder of this section.)
The most common form of primary hypothyroidism in areas of normal iodine intake is acquired primary hypothyroidism. It is most frequently a result of autoimmunity and is referred to as autoimmune thyroid disease (AITD) or autoimmune thyroiditis (Hashimoto’s disease).1,7,8 Antibodies are formed that bind to the thyroid (specifically against the thyroid peroxidase [TPO] enzyme, thyroglobulin, and TSH receptors) and prevent the manufacture of sufficient levels of thyroid hormone. In addition to binding to thyroid tissue, these antibodies also may bind to the adrenal glands, pancreas, and parietal cells of the stomach. Autoimmunity as an etiologic factor is supported by the presence of lymphatic infiltration of the thyroid gland and the presence of circulating thyroid autoantibodies in nearly all affected patients.8 In fact, the most common risk factor for both hypothyroidism and hyperthyroidism is the presence of TPO autoantibodies.1 Genetic predisposition (autosomal dominant inheritance) is a major factor in the etiology of AITD, accounting for as much as 79% of susceptibility to autoimmunity.1,8 Hormonal and environmental factors appear to account for the remaining etiologies.1 Autoimmune thyroiditis is increased in areas of high iodine intake, for example, in Iceland, suggesting an antigenic response.1,8
Other causes of hypothyroidism include iatrogenesis secondary to radiation or medications that interfere with thyroid function, genetic defects of the T3 hormone receptors and excessive consumption of goitrogens (substances that interfere with thyroid hormone production and release). Postpartum hypothyroidism is a transient form of hypothyroidism that affects 5% to 10% of postpartum women in the United States.11 Transient hypothyroidism may occur secondary to subacute thyroiditis caused by infection. Primary hypothyroidism is often idiopathic, with no definable cause.7
The long-term consequences of untreated overt hypothyroidism are significant, and include elevated cholesterol and atherosclerosis, cardiac, renal, and neurologic diseases, increased susceptibility to infectious diseases, possibly increased rates of reproductive cancers, and ultimately, multiple organ failure if the disease progresses.7,12,13 Hypothyroidism is readily detectable and treatable; therefore, these consequences should be almost entirely avoidable with screening and early treatment.
Subclinical Hypothyroidism
Subclinical hypothyroidism refers to patients with primary hypothyroidism with normal serum free thyroxine (free T4) and elevated thyroid-stimulating hormone (TSH).2 These individuals may or may not be symptomatic. Low Dog suggests that symptomatic euthyroid state is a more appropriate label for these patients.10
The prevalence of subclinical hypothyroidism is highest in the United States among white women (5.8%), and is 5.3% and 1.2% among Hispanic-American and African-American women, respectively. Rates tend to increase significantly with age, reaching as high as 8% to 10% in women ages 45 to 74 years, and 17.4% in women over 75 years.14
There is strong evidence from high-quality longitudinal studies that subclinical hypothyroidism places women at significant risk for the later development of overt hypothyroidism, yet it frequently goes undetected and untreated.2 Untreated subclinical hypothyroidism can lead to daily interference with optimal physical, neurologic, psychological, and emotional functioning, and can cause a diminished quality of life. Controversy exists regarding the routine screening and treatment of subclinical hypothyroidism for all women, a practice that has not been well studied or determined to be conclusively beneficial. 7 8 9 Its proponents argue that preventative treatment with thyroxine is relatively safe, effective, and inexpensive, and can prevent the development of overt hypothyroidism and its consequences.7,8 Further, women who have been treated for subclinical hypothyroidism have retrospectively reported improvements in their physical and mental wellness.7 Patients with subclinical hypothyroidism and abnormal lipid profiles may experience improvement within 1 month of thyroxine treatment.7 Subtle and reversible changes in myocardial performance also have been reported in women with mild hypothyroidism.8 Careful follow-up is essential, with periodic re-evaluation of relevant laboratory markers and symptoms. Because of the frequency of hypothyroidism in older women, routine screening and treatment may be justified in this population. Routine screening also may be prudent during pregnancy, because of the serious consequences of long-term cognitive dysfunction and decreased intelligence in the offspring of women with untreated prenatal hypothyroidism.6
Secondary Hypothyroidism
Secondary hypothyroidism can result from diseases that interfere with thyrotropin-releasing hormone (TRH) production by the hypothalamus, its delivery by the pituitary stalk, or with problems of pituitary thyrotropin production (e.g., pituitary adenomas, hypothalamic tumors, or their treatments such as surgery or radiation therapy). Head trauma, metastatic disease, and infection can also lead to secondary hypotyroidism.8 Iatrogenic hypothyroidism is the second most common cause and is the result of radioactive iodine therapy or ablation treatment for Graves’ disease and other forms of hyperthyroidism.
Signs and Symptoms
Any of the symptoms listed in Box 6-2 may be present in degrees ranging from mild (requiring careful discernment of the clinical picture) to severe. Hypothyroidism may also be asymptomatic, detectable only by laboratory screening. Hypothyroidism is commonly overlooked clinically because of the presence of these symptoms in any number of other diseases.
Diagnosis
TSH measurement is commonly accepted as the most significant and sensitive measurement for hypothyroidism diagnosis. Elevated TSH identifies patients with primary hypothyroidism regardless of the cause or severity.8 Primary hypothyroidism presents with a low serum T4 with attendant elevation of serum TSH. Subclinical hypothyroidism is marked by normal serum T4 levels with slight to moderately increased TSH levels and a normal FTI (Table 6-1). Laboratory tests are considered generally unnecessary to determine the underlying cause of primary hypothyroidism. Factors such as previous neck/thyroid irradiation or surgery, or other exposure to radiation (e.g., pharmaceutical exposure) postpartum status, or other known contributing factors is adequate. Autoimmune causes can be assumed on the basis of ruling out other possible etiologies.8 An important note is that serum TSH levels may rise in the recovery phase of illness, mimicking values associated with hypothyroidism. Therefore, measurement of TSH after complete recovery is appropriate. Free T4 is required to give an accurate measurement of thyroid hormone activity, given that only 0.03% of total T4 hormone is unbound and reflects the thyroid hormone activity of T4. The remaining 99.97% of total T4 is bound to carrier proteins and is metabolically inactive. The fT4 or FTI in conjunction with a TSH can be used to categorize most cases of thyroid dysfunction. The exception occurs when FT4 remains normal but FT3 is abnormal, as may occur when there is a deficient conversion of T4 to T3.
| THYROID DISORDER | TSH LEVEL | THYROID HORMONE LEVEL |
|---|---|---|
| Overt hypothyroidism | >5 mU/L | Low FT4 |
| Subclinical hypothyroidism | >5 mU/L | Normal FT4 |
| Overt hyperthyroidism | Low or undetectable | Elevated FT4 or FT3 |
| Subclinical hyperthyroidism | Low or undetectable | Normal FT4 or FT3 |
Data from Helfand M: Screening for subclinical thyroid dysfunction in nonpregnant adults: a summary of the evidence for the U.S. Preventive Services Task Force, Ann Int Med 140(2):128-141, 2004.
Conventional Treatment
Treatment of hypothyroidism with thyroid extract has been practiced since 1891, when Murray first reported the use of sheep thyroid extract. Thyroid hormone was first crystallized in 1914, and initial testing with thyroxine began in 1927.8 Exogenous thyroid hormone replacement remains the standard treatment, with thyroxine (T4) considered the treatment of choice based on its general efficacy and relatively small risk of adverse effects when given at the proper dose.7,8 Conventional practice advocates the use of thyroxine alone over T3 and T4 combinations, the latter of which may provide T3 in excess of normal thyroid secretion.7 However, many physicians find that the addition of T3 can be beneficial for patients not responding optimally to T4 alone.
Dosing of thyroid replacement therapies should be carefully monitored because of the narrow toxic-to-therapeutic ratio of thyroid hormone, with the patient maintaining on the lowest possible effective dose, which will be individually determined. The typical required daily dose is 1.5 µg/lb body weight, with doses for older adults at approximately 70% of that required for younger women.7 It has been estimated by some researchers that as many as 20% of hypothyroid patients are receiving excessive doses. Adverse reactions to thyroxine are usually related to excessive dosing or increased thyroid hormone activity.9 T3 supplementation may be implemented for patients unresponsive to T4 treatment alone.
No studies of controlled treatment of subclinical hypothyroidism have been conducted.2
Botanical Treatment
Traditionally, hypothyroidism would have been recognized and treated by herbal practitioners on the basis of its presenting metabolic deficiency symptoms, rather than as a discrete disease entity. The botanical practitioner recognized the patient picture as one of overall depletion. Herbalists today also view hypothyroidism with the goal of improving overall metabolism and the general integrity of the endocrine system. Many consider primary thyroid dysfunction to be a treatable condition with herbs and specific nutritional supplements (Table 6-2). Symptoms of hypothyroidism (e.g., constipation) may be treated with a symptom-specific protocol.
Adaptogens
Ashwagandha (Withania somnifera) is the only adaptogen for which a thyroid-related study was identified. In one study, the effects of daily administration of Ashwagandha root extract (1.4 g/kg body wt.) and Bauhinia purpurea bark extract (2.5 mg/kg body wt.) for 20 days on thyroid function in female mice were investigated. T3 and T4 concentrations were increased significantly by Bauhinia, and serum T4 concentration was enhanced by Withania. Both the plant extracts showed an increase in hepatic glucose-6-phosphatase (G-6-Pase) activity and antiperoxidative effects as indicated either by a decrease in hepatic lipid peroxidation (LPO) and/or by an increase in the activity of antioxidant enzyme(s). It appears that these plant extracts are capable of stimulating thyroid function in female mice.15 The importance of Withania somnifera root extract in the regulation of thyroid function with special reference to type-I iodothyronine 5′-monodeiodinase activity in mouse liver was investigated. Although the extract (1.4 g/kg, p.o. for 20 days) increased serum T3 and T4 concentrations and hepatic glucose-6-phosphatase activity, hepatic iodothyronine 5′-monodeiodinase activity did not change significantly. Furthermore, the extract significantly reduced hepatic lipid peroxidation, whereas the activities of antioxidant enzymes such as superoxide dismutase and catalase were increased. It was concluded that the extract stimulates thyroid activity and also reduces lipid peroxidation of hepatic tissue.16
Bladderwrack
Many herbalists and naturopathic physicians have relied on seaweed species in the treatment of hypothyroidism predicated on their iodine content. Fucus vesiculosus, or bladderwrack, for example, contains variable amounts of iodine, up to 600 mg/g. Much of the iodine content is organically bound, a more potent thyroid stimulating form than mineral bound iodine.17 There are case reports of seaweed, especially bladderwrack, causing both hypothyroidism and hyperthyroidism, and evidence suggests thyroid activity. However, there are no studies of efficacy, dosing, or safety to support its use, and no standardization of iodine content.18,19 Using seaweeds with the rationale that its iodine content is what is affecting treatment may be erroneous, as most thyroid insufficiency in the United States is not attributable to iodine deficiency. Further, excess iodine, as discussed, can contribute to or worsen hypothyroidism. Bladderwrack may interfere with thyroid replacement therapies such as thyroxine.17 Bladderwrack also contains organically bound arsenic, which although rapidly excreted, should suggest caution when using large amounts.19
Coleus
Coleus spp. has been used for centuries in Ayurvedic medicine.20 Forskolin stimulated thyroid function with increased thyroid hormone production in the isolated gland. However, in vitro, low forskolin concentrations inhibited thyroid function.19 No other research on the use of this herb for thyroid conditions was identified.
Guggul
Guggul has shown thyroid stimulating activity, but not via the pituitary-TSH mechanism. It is thought to have a direct action on the thyroid gland. It acts on the peripheral conversion of T4 to T3 increasing T3 levels without changing T4 levels. By increasing thyroid metabolism and activity, guggul reduces LDL cholesterol in individuals with functional hypothyroidism, which may be related to the stimulation of T3 by guggulsterones.21 The effect of a petroleum ether extract of Commiphora mukul was tested on mice thyroid gland grown in organotype of culture using modified Dulbecco’s eagle medium. There was significant increase in the structure and function of thyroid cultivated explants using media containing the guggul extract with raised media T3 resin uptake, PBI, and free thyroxine index. It is inferred that extract of Commiphora mukul augment thyroid hormone synthesis and release.22
Nutritional Considerations
| Coleus | (Coleus forskohlii) | 20 mL |
| Ashwagandha | (Withania somnifera) | 20 mL |
| Bladderwrack | (Fucus vesiculosus) | 15 mL |
| Licorice | (Glycyrrhiza glabra) | 10 mL |
| Guggul | (Commiphora mukul) | 10 mL |
| Nettles | (Urtica dioica) | 10 mL |
| Reishi mushroom | (Ganoderma japonica) | 10 mL |
| Ginger | (Zingiber officinalis) | 5 mL |
| Total: 100 mL |
treatment of autoimmune hypothyroidism. The ingestion of goitrogens—foods that block iodine utilization—are best limited in those patents with goiter. These include such foods as turnips, cabbage, mustard, cassava root, soybean, peanuts, pine nuts, and millet. Cooking usually inactivates goitrogens.23 Rich sources of iodine include ocean fish, sea vegetables (kelp, dulse, arame, hijiki, nori, wakame, kombu), and iodized salt, and should be included when there is iodine deficiency, but reduced when there is iodine excess.
Thyroid function may be supported nutritionally, even with the use of thyroid replacement therapy. Nutrients that may be beneficial supplements include selenium, zinc, tyrosine, and vitamins A, D, E, and C.23 Good sources of zinc include seafood (especially oysters), beef, oatmeal, chicken, liver, spinach, nuts, and seeds. The richest food source of selenium is Brazil nuts, especially those that are unshelled.
Selenium is a cofactor in normal thyroid hormone production. Selenium deficiency decreases conversion of T4 to T3. People with selenium deficiency have elevated T4 and TSH. Patients with normal circulating hormone levels who display clinical hypothyroid symptoms may be selenium deficient; thus, selenium levels should be evaluated and supplementation provided if deficiency is present. In a double-blind, placebo-controlled trial of selenium supplementation of 100 µg/day for 3 months among older subjects showed an improvement in selenium indices, a decrease in T4, and a trend toward normalization of T3:T4 ratio.10
Zinc is involved with synthesis of hypothalamic thyrotropin-releasing hormone (TRH); a zinc deficiency may lower 5′-deiodinase function, thereby contributing to a lower conversion of T4 to T3. Supplementation with zinc acts to normalize the TRH-induced TSH reaction and increase conversion of T4 to T3. The recommended dose is zinc picolinate, 30 mg/day.23
Tyrosine is an amino acid used as a precursor for making thyroid hormone. Tyrosine deficiency can contribute to low thyroid function. Low protein diets may provide insufficient tyrosine for normal thyroid hormone production. Supplementation of tyrosine at a dose of 500 to 1500 mg daily has therapeutic benefits in hypothyroidism.
Exercise
Regular daily exercise stimulates thyroid gland function and increases tissue sensitivity to thyroid hormone.23 Exercise is especially important for dieting overweight hypothyroid patients, as dieting can often put the body into a lower metabolic rate as the body tries to conserve fuel. Adjunctive regular exercise prevents the metabolic rate from dropping with the decrease in caloric intake.
CASE HISTORY: HYPOTHYROIDISM
| Coleus | (Coleus forskohlii) | 20 mL |
| Ashwagandha | (Withania somnifera) | 20 mL |
| Bladderwrack | (Fucus vesiculosus) | 15 mL |
| Licorice | (Glycyrrhiza glabra) | 10 mL |
| Guggul | (Commiphora mukul) | 10 mL |
| Nettles | (Urtica dioica) | 10 mL |
| Reishi mushroom | (Ganoderma japonica) | 10 mL |
| Ginger | (Zingiber officinalis) | 5 mL |
| Total: 100 mL |
HYPERTHYROIDISM
Pathophysiology
Hyperthyroidism, or thyrotoxicosis, is the result of excessive levels of circulating thyroid hormones. It is characterized by elevated total T4, free T4, free T4 index, and/or T3 and T3 resin uptake. Low TSH and normal levels of T3 and T4 characterize subclinical hyperthyroidism, and it has the same causes as overt hyperthyroidism.2 Graves’ disease, an autoimmune disorder in which stimulatory anti-TSH receptor antibodies are formed, comprises the majority of hyperthyroid cases. In fact, the strongest risk factor for both hypothyroidism and hyperthyroidism is the presence of TPO antibodies.1 These antibodies are directed toward the receptors in the cell membrane of the thyroid gland, causing the gland to increase growth, size, and function. Graves’ disease is characterized by several common features, including thyrotoxicosis, goiter, exophthalmos, and pretibial myxedema. Graves’ disease is eight times more common in women than men, typically presents between the ages of 20 and 40 years old, and the most common presentation is a diffuse nonpainful goiter. It may be more prevalent in some genetic HLA haplotypes.24
There are several types of thyroiditis that can cause hyperthyroidism, including Hashimoto’s thyroiditis, subacute thyroiditis, painless thyroiditis, postpartum thyroiditis, and radiation thyroiditis. Other contributing factors include stress, smoking, and iodine supplements/excessive iodine intake, drug-induced hypothyroidism, higher pregnancy frequency, being postpartum, and microbial infections. Hyperthyroid patients have a significantly lower exposure to exogenous estrogens than euthyroid patients.1
Toxic adenoma is a solitary nodule within the thyroid that produces excessive amounts of thyroid hormones. It typically occurs in the middle-aged and older populations.10
Thyroid storm, or thyrotoxic crisis, can occur as a result of a serious stressor, such as surgery, infection, or trauma in a poorly managed case. The mortality rate is approximately 25% even with proper medical treatment.10
Hyperthyroidism and subclinical hyperthyroidism affect quality of life, producing symptoms mimicking adrenergic overactivity. Subclinical hyperthyroidism exerts significant effects on the cardiovascular system. It is associated with a higher heart rate and increased risk of supraventricular arrhythmias, and with an increased left ventricular mass, often accompanied by impaired diastolic function and sometimes by reduced systolic performance on effort and decreased exercise tolerance. These changes usually precede the onset of more severe cardiovascular disease, thus potentially contributing to increased cardiovascular morbidity and mortality. Subclinical hyperthyroidism may accelerate the development of osteoporosis and hence increased bone vulnerability to trauma, particularly in postmenopausal women with a pre-existing predisposition. Fortunately, subclinical hyperthyroidism and its symptoms are readily preventable, and reversible with timely treatment.25
Signs and Symptoms
Symptoms of hyperthyroidism are listed in Box 6-3. Menstrual symptoms associated with hyperthyroidism can vary, and may range from amenorrhea to oligomenorrhea, but menstrual cycles also may appear normal. Anxiety, nervousness, and depression rates are higher in hyperthyroid patients than in euthyroid controls.2 Graves’ disease is characterized by a triad of hyperthyroidism, exophthalmos, and pretibial myxedema. Hyperthyroidism symptoms in postmenopausal women present differently than in younger women. Symptoms are usually confined to a single organ system, particularly the cardiovascular or central nervous system. Goiter is usually absent in 40% of cases, and in older women, a co-occurring disease such as infection of coronary heart disease is usually predominant. The triad of weight loss, constipation, and appetite loss occurs in about 15% of older patients, whereas ophthalmic disease is rare. Practitioners may notice failure to thrive in older patients, with signs of heart disease, unexplained weight loss, and mental or psychological changes signaling possible hyperthyroidism.7
Diagnosis
Definitive laboratory diagnosis is based on elevated serum free T4, total T4, free thyroxine index, and T3 resin uptake. If these are borderline elevated, the T3 should be checked as it is often elevated out of proportion to the T4. TSH is typically decreased. Test for Graves’ disease using the serum TSH receptor antibodies (TSH-R-Ab) test. If nodular goiter presents, a thyroid scan to rule out cancer is recommended.26 As with hypothyroidism, controversy exists as to whether to routinely screen for subclinical hyperthyroidism. Proponents of screening advocate for the potential benefit via prevention of atrial fibrillation, osteoporotic fractures, and other complications of overt hyperthyroidism. Controlled studies of the treatment of subclinical disease have not been conducted.2
Conventional Treatment
The primary goal of conventional medicine is to limit the amount of thyroid hormone production by the thyroid gland.11 Three main treatment methods are available: (1) antithyroid drug therapy, (2) surgery, or (3) radioactive iodine therapy. Although Graves’ disease is an autoimmune disorder, conventional treatment of the disorder is aimed at managing the hyperthyroidism.
Antithyroid drug therapy seems to be most useful in young patients with mild disease. The drugs propylthiouracil, carbimazole, and methimazole may be given until spontaneous remission occurs. Twenty to forty percent of patients have spontaneous remission within 6 months to 15 years duration. There is a fifty to sixty percent relapse rate in patients treated with this method of therapy.10,24
In radioactive iodine therapy, radioactive iodine is given in one dose, following which the gland shrinks and the patient becomes euthyroid over a period of 6 to 12 weeks. The major complication of this method of therapy is hypothyroidism, which develops in 80% of patients treated.27
