Hormones

There are five major classes of hormones (classified by their molecular weight and size and their precursor substrates; see Table 22-1),⁹ and their function can be broadly classified into three areas of physiologic activity: growth and differentiation; maintenance of homeostasis; and reproduction.

Hormone release is the end-product of a long cascade of intracellular events. Polypeptide hormones, for example, require neural or endocrine stimulation of the cell to initiate transcription from DNA to a specific messenger RNA (mRNA) and subsequent translation into a polypeptide product. This product is often a precursor molecule or “prohormone” that is biologically inactive, and is then further processed and packaged into granules, in the Golgi apparatus. These granules are transported to the plasma membrane before release, which is itself regulated by a complex combination of intracellular regulators.

Hormone secretion can be (1) continuous, as seen with the thyroid hormones, with a half-life of 7–10 days for T4 and 6–10 hours for T3, and with little variation in levels over the day, month, and year; or (2) pulsatile, which is the normal pattern for the gonadotrophins—that is, luteinizing hormone (LH) and follicle-stimulating hormone (FSH)—with a large amount of hormone released in a pulse every 1–2 hours, depending on the phase of the menstrual cycle. Growth hormone (GH) is also secreted in a pulsatile fashion, but with undetectable levels between pulses.

There are major factors that control the release of various hormones over days, for example the circadian rhythm, weeks, and months, and in the case of the growth and sex hormones over years.¹⁰ The menstrual cycle is an example of a longer and more complex (28-day) biologic rhythm.¹¹ Other regulatory factors include physiologic “stress” and acute illness, which produce rapid increases in adrenocorticotropic hormone (ACTH) and cortisol, GH, prolactin, epinephrine, and norepinephrine. Over the course of the sleep–wake cycle the secretion of GH and prolactin is increased, especially during the rapid eye movement (REM) phase of sleep. Food intake results in many hormones being released to regulate the body’s control of energy intake and expenditure, and these are therefore profoundly influenced by feeding and fasting. Secretion of insulin is increased, while testosterone and GH are decreased after ingestion of food, and secretion of a number of hormones is altered during prolonged food deprivation.

Hormone Receptors

These are broadly divided as follows:

• Cell surface or membrane receptors: typically, transmembrane receptors that contain hydrophobic sections spanning the lipid-rich plasma membrane and trigger internal cellular messengers.
• Nuclear receptors: these typically bind hormones and translocate them to the nucleus, where they bind hormone-response elements of nuclear DNA via characteristic amino acid sequences (so-called zinc fingers). Abnormalities of hormone receptors can be a rare cause of endocrine disease. The activation of intracellular kinases, phosphorylation, release of intracellular calcium and other “second messenger” pathways, and the direct stimulation of DNA transcription result in some or all of the following:
  • Stimulation or release of preformed hormone from storage granules.
  • Stimulation or synthesis of hormone and other cellular components.
  • Opening or closing of ion (e.g., calcium channels) or water channels (e.g., aquaporin water channels).
  • Activation or deactivation of other DNA-binding proteins, leading to stimulation or inhibition of DNA transcription.

The sensitivity and/or number of receptors for a hormone can be decreased after prolonged exposure to a high hormone concentration (downregulation). Equally, the reverse is true when stimulation is absent or minimal: the receptors are increased in number and/or sensitivity (upregulation).

Basal Blood Level

Basal hormone levels are especially useful for systems with long half-lives (e.g., T4 and T3, insulin-like growth factor-1 [IGF-1], androstenedione, SHBG) that vary little over the short term and so samples taken at any specific time are satisfactory.

For those hormones that fluctuate in accordance with the circadian rhythm (e.g., testosterone and cortisol), measurements must be taken at an appropriate time of day, which is 11:00 am for testosterone, while the patient is fasted, and between 8:00 and 11:00 am for cortisol, also with the patient fasted. LH/FSH, estrogen, and progesterone vary with time of menstrual cycle, and renin/aldosterone may vary with sodium intake, posture, and age.

Measurement of stress-related hormones (e.g., catecholamines, prolactin, GH, and cortisol) can be problematic, as the patient may be stressed by their attendance at the hospital or by the venipuncture itself, leading to falsely high levels. Sampling via an indwelling cannula at some time after the initial venipuncture overcomes this problem.

Urine Collection

This is done over the course of 24 hours and has the advantage of providing an “integrated mean” of a day’s secretion of select hormones, namely the catecholamines and cortisol. However, in practice these results are often complicated by poor patient compliance and incomplete/wrongly timed collection. Age, sex, and weight of the patient are also confounding factors.

Saliva

Salivary analysis has the advantage of avoidance of venipuncture, and is being increasingly used, especially in children (for steroid estimations) or for samples collected at home.^13,14

Stimulation and Suppression Tests

In general, stimulation tests are used to confirm suspected deficiency, and suppression tests to confirm suspected excessive levels of hormone secretion. These tests are valuable in instances when the secretory capacity of a gland is damaged, such that despite maximal stimulation by the trophic hormone, there is diminished output of primary hormone. For example, with the short ACTH stimulation test for adrenal reserve, the healthy subject shows a normal response, while the subject with primary hypoadrenalism (Addison’s disease) demonstrates an impaired cortisol response to the injection of cosyntropin (Synacthen®, Mallinckrodt, Dublin, Ireland), a potent ACTH analogue.¹⁵

Hormone Excess

Hormone excess can be caused by autoimmune disorders, the excess therapeutic administration of hormones, or autonomous release with tumors, as can be seen with benign adenomas of the parathyroid, pituitary, and adrenal glands.

Hormone Deficiency

The commonest cause of hormone deficiency is from glandular destruction by autoimmune diseases (Table 22-4) and iatrogenic causes, namely surgery and radiotherapy. Rare cases include infection, inflammation, infarction, hemorrhage, or tumor infiltration. Autoimmune-mediated damage is highly prevalent, as seen with Hashimoto’s thyroiditis and that of the pancreatic islet β cells in type 1 diabetes mellitus (T1DM).

Hormone Resistance

Hormone resistance results in a disease state that is similar to that seen with hormone deficiency, but diagnosis is more difficult and complicated as there are usually normal levels of the hormone on testing. The more severe hormone resistance disorders are due to inherited defects in membrane receptors, nuclear receptors, or the pathways that transduce receptor signals. These disorders are characterized by defective hormone action despite the presence of increased hormone levels. The most prevalent acquired forms of functional hormone resistance include insulin resistance in type 2 diabetes mellitus (T2DM) and leptin resistance in obesity.^8,18

Hypothalamus

The hypothalamus (Figure 22-3) contains vital sensors to monitor and control key functions such as appetite, thirst, thermal regulation, the sleeping/waking cycle (circadian rhythm), the menstrual cycle, and the response to stress, exercise, and mood. It serves to integrate the many neural and endocrine inputs to control the release of pituitary hormone-releasing factors. The hypothalamic neurons secrete both pituitary hormone-releasing and pituitary-inhibitory factors (and hormones) via the portal (vein) system, which passes down the stalk into the pituitary.¹⁹

Pituitary Gland

The pituitary gland is a pea-sized structure situated at the base of the brain within the sella turcica, and is in intimate association with the hypothalamus. It plays a key role in the control of the endocrine system via feedback mechanisms, and hence has been termed the “conductor of the endocrine orchestra.”²⁰

The pituitary gland is divided into two anatomically, functionally, and developmentally distinct structures: the anterior and posterior lobes.

Posterior Pituitary (Neurohypophysis)

The posterior pituitary (Figures 22-3 and 22-4) is a group of neural cells that are an extension of the hypothalamus and have secretory capacity. The posterior pituitary only secretes two hormones, arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), and oxytocin, both of which are nonapeptides (oligopeptides formed from nine amino acids; Figure 22-5). The primary physiologic functions of oxytocin include contraction of the myoepithelial cells of the alveoli of the mammary gland, which is important during lactation as part of the “let-down response,” and contraction of the uterus during childbirth and immediately postpartum.

Hormone Excess

Hormone excess is seen with pituitary adenomas that are usually benign and slow growing. The symptoms related to the physical enlargement of the adenoma include visual impairment or headache. Occasionally these are detected incidentally as a finding on a magnetic resonance imaging (MRI) or computer tomography (CT) scan. They can result in increased secretion of the hormone(s) produced by the cells represented in these lesions and/or decreased secretion of other hormones due to compression by the tumor. In contrast, pituitary apoplexy (pituitary infarction) has a dramatic presentation with a sudden and severe headache, often with diplopia. Evaluation of masses within the sella turcica is best done with MRI (see Figure 22-6) and evaluation of the hormonal profile.

Hypopituitarism

Defects of the hypothalamic-releasing hormones or of the pituitary trophic hormones can be selective or multiple. Selective deficiencies of GH, LH/FSH, ACTH, TSH, and vasopressin (ADH) are all seen from a variety of causes. Multiple deficiencies usually result from a tumor. There is generally a progressive loss of anterior pituitary function, with GH and the gonadotrophins usually being the first trophic hormones affected. Hyperprolactinemia, rather than prolactin deficiency, occurs relatively early, because of loss of tonic inhibitory control by dopamine. TSH and ACTH secretion is usually the last to be affected. Panhypopituitarism refers to deficiency of all anterior pituitary hormones and it is most commonly caused by pituitary tumors, or as a consequence of the surgery or radiotherapy used in the treatment of such tumors. ADH and oxytocin secretion will only be significantly affected if the hypothalamus is involved, either by a hypothalamic tumor or by suprasellar extension of a pituitary lesion. ADH and oxytocin deficiency is rarely seen with an uncomplicated pituitary adenoma. In general, the symptoms of deficiency of a pituitary-stimulating hormone are the same as primary deficiency of the peripheral endocrine end-organ; for example, TSH deficiency results in primary hypothyroidism and so causes similar symptoms due to lack of thyroid hormone secretion.²²

Growth Hormone

GH is the pituitary factor responsible for growth in humans. GH secretion is stimulated by growth hormone-releasing hormone (GHRH), released into the portal system from the hypothalamus (Figure 22-7). There is a separate GH-stimulating system that interacts with ghrelin, a hormone that is synthesized by the stomach. It is unknown how the two systems interact. GH binds to receptors mainly found on liver cells, which results in turn in the release of IGF-1, for which there are multiple binding proteins (IGF-BP) in the plasma. Of these, IGF-BP3 can be measured to assess GH status. The metabolic actions of this system are increased collagen and protein synthesis; retention of calcium, phosphorus, and nitrogen (necessary for anabolism; i.e., the building of molecules); and opposing the actions of insulin. GH release is intermittent, mainly nocturnal during REM sleep, and is significantly increased during adolescence, but afterward declines.

Apart from GH, the following factors play a role in the normal linear growth of humans:

• Genetics: children of short parents will probably be short and vice versa.
• Nutrition: inadequate nutrients result in impaired growth, either from inadequate dietary intake or small bowel disease, for example coeliac disease.
• General health: serious systemic disease, such as chronic infection, will impair growth.
• Intrauterine growth retardation: this will result in poor long-term growth, whereas premature infants tend to catch up.
• Emotional deprivation and psychologic factors: these play a role in growth and development, although the mechanisms are complex and not fully understood.

Growth Assessment and Treatment

Growth charts and associated computer programs are now available for national and specific ethnic groups to monitor and predict a child’s final height. The Centers for Disease Control and Prevention (CDC) have readily available (downloadable) growth charts consisting of a series of percentile curves that illustrate the distribution of selected body measurements in US children (Figures 22-8 and 22-9).^23,24 These growth charts are also essential for predicting the treatment and prognosis of orthodontic and/or orthognathic treatment.²⁵

Acromegaly and Gigantism (Growth Hormone Excess)

GH is released from the somatotropic cells within the lateral wings of the anterior pituitary gland and is the primary trophic hormone responsible for postnatal growth and development. GH excess causes what is more formally termed pituitary gigantism in children if this occurs before fusion of the epiphyseal plate (growth). Gigantism is a nonspecific term that denotes excessive growth in a pediatric patient.²⁹ GH excess results in acromegaly if it occurs after the bony growth plates have fused. In almost all cases this is due to GH-secreting pituitary adenoma.

GH’s major trophic effect is the release of IGFs from the liver. IGFs, as their name suggest, are proteins with significant homology to insulin, with a wide range of functions, but principally act to increase bone growth (specifically bone length). Although many cells have GH receptors and may respond to GH, the vast majority of the growth-stimulating effects of GH are mediated by IGF-1. GH release is under positive regulation by the hypothalamic peptide GH-releasing hormone. The amount and pattern of GH production and IGF release change markedly across the life cycle, with maximal release during the intense growth periods of late childhood and adolescence and low levels with advanced age. GH is released from the pituitary in a pulsatile fashion, with peak secretion at night. Thus, serum GH values vary considerable over the course of a 24-hour period, so a random sample may not reliably indicate true GH levels. In contrast, IGF-1 serum levels are relatively constant over the course of the day, so an IGF-1 sample can be taken at any time of the day and is indicative of GH levels.

Gigantism is very rare, with 0.6% reported in a large pediatric cohort.³⁰ Acromegaly is rare, with an overall prevalence of estimated prevalence in Europe of 30–70 individuals per million, affecting men and women equally.³¹ The rapid growth seen with gigantism can be distinguished from that of precocious puberty. In gigantism, growth occurs in the absence of early secondary sexual characteristics, as the pituitary tumors (somatotroph adenomas) that lead to GH excess result in the loss of production of other pituitary hormones, particularly the gonadal trophic hormones, FSH, and LH, which are responsible for sexual development. Mild to moderate obesity is also commonly seen in these patients.

The mean age at diagnosis of acromegaly is usually 40–45 years, but as the progression of disease is so slow, the interval from the onset of symptoms until diagnosis can be as much as 12 years. Manifestations include the classic facial appearance of coarse facies, macrognathia, macroglossia, large diastemas, and enlargement of the nose and frontal bones (frontal bossing) (Figure 22-10). Soft tissue edema, due to a direct effect of GH on sodium retention, leads to a “doughy” feel to the hands and feet, as well as an increase in shoe, hat, glove, and ring sizes. Patients can also have increased sweating, deepening of the voice due to enlargement of the thyroid cartilage and vocal cords, enlargement of the synovium and cartilages with hypertrophic arthropathy (knees, ankles, hips, spine, and other joints), skin tags, nerve compression (causing paresthesia of the hands, as in carpal tunnel syndrome), enlargement of the soft tissues of the pharynx and larynx (which can lead to obstructive sleep apnea), increased risk of uterine leiomyomata, colonic polyps, and organomegaly (including the thyroid, heart, liver, kidneys, and prostate). Some 50% of patients with GH excess develop hypertension, 10% develop cardiomegaly with heart failure, which accounts for much of the increased mortality associated with acromegaly and 30% develop insulin resistance or T2DM. Surprisingly, patients seldom independently seek care as the changes are so insidious, and treatment is often initiated when a relative or friend, who has not seen the patient for some time, notes the typical changes as described here.¹⁷

Treatment

Untreated acromegaly results in significant morbidity and increased rate of premature death. The aims of treatment are to establish a “safe” GH level and a normal IGF-1 level. If present, hypopituitarism also needs to be addressed. Concurrent hypertension and/or diabetes should be treated with conventional agents, but usually resolve with treatment of the acromegaly.

Treatment is usually surgical, most commonly by a transsphenoidal approach, or transfrontal for large adenomas, with radiotherapy reserved for situations in which GH levels fail to normalize. There are three potential targets for medical therapy: (1) somatostatin receptor agonists, either octreotide or lanreotide, which are given as monthly depot injections—these are generally effective, but do increase the risk for the development of gallstones; (2) dopamine agonists, either bromocriptine or cabergoline, which are best for patients with mild residual disease; and (3) growth hormone receptor antagonist, that is pegvisomant, a genetically modified analogue of GH that is reserved for patients who otherwise fail all other interventions.³³

Thirst Axis

Thirst and the symptoms of thirst, xerostomia and the signs of dehydration, namely hyposalivation and dry mucous membranes of the mouth, are of course of great relevance to the clinical practice of oral healthcare providers. Thirst and water regulation are largely controlled by vasopressin, also known as antidiuretic hormone (ADH). ADH is synthesized in the hypothalamus and then migrates in neurosecretory granules via axonal pathways to the posterior pituitary. Pituitary diseases that spare the hypothalamus do not lead to ADH deficiency, as the hormone still can “leak,” even from the end of a damaged axon.

The kidney is the predominant site of action of ADH at normal concentrations. ADH stimulation of the vasopressin-2 (V2) receptors allows the collecting ducts to become permeable to water, via the migration of aquaporin-2 water channels, resulting in the reabsorption of hypotonic luminal fluid. ADH acts to reduce diuresis (i.e., less urine) and results in retention of water. At high concentrations, ADH can also cause vasoconstriction, via the V1 receptors present in the vascular tissues, thus limiting blood supply to the kidneys, resulting in further water retention and less urine output.

ADH is regulated by osmoreceptors in the anterior hypothalamus that can sense plasma osmolality. ADH secretion is suppressed at levels below 280 mOsm/kg, thus allowing maximal urine formation (diuresis). Above this level, plasma vasopressin increases in direct proportion to plasma osmolality. At the upper limit of normal (295 mOsm/kg), maximum antidiuresis is achieved (little if any urine production), with thirst being experienced at about 298 mOsm/kg.

Epidemiology

Thyroid disease has prevalence of 6% as of 2019 and it is estimated that over 12% of Americans will develop some form of thyroid disease over the course of their lifetime.⁴⁸ Of these, some 60% are unaware of their condition. Thyroid diseases are far more common in women. The management for most thyroid disorders is life-long and well tolerated. In the United States, autoimmune inflammation is the most common cause of thyroid disease whilst worldwide hypothyroidism and goiter due to iodine deficiency is much more common.⁴⁹ Although thyroid nodules are common, thyroid cancer is rare. Thyroid cancer accounts for less than 1% of all cancer in the US,⁵⁰ although it is the most common endocrine tumor and makes up greater than 90% of all cancers of the endocrine glands.⁵¹

Thyroid Gland: Anatomy and Physiology

The thyroid gland consists of two lateral lobes connected by an isthmus, closely attached to the thyroid cartilage and to the upper end of the trachea, and thus moves on swallowing. Embryologically, it originates from the base of the tongue and descends to the middle of the neck. Remnants of thyroid tissue can sometimes be found at the base of the tongue (lingual thyroid) and along the line of its descent.

Internally, the thyroid gland consists of follicles lined by cuboidal epithelioid cells within which is colloid (iodinated glycoprotein thyroglobulin), synthesized by the follicular cells. Each follicle is surrounded by basement membrane, and between them are parafollicular cells containing the C cells that secrete calcitonin. The thyroid also synthesizes triiodothyronine (T3), which acts at the cellular level, and L-thyroxine (T4), which is the prohormone. Inorganic iodine is essential for the synthesis of the two thyroid hormones and the precursor molecule, thyroglobulin (Figure 22-11). Globally, dietary iodine deficiency is a major cause of thyroid disease. Dietary supplementation of salt and bread has reduced the number of areas where “endemic goiter” still occurs. Surprisingly, in Western countries iodine deficiency is now a concern, given the decline in adventitious iodine in dairy products with use of noniodoform disinfectants in milk production and “food fads,” with the use of noniodized rock salt in place of iodized salt in cooking. In the United States iodine intakes have fallen, and it is uncertain whether the iodine status for most pregnant woman is satisfactory, leading to calls for systematic iodine supplementation.⁵²

In plasma, more than 99% of all T4 and T3 is bound to hormone-binding proteins: TBG, thyroid-binding prealbumin, and albumin. Only unbound—that is, free—hormone is biologically active. Circulating T4 is peripherally deiodinated to T3, which has a far greater affinity for its receptors than T4. T3 binds to the two thyroid hormone nuclear receptors (TR-α and TR-β) of the target cells to cause gene transcription.

Control of the hypothalamic-pituitary-thyroid axis is, as is universal throughout the endocrine system, by negative feedback control. Thyrotropin-releasing hormone (TRH) is a peptide produced in the hypothalamus, which stimulates the pituitary to secrete TSH (Table 22-8). TSH, in turn, stimulates growth and activity of the thyroid follicular cells, which consequently secrete T3 and T4 into the circulation. T3 and T4 both exert negative feedback on the hypothalamus, leading to a decrease in the secretion of TRH and so a decrease in TSH and in turn a decrease in T3 and T4. The decrease in circulating T3 and T4 prompts increased release of TRH and, again, in turn an increase in TSH and then T3 and T4.

Hypothyroidism

Hypothyroidism, defined as the inadequate release of the two thyroid hormones T3 and T4, is usually primary; that is, due to disease of the thyroid gland, However, it may be secondary, due to disease of hypothalamic or pituitary, with consequent reduction in TSH, and so a decline in T3 and T4 release by an otherwise intact thyroid gland.

Hypothyroidism is one of the most common endocrine conditions, with a prevalence rate of 4.6% for the US population. Approximately 0.3% present with clinically overt disease and the remaining 4.3% with subclinical disease (decreased T3 and T4 levels but no clinical evidence of disease).⁵³ Of those with subclinical hypothyroidism, 2% per annum develop clinically evident hypothyroidism, hence the lifetime prevalence for an individual is higher—perhaps as high as 9% for women and 1% for men, with mean age at diagnosis around 60 years.⁵⁴

Hyperthyroidism

Hyperthyroidism (also termed thyrotoxicosis) is defined as thyroid overactivity with consequent increased release and greater circulating levels of T3 and T4. Hyperthyroidism is common. The reported overall prevalence is about 3%, with men and women over 65 years having the highest prevalence, of which 50% are taking levothyroxine. In the National Health and Nutrition Examination Survey, there was a bimodal distribution based on age, with prevalence highest in those subjects aged 20–39 years and those aged older than 79 years.⁵³

Graves’ Orbitopathy

Graves’ orbitopathy, also known as thyroid eye disease (TED), is an autoimmune inflammatory disorder of the orbit and periorbital tissues. It has distinctive clinical features, including the “stare,” due to retraction of the upper eyelid with lid lag, and swelling of the orbit, causing an exophthalmos of variable severity. It occurs most commonly in association with Graves’ disease, but can also be seen, albeit more rarely, with Hashimoto’s thyroiditis, and even in patients who are otherwise euthyroid. The condition mostly affects the middle-aged (30–50 years of age) and predominantly women. Cigarette smoking raises the incidence eightfold. Annual incidence is 16 per 100,000 in women and 3 per 100,000 in men.⁷¹ About 3–5% have severe disease with intense pain, and sight-threatening corneal ulceration or compression of the optic nerve. Unilateral orbitopathy can occur, but this is rare.

Initial treatment entails regulation of thyroid hormone levels and limitation of further damage to the eye, with the use of topical lubricants to prevent corneal damage. High-dose corticosteroids are effective in the initial reduction of the orbital inflammation. Radiotherapy has been trialed, but there is controversy as to its efficacy, as is the case with selenium, which is limited to the treatment of mild disease. As of January 2020, the US Food and Drug Administration (FDA) approved the use of the medication Tepezza® (teprotumumab-trbw; Horizon Therapeutics, Lake Forest, IL, USA) for the treatment of adults with TED.⁷² Teprotumumab-trbw is a monoclonal antibody that binds IGF-1R. In TED pathogenic orbital disease, autoantibodies stimulate the orbital fibroblasts, resulting in the production of hyaluronan (a high molecular mass polysaccharide), causing the marked infiltration and so swelling of the eyelids and orbital tissues and resulting in the clinical features of TED. Teprotumumab blocks the stimulatory effects of pathogenic autoantibodies on the orbital fibroblasts.⁷³ Orbital decompression surgery is indicated in severe eye disease to prevent blindness from optic nerve compression. Surgery is also indicated, after the incipient thyroid disease has been stable for six months, to improve function and to increase lubrication of the corneal surface to prevent corneal keratitis and for cosmesis.⁷⁴

Thyroid Crisis

A thyroid crisis (or “thyroid storm”) is a rare, life-threatening exacerbation of hyperthyroidism, which presents with fever, delirium, seizures, coma, vomiting, diarrhea, and jaundice. The mortality rate due to cardiac failure, arrhythmia, or hyperthermia is as high as 30%, even with treatment. Thyrotoxic crisis is usually precipitated by acute illness (e.g., stroke, infection, trauma, diabetic ketoacidosis), surgery (especially involving the thyroid), or radioiodine treatment of a patient with partially treated or untreated hyperthyroidism. In-hospital management is required, which includes intensive monitoring, supportive care, identification and treatment of the precipitating cause, and measures that reduce thyroid hormone synthesis; that is, large doses of antithyroid drugs, such as propylthiouracil. Propranolol is also given to reduce tachycardia and other adrenergic manifestations.

Thyroid Hormone Resistance

This occurs when the effectiveness of thyroid hormone is reduced and includes flaws in thyroid hormone action, transport, or metabolism. These are rare, in general have a genetic basis, and to date there is limited effective treatment. There are three main causes:

• Thyroid hormone cell membrane transport defect.
• Thyroid hormone metabolism defect.
• Thyroid hormone action defects.

Goiter (Thyroid Enlargement)

Goiter is a swelling of the anterior base of the neck resulting from an enlarged thyroid gland, which may be visible or only evident on palpation (see Table 22-9). In the United States where iodine deficiency is rare, up to 15% of the population have palpable goiter and as many as 50% microscopic nodules. In areas of the world where iodine deficiency is common and widespread, up to 90% of the population have significant goiter, termed “endemic goiter.”^75,76

The initial screening for thyroid dysfunction starts by examining and then palpating the thyroid gland for diffuse changes or nodules, which may be single or multiple. It is performed as part of a head and neck examination, which could be argued to be within the remit of dentists and represents a comprehensive examination of the patient, with a focus on dental disease, but in the context of potential disease of the related regional anatomy. The thyroid gland is examined with the patient’s head extended to one side and with the examiner using the fingers of both hands to palpate the thyroid gland. Next, the patient is instructed to swallow, during which time the examiner can evaluate the anatomic extent of the lobules using the last three fingers of one hand. Note that the right lobule is usually larger than the left and that on relaxation, the thyroid outline cannot be observed in a healthy patient. Any anatomic abnormality of the thyroid gland is defined by its consistency, size, tenderness, and growth. If an abnormal finding is discovered, hormone and function and imaging studies, particularly ultrasound, needs to follow, with consideration for ultrasound-guided fine needle aspiration (FNA) biopsy.⁷⁷

Thyroid Malignancies

Thyroid carcinoma is the most common malignancy of the endocrine system. Thyroid neoplasms can arise in each of the cell types that populate the gland, including thyroid follicular cells, calcitonin-producing C cells, lymphocytes, and stromal and vascular elements, as well as metastases from other sites (Table 22-10). Over the last 30 years, the incidence of thyroid cancer has increased from 4.9 to 14.3 cases per 100,000 individuals in the United States, with over 65,000 cases diagnosed in 2015.⁷⁸

The risk factors for thyroid malignancy are (1) exogenous, namely exposure to radiotherapy of the head and/or head and neck region, which can include cranial radiotherapy, or from nuclear fallout following explosions of nuclear power plants, at Chernobyl (1986)⁷⁹ and more recently Fukushima (2011);⁸⁰ and (2) endogenous, specifically genetic abnormalities, patients who have a family history of papillary thyroid cancer in two or more first-degree relatives, multiple endocrine neoplasia type 2 (MEN 2), or other genetic syndromes associated with thyroid malignancy, such as Cowden’s syndrome, familial polyposis, and Carney complex.⁵¹

Stomatognathic Manifestations and Complications of Thyroid Disease

Both hypothyroidism and hyperthyroidism can occur in the same patient, because patients with clinically significant hypothyroidism are on replacement levothyroxine, and there is the risk of overtreatment and iatrogenic thyrotoxicosis. Similarly, patients on treatment for their hypothyroidism can develop marked hypothyroidism if they omit a number of doses, or if they are on an insufficient dose. Therefore, dentists need to be familiar with the symptoms and signs of both hypothyroidism and hyperthyroidism.

Patients with a history of thyroid cancer have probably undergone surgery or radioactive iodine therapy that can affect the adjacent regional tissues. Salivary gland dysfunction is one of the most common side effects of high-dose ¹³¹I therapy for thyroid cancer.^{84,85 131}I targets the salivary glands, where it is concentrated and secreted into saliva. Dose-related damage to the salivary parenchyma results from ¹³¹I irradiation and causes salivary gland swelling, pain, and hypofunction.^86–89

Dental Management of the Patient with Thyroid Gland Disorders

Patients with autoimmune thyroid diseases (Hashimoto’s thyroiditis) may also be susceptible to other autoimmune connective tissue disorders, including Sjögren syndrome. Antinuclear antibodies (ANAs) are found in one-third of patients with autoimmune thyroid disorders, and Sjögren syndrome is found in nearly one-tenth of ANA-positive patients with autoimmune thyroid disorders.⁹⁰ The most common additional autoimmune disease identified in patients with primary Sjögren syndrome has been hypothyroidism;⁹¹ also, there is a 7–17% prevalence of detectable thyroid antibodies in patients with Sjögren syndrome and rheumatoid arthritis.⁹² Therefore, the thyroid patient who presents with signs and symptoms of hyposalivation and xerophthalmia should be evaluated for Sjögren syndrome.^84,93–95

Cushing’s Syndrome (Glucocorticoid Excess)

Cushing’s syndrome reflects a constellation of clinical features that result from the chronic effects of glucocorticoid excess, of any etiology and any source. Cushing’s syndrome is rare, with an annual incidence of 1–2 per 100,000 population. The disorder can be ACTH dependent (e.g., pituitary corticotrope adenoma) or ACTH independent (e.g., adrenocortical tumor). Overwhelmingly, the medical use of glucocorticoids is the commonest cause of Cushing’s syndrome. Only 10% of patients with Cushing’s syndrome have a primary—that is, adrenal—cause of their disease.¹⁰³ The term “Cushing’s disease” is specific to glucocorticoid excess caused by a pituitary adenoma secreting ACTH.

Ectopic ACTH production is predominantly caused by occult carcinoid tumors, most frequently in the lung, but also in the thymus or pancreas. Advanced small cell lung cancer can also cause ectopic ACTH production.¹⁰⁴

Clinical Manifestations

Given that glucocorticoids (see Table 22-11) affect almost all cells of the body, the signs of cortisol excess impact multiple physiologic systems. In addition, excess glucocorticoid secretion overcomes the ability of a key kidney enzyme system (11 β-hydroxysteroid dehydrogenase type 2 or 11β-HSD2) to rapidly inactivate cortisol to cortisone. Cortisone has minimal mineralocorticoid activity, whereas cortisol has some degree of mineralocorticoid action, which manifest as diastolic hypertension, hypokalemia, and edema. Excess glucocorticoids also interfere with central regulatory systems, leading to suppression of gonadotropins with subsequent hypogonadism and amenorrhea, and suppression of the hypothalamic-pituitary-thyroid axis, resulting in decreased TSH secretion.

Organ/ Physiologic System	Increased or Stimulated	Decreased or Inhibited
Metabolic	Gluconeogenesis Glycogen deposition Protein catabolism Fat deposition	Protein synthesis
Renal (Kidneys) System	Sodium retention Potassium loss Uric acid production	Free water clearance
Hematologic System	Circulating neutrophils	Host response to infection, delayed hypersensitivity response Lymphocyte transformation, circulating lymphocytes, circulating eosinophils

The diagnosis of Cushing’s syndrome should be considered when the following key clinical features are evident in the patient (see Figure 22-14): fragility of the skin, with easy bruising and broad (>1 cm), purplish striae, and signs of proximal myopathy, with the patient struggling to stand up from a chair (without the use of hands). Patients with Cushing’s syndrome may develop marked hypercoagulopathy, so are at acutely increased risk of deep vein thrombosis and subsequent pulmonary embolism. Psychiatric symptoms of marked anxiety and/or depression are also common, but acute paranoia or frank psychosis may also occur.¹⁰¹

Overt untreated Cushing’s syndrome is associated with a poor prognosis. In ACTH-independent disease, treatment consists of surgical removal of the adrenal tumor. In Cushing’s syndrome, the treatment of choice is selective removal of the pituitary corticotrophic-producing tumor, usually via a transsphenoidal approach.

Conn’s Syndrome (Mineralocorticoid Excess)

Hyperaldosteronism, the excessive release of the principal mineralocorticoid, aldosterone, typically presents as hypertension, given the adverse effects on the renin-angiotensin system that so powerfully controls renal perfusion and homeostasis, and blood pressure. The commonest cause is primary hyperaldosteronism, excess production of aldosterone by the adrenal zona glomerulosa, typically occurring with bilateral micronodular adrenal hyperplasia. Infrequently, Conn’s syndrome occurs due to an adrenocortical carcinoma.

The clinical hallmark of mineralocorticoid excess is hypokalemic hypertension, but not hypernatremia, with the serum sodium tending to be normal due to the concurrent fluid retention, which in some cases can lead to marked peripheral edema. Severe hypokalemia can be associated with muscle weakness, overt proximal myopathy, or, in severe cases, hypokalemic paralysis, or tetany.¹⁰⁵ Diagnostic screening for mineralocorticoid excess is not currently recommended for all patients with hypertension, but should be considered in hypertensive patients younger than 40 years, treatment-refractory hypertension, hypokalemia, or the finding of an adrenal mass. The accepted screening test is concurrent measurement of plasma renin and aldosterone with subsequent calculation of the aldosterone–renin ratio, but the serum potassium needs to be normalized prior to testing.

With the diagnosis of hyperaldosteronism, CT imaging of the adrenal glands is needed. The treatment provided is dependent on the patient’s age and fitness for surgery. Laparoscopic adrenalectomy is the preferred approach. Medical treatment, which can also be considered prior to surgery to avoid postsurgical hypoaldosteronism, is usually with the mineralocorticoid receptor antagonist spironolactone.¹⁰⁶

Addison’s Disease (Adrenal Insufficiency)

The US prevalence of adrenal insufficiency (Table 22-12) is 5 in 10,000 in the general population. Disorders of the hypothalamic-pituitary axis are more frequent, with a prevalence of 3 in 10,000, whereas primary adrenal insufficiency has a prevalence of 2 in 10,000, with about half of cases due to genetic causes (e.g., congenital adrenal hyperplasia). Primary adrenal insufficiency is most commonly caused by autoimmune destruction of the adrenal gland, with some 60–70% developing adrenal insufficiency as part of an autoimmune polyglandular syndrome (APS). APS1, an autosomal recessive disorder also termed APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy), is the underlying cause in 10% of patients affected by APS.¹⁰⁷ These patients invariably develop chronic mucocutaneous candidiasis, which usually manifests in childhood and precedes adrenal insufficiency by years or decades. Coincident autoimmune-induced endocrinopathies most frequently include thyroid autoimmune disease, vitiligo, and premature ovarian failure. Less commonly, T1DM and pernicious anemia (with consequent vitamin B₁₂ deficiency) may occur. Rare causes of adrenal insufficiency involve destruction of the adrenal glands as a consequence of infection, with tuberculous adrenalitis still a frequent cause of disease in developing countries. Hemorrhage, or more rarely bilateral bulky metastatic infiltration with replacement of the adrenal glands, can also result in hypoadrenalism.

The commonest cause of adrenal insufficiency is iatrogenic, arising from suppression of the HPA axis as a consequence of exogenous glucocorticoid treatment (see Tables 22-13 and 22-14).¹⁰⁸ This has a reported prevalence of some 0.5–2% of the population in developed countries. Secondary adrenal insufficiency is the consequence of dysfunction of the hypothalamic-pituitary component of the HPA axis. Excluding iatrogenic impairment of the HPA axis (exogenous corticosteroid use), the majority of cases are caused by pituitary or hypothalamic tumors, or their treatment by surgery or radiotherapy.

In principle, the clinical features of primary adrenal insufficiency (Figure 22-15) are characterized by the loss of both glucocorticoid and mineralocorticoid secretion. In contrast, in secondary adrenal insufficiency only glucocorticoid deficiency is evident, as the adrenal itself is intact and can still be regulated by the RAA system. Adrenal androgen secretion is disrupted in both primary and secondary adrenal insufficiency. Hypothalamic-pituitary disease can lead to additional clinical manifestations due to the involvement of other endocrine axes, or visual impairment with bitemporal hemianopia caused by compression of the optic chiasma. Iatrogenic adrenal insufficiency caused by exogenous glucocorticoid suppression of the HPA axis and its abrupt cessation can cause all of the symptoms associated with glucocorticoid deficiency, but the patient will appear cushingoid from the preceding “overexposure” to glucocorticoids.

Acute adrenal insufficiency usually occurs after a prolonged period of nonspecific complaints and is more frequently observed in patients with primary adrenal insufficiency, due to the loss of both glucocorticoid and mineralocorticoid secretion. The associated postural hypotension is a “red flag,” as the patient may then progress to hypovolemic shock. Adrenal insufficiency may also mimic the features of an acute abdomen with abdominal tenderness, nausea, vomiting, and fever. An adrenal crisis can be triggered by an intercurrent illness, surgery, or other stress.¹⁰⁹

The diagnosis of adrenal insufficiency is established by the short cosyntropin test (Synacthen), a safe and reliable tool with excellent diagnostic sensitivity. The ITT is an alternate, but can be hazardous to the patient, and requires supervision by a specialist physician.

Acute adrenal insufficiency requires immediate rehydration (1 L/hour of saline infusion) with cardiac monitoring and glucocorticoid replacement by bolus injection of 100 mg hydrocortisone, followed by further hydrocortisone supplementation (100–200 mg hydrocortisone over the course of 24 h). Mineralocorticoid replacement can wait until the daily hydrocortisone dose has been reduced to <50 mg, because at higher doses the hydrocortisone provides sufficient stimulation of the mineralocorticoid receptors.

Glucocorticoid replacement (Table 22-15) for the treatment of chronic adrenal insufficiency should be administered at a dose that replaces the physiologic daily cortisol production, typically orally administered hydrocortisone at a dose of 15–25 mg, in two divided doses: 10–20 mg in the mornings and 5 mg in the evenings, mimicking the natural circadian levels of cortisol.

Mineralocorticoid replacement in primary adrenal insufficiency is achieved by the use of 100–150 μg of fludrocortisone. Its efficacy is assessed by measuring the blood pressure, while both sitting and standing, to detect a postural drop indicative of hypovolemia, and assessing serum sodium, potassium, and plasma renin levels. Adrenal androgen replacement is an option for patients with a lack of energy, or with features of androgen deficiency, such as loss of libido.

Pheochromocytoma

This is an adrenal tumor that produces epinephrine, norepinephrine, or both catecholamines. Patients are hypertensive, with headache, sweating, tachycardia, palpitations, and pallor. Occasionally, these can be syndromic, as part of Multiple Endocrine Neoplasia Syndrome Type 2B (MEN2B) presenting with a marfanoid habitus, high arched palate, neuromas (of the tongue, buccal mucosa, lips, conjunctivae, and eyelids), and corneal nerve thickening. The diagnosis of pheochromocytoma is confirmed by measuring urinary and plasma catecholamine levels.¹¹⁰

Stomatognathic Manifestations and Complications of Disorders of the Adrenal Gland

Dental Management of Patients with Adrenal Gland Disorders

Use of Replacement Corticosteroid Therapy (“Stress Steroids” or “Steroid Cover”)

Cortisol (hydrocortisone) is essential to maintain vasomotor tone, and so normal blood pressure, by sensitizing the alpha-adrenergic receptors (alpha 1A, 1B, and 1D receptors) of the vasculature to circulating epinephrine and norepinephrine and increasing catecholamine release from the adrenal cortex. If insufficient cortisol is produced at times of marked physiologic stress, this can result in vasodilation, reduced cardiac return, and potential hypotensive cardiac shock, leading to collapse and death. Significant physiologic stressors include severe infection and/or injury; that is, surgery and intubation associated with general anesthesia.^115–117

Risk Category	Dental Procedure			Hydrocortisone	Prednisone	Dexamethasone
Negligible	Nonsurgical & in chair +/- local anesthetic			Nil	Nil
Mild	Minor oral surgery Minor periodontal surgery	}	in the dental chair			Nil
Moderate to severe	Major oral or periodontal surgery—multiple extractions/implants Procedure >60 mins Significant blood loss general anesthetic/intubation			50–100 mg day of surgery and 24 hours afterward	10–20 mg within 2 hours of procedure	~2–4 mg (long-acting) >48 hours
Monitoring	BP (100/60) systolic >100; diastolic >60 →if lower give fluids (5% dextrose saline)

Iatrogenic adrenal insufficiency is caused by suppression of the HPA axis due to exogenous glucocorticoid therapy. The mean cortisol production rate is 5.7 mg/m²/day, or about 10 mg/day (equal to 2.5 mg of prednisone or 0.5 mg of dexamethasone) (see Table 22-15).¹¹⁸ Body surface area (BSA) is used to calculate the dose of a drug relative to the patient’s “ideal” body weight, resulting in a dose per meter squared (m²). The BSA is a better indicator of the patient’s “ideal” body weight because it is less affected by abnormal adipose mass, and this is useful when giving drugs with a narrow therapeutic safety index, such as chemotherapy agents. Of the various formulations, the Mosteller equation is simpler and considered more accurate:

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