Anatomy

The pituitary gland weighs from 500 to 1000mg and sits in the sella turcica immediately behind the sphenoid sinus. It has anterior and posterior bony walls and a bony floor. Above is a layer of dura (diaphragma sella) and then the optic chiasma, hypothalamus, and third ventricle. Laterally on each side is the cavernous sinus, inclusive of the internal carotid artery and cranial nerves III, IV, V₁, V₂, and VI.

The optic chiasma may be in front of (15%), above (80%), or behind the sella (5%). Within this optic chiasma, nerve fibers from the nasal half of the retina cross over to the opposite optic tract while those from the temporal half remain uncrossed. The close association of the pituitary gland with the optic chiasma explains the visual symptoms associated with expanding masses in this region.¹

The median eminence is an intensely vascular component at the baseline of the hypothalamus that forms the floor of the third ventricle. The pituitary stalk arises from the median eminence. The hypothalamus extends anteriorly to the optic chiasma and posteriorly to the mammillary bodies. It was not until the mid-1960s that hypothalamic releasing hormones were isolated and identified (Table 22-1).

Table 22-1 Pituitary Hormones, Hypothalamic Hormones, and Other Regulatory Factors

TRH, thyrotropin-releasing hormone; CRH, corticotropin-releasing hormone;

LH-RH, luteinizing hormone-releasing hormone; GH-RH, growth hormone-releasing hormone; PRF, prolactin-releasing factor; Pit-1, pituitary-specific transcription factor; ADH, antidiuretic hormone.

Physiology

Thyrotropin-releasing hormone (TRH) was the first releasing hormone to be identified. In subsequent years, other releasing hormones were identified. Of note, prolactin is under tonic inhibitory influence, with dopamine acting as a prolactin release-inhibiting factor. Magnetic resonance imaging (MRI) is the best method for visualization of hypothalamic–pitutiary anatomy, because the optic chiasma, vascular structures, and tumor extension to the cavernous sinuses can be well visualized on MRI compared to other imaging techniques.

Pituitary Tumors

Pituitary tumors may present with either hypofunction or hyperfunction, as well as symptoms directly related to the mass effect of the tumor (Table 22-2). Since the advent of computed tomography (CT), microadenomas have been arbitrarily designated as equal to or less than 10mm in diameter and macroadenomas as greater than 10mm in diameter. They are invariably benign, with no sex predilection. Pituitary adenomas are rarely associated with parathyroid and pancreatic hyperplasia or neoplasia as part of the multiple endocrine neoplasia type I (MEN I) syndrome. Pituitary carcinomas are rare, but metastases from other solid malignancies can occur more frequently.²

Table 22-2 Clinical Manifestations of Pituitary Tumors

SIADH = syndrome of inappropriate antidiuretic hormone; GH = growth hormone; LH = luteinizing hormone; FSH = follicle-stimulating hormone.

Prolactinoma

Acromegaly

Acromegaly may occur at a rate of 3 to 4 cases per million per year, with mean age at diagnosis of 40 years in men and 45 years in women. The GH-secreting tumors tend to be more aggressive in younger patients. Classical clinical features are listed in Table 22-4. More than 95% of cases of acromegaly are caused by GH-secreting pituitary tumors. In rare cases, they are caused by ectopic GH-releasing hormone (GH-RH) secretion, mainly carcinoids and pancreatic islet cell tumors. Patients with acromegaly have a 3.5-fold increased mortality rate, with cardiovascular disease being the most common cause of death. Somatotrope adenomas appear to be monoclonal in origin. A gsp mutation in a Gsp_Ia subunit in GH cells, leading to continuous GH secretion, has been shown to cause acromegaly.⁶

Table 22-4 Clinical Signs and Symptoms of Acromegaly

Due to the pulsatile nature of GH secretion, random GH levels can overlap in acromegalic patients and controls. Therefore, a single GH level is usually inadequate to establish the diagnosis.

Insulin-like growth factor-I has a longer plasma half-life than GH and is an excellent initial screening test for those suspected to have acromegaly. An elevated IGF-I level in a clinical setting suggestive of acromegaly almost always confirms the diagnosis. Patients with poorly controlled diabetes and malnutrition may have falsely low serum IGF-I levels. The oral glucose tolerance test remains the gold standard test to confirm the diagnosis. Normal individuals suppress their GH level to less than 1μg/L (using chemiluminescent assays) within 2 hours after ingestion of 100 grams of oral glucose solution.

With respect to women’s health, one should note that GH-secreting tumors may also cosecrete prolactin; thus, women may present with symptoms of hyperprolactinemia and only subtle symptoms of acromegaly. This cosecretion may occur over several years. The patient may initially present with high prolactin levels and several years later may start secreting excess GH.

Particular attention to early detection of cardiovascular disease should be made, because it is the primary cause of mortality in these patients. Patients with acromegaly have increased risk of colon polyps with potential for increased risk of malignancy, affecting their life expectancy. For this reason they should undergo colonoscopy every 3 to 5 years until more outcome data are available. It is not clear if more rigorous screening for a variety of cancers, including breast, lung, or prostate cancer, is indicated.

Cushing’s Disease

Corticotropin-secreting pituitary adenoma is the most common cause of endogenous Cushing’s syndrome (60%), with the rest being adrenal (25%) or ectopic (15%) in origin. The term Cushing’s disease refers specifically to a pituitary tumor as the cause. Signs and symptoms suggestive of hypercortisolism are listed in Table 22-5. Many signs and symptoms of Cushing’s disease are nonspecific, including hypertension, abnormal glucose tolerance, menstrual irregularities, and psychiatric disturbances, including depression. Most women with Cushing’s disease have reduced fertility.⁹

Table 22-5 Signs and Symptoms of Cushing’s Syndrome

Women with Cushing’s disease typically have fine facial lanugo hair and may have acne and temporal scalp hair loss secondary to increased adrenal androgen secretion. There is usually a 3- to 6-year delay in diagnosis of patients with Cushing’s disease, and it may be possible to date the onset of the disease by determining which scars are pigmented due to excess secretion of corticotropin and other melanotropins.

Diagnosis

Twenty-four hour urinary free cortisol measurement is the single best test for diagnosis of Cushing’s syndrome (Fig. 22-1). Because of the significant overlap between normal individuals and those with Cushing’s syndrome, random serum cortisol has no role in the diagnosis of Cushing’s syndrome. A 1-mg overnight dexamethasone suppression test with a morning cortisol level below 1.8μg/dL virtually rules out the disease but is associated with an up to 40% false-positive rate.

Figure 22-1 Laboratory investigation of a patient with a clinical suspicion of Cushing’s syndrome. ULN, upper limit of normal; ON DST, overnight dexamethasone suppression test; UFC, urinary free cortisol; CRH, corticotropin-releasing hormone; CXR, chest x-ray; MRI, magnetic resonance imaging; Abd. CT, abdominal computed tomography.

A combination of low-dose dexamethasone suppression test and corticotropin-releasing hormone (CRH) stimulation test has been shown to have 100% diagnostic accuracy in a National Institutes of Health study. This test may have a significant value in establishing the diagnosis in those with pseudo-Cushing’s and elevated 24-hour urinary free cortisol. Other tests useful in establishing the diagnosis of Cushing’s disease include midnight serum and salivary cortisol (see Fig. 22-1).

Once the diagnosis of Cushing’s syndrome has been established, the next step is to find out whether cortisol hypersecretion is corticotropin dependent (see Fig. 22-1). Although an undetectable or low corticotropin level is consistent with adrenal etiology, low-normal corticotropin may be seen in both ectopic Cushing’s syndrome and corticotropin-secreting pituitary tumor. The CRH stimulation test is used to differentiate between the two. Although corticotropin levels tend to be higher in those with ectopic Cushing’s syndrome compared to patients with pituitary disease, there is considerable overlap. The high-dose dexamethasone test or the CRH stimulation test is helpful in differentiation of the two disorders. Cortisol levels are not suppressed with the high-dose (8 mg) dexamethasone test in patients with ectopic corticotropin syndrome, and CRH stimulation may not lead to a further rise in corticotropin.¹⁰ The gold standard test to differentiate pituitary Cushing’s syndrome from ectopic corticotropin-producing tumor is inferior petrosal sinus sampling. This test should be performed by an experienced neuroradiologist; it is essential to note that it cannot be used to make the diagnosis of Cushing’s syndrome.

Nonsecretory and Glycoprotein-Secreting Pituitary Adenomas

Growth Hormone Deficiency

Growth hormone deficiency is now recognized as a pathologic state in adults, and many patients with GH deficiency now receive GH replacement. GH deficiency may contribute to increased mortality in patients with hypopituitarism, with cardiovascular disease being the most common cause of mortality. The symptoms of GH deficiency in adults are subtle and include decreased muscle strength and exercise tolerance and reduced sense of well-being (e.g., diminished libido, social isolation).

Patients with GH deficiency have increased body fat, particularly intra-abdominal fat, a well as decreased lean body mass compared to normal adults. Some patients have decreased bone mineral density, which may improve with GH replacement.

A trial of GH replacement in adults with documented GH deficiency and symptoms or metabolic abnormalities suggestive of GH deficiency is indicated. The most common side effects of GH therapy include fluid retention, carpal tunnel syndrome, and arthralgia. These side effects are usually dose-related and improve with dose reduction.

Gonadotropin Deficiency

Gonadotropin deficiency may be secondary to a pituitary defect, hypothalamic deficiency of GnRH, or a functional abnormality such as hyperprolactinemia, anorexia nervosa, and severe disease state. In women gonadotropin deficiency causes infertility and menstrual disorders, including amenorrhea. It is often associated with lack of libido and dyspareunia. In men hypogonadism is diagnosed less often, because decreased libido and impotence may be considered as a function of aging. Hypogonadism is often diagnosed retrospectively when the patient presents with a mass effect. Osteopenia is a consequence of longstanding hypogonadism and usually responds to hormone replacement therapy.

Corticotropin Deficiency

The symptoms of secondary adrenal insufficiency from corticotropin deficiency are similar to primary adrenal insufficiency with one important difference. Mineralocorticoid secretion is mainly regulated by the renin and angiotensin system and is preserved in patients with pituitary disorders. For this reason the symptoms are more chronic in nature and commonly include malaise, loss of energy, and anorexia. Hyperkalemia is not a feature of secondary adrenal insufficiency. An acute illness may precipitate vascular collapse, hypoglycemia, and coma.

Thyrotropin Deficiency

Thyrotropin deficiency is a relatively late finding in patients with pituitary disorders, with symptoms being similar to those seen with primary hypothyroidism, including malaise, leg cramps, lack of energy, and cold intolerance. The degree of hypothyroidism depends on the duration of thyrotropin deficiency.

Causes of Hypopituitarism

Anatomy and Physiology

The adrenal gland consists of the medulla and the cortex. The cortex is further divided into the zona reticularis, the zona fasciculata, and the zona glomerulosa. The medulla produces norepinephrine and epinephrine. The zonae fasciculata and reticularis produce cortisol and androgens, mainly dehydroepiandrosterone sulfate (DHEAS). The zona glomerulosa produces aldosterone. As a result of the absence of 17-hydroxylase in the zonal glomerulosa, cortisol and androgens cannot be produced in that layer.

The zonae reticularis and fasciculata are under the control of corticotropin released by the pituitary gland in response to hypothalamic CRH. CRH in turn is regulated by cortisol-negative feedback, stress, and a circadian rhythm. Besides increasing the synthesis of cortisol, corticotropin is trophic for the adrenal gland so that a lack of corticotropin results in atrophy of the zonae fasciculata and reticularis. Although corticotropin has some effect on aldosterone production, the zona glomerulosa is predominantly under the control of renin. Understanding the anatomy and physiology of the adrenal gland is crucial to understanding its hypofunction and hyperfunction.¹⁷

Adrenal Insufficiency

Secondary adrenal insufficiency is a result of adrenal gland atrophy from corticotropin deficiency. This most often results from pituitary corticotroph atrophy owing to previous exogenous glucocorticoid use,¹⁹ hypopituitarism, or isolated corticotropin deficiency (usually postpartum).

Clinical Presentation

The underlying etiology of adrenal insufficiency determines the clinical presentation (Table 22-7). Under the regulation of corticotropin, cortisol and adrenal androgens are lost in both primary and secondary adrenal insufficiency. Aldosterone production, predominantly regulated by renin, remains intact in secondary adrenal insufficiency. Therefore, hyperkalemia and profound dehydration with orthostatic hypotension are seen in primary adrenal insufficiency only. Likewise, hyperpigmentation of the skin or mucous membranes (secondary to increased corticotropin) is seen in primary adrenal insufficiency only. The absence of hyperkalemia or hyperpigmentation does not exclude adrenal insufficiency. In addition to hyponatremia and hyperkalemia, laboratory abnormalities in adrenal insufficiency may include hypoglycemia (usually chronic), hypercalcemia, eosinophilia, and lymphocytosis.

Table 22-7 Adrenal Insufficiency Signs and Symptoms

Late-Onset CAH and Pregnancy

Fertility rates may be lower in women with CAH, but with successful medical management, women, especially those with 21-hydroxylase deficiency, may conceive.²³

From a fetal and neonatal standpoint, accurate prenatal diagnosis of 21-hydroxylase deficiency and 11β-hydroxylase deficiency is necessary to allow for prenatal treatment using dexamethasone in an attempt to minimize clinical problems in the neonate. Dexamethasone can cross the placenta and suppress fetal adrenal steroidogenesis and potentially prevent masculinization of affected female fetuses.²⁴

Large quantities of estrogen are produced during normal human pregnancy, and, after the first 3 to 4 weeks of gestation, the placenta produces nearly all of the estrogen. The major precursor for estrogen production is DHEAS, which is synthesized in the fetal adrenal gland. The adrenals of the human fetus at term are as large as those of adults, weighing 8 to 10g or more. The fetal adrenals are principally composed of an inner fetal zone that accounts for 85% of the total volume. The outer zone, the neocortex, develops into the mature adrenal cortex, which is only 15% of the total volume. The capacity of the fetal adrenals for steroidogenesis is enormous, and near term, the fetal adrenals secrete 100 to 200mg of the steroid per day. The total daily steroid production by the adrenals in an unstressed adult is approximately 35mg.²⁵

In addition to its role in providing precursors for placental estrogen formation, the fetal adrenal cortex may participate in the events that lead to the initiation of labor and maturation of the fetal lungs. Corticotropin levels in human fetal blood decline as gestation progresses, but the adrenals continue to grow in late gestation. The trophic stimulus for the fetal adrenal may not be corticotropin, and the pattern of steroids secreted by the fetal adrenal is also different. Therefore, a trophic role has been proposed for other hormones, including GH, human chorionic gonadotropin (hCG), prolactin, and human placental lactogen. More than 90% of the estradiol and estriol and 85% or more of the progesterone formed in the trophoblast are secreted into the maternal compartment. The net transfer of steroids to maternal blood is approximately 10 times that of the net transfer to fetal blood.

Only a small amount of the steroids in the maternal circulation reach the fetal compartment in normal pregnancy. For example, a small amount of cortisol in maternal plasma crosses the placenta, both because the reentry pathway dominates and because cortisol within the trophoblast is converted to cortisone by 11β -hydroxysteroid dehydrogenase. Circulating 19-carbon steroids in the maternal compartment, such as DHEAS, DHEA, androstenedione, and testosterone, do not reach the fetal compartment because of the presence of aromatase enzymes of the syncytiotrophoblast that are used for the conversion of 19-carbon steroids to estrogens. This mechanism protects the female fetus from possible virilization in women who may be hyperandrogenic during pregnancy.

Pathophysiology

Cushing’s syndrome is a result of glucocorticoid excess. Endogenously, this may be due to increased corticotropin secretion by the pituitary gland (Cushing’s disease) or ectopically or to autonomous cortisol secretion by an adrenal tumor. The most common cause of Cushing’s syndrome, however, is exogenous use of glucocorticoids.

Clinical Presentation

The clinical features of Cushing’s syndrome are listed in Table 22-5. With respect to specificity for Cushing’s syndrome, thinning of the skin, purple striae, and bruising are the best clinical signs. Hypokalemia, edema, and hyperpigmentation are more commonly seen in ectopic corticotropin secretion, in which corticotropin and cortisol levels tend to be much higher. If a pregnant woman is in a hypercortisolemic state due to exogenous glucocorticoid therapy, the fetus is at potential risk of hypoadrenalism and one needs to forewarn the neonatologist.

Diagnosis

The diagnosis of Cushing’s syndrome revolves around the inability to suppress the HPA axis. Two screening tests are employed:

The 24-hour urinary free cortisol and creatinine is more specific but is also more cumbersome. The value may be elevated in depression, acute illness, and alcoholism. The 1-mg overnight dexamethasone suppression test is easy to perform but false-positive and false-negative responses are common.

Causes of a false-positive test result include increased cortisol-binding globulin (high circulating estrogen), depression, acute illness, and alcoholism. Drugs that increase the metabolism of dexamethasone (rifampin, phenobarbital, and phenytoin) may also result in a false-positive response. False-negative test results may be seen in Cushing’s disease or cyclic intermittent Cushing’s syndrome.

Differential Diagnosis

Figure 22-1 will allow confirmation of hypercortisolism and assessment of potential causes. If an abnormal result is obtained by either the 24-hour urinary free cortisol or the 1-mg overnight dexamethasone suppression test, the pseudo-Cushing’s state of alcoholism or endogenous depression should first be sought by a careful history, physical examination, and laboratory evaluation. A repeat urinary free cortisol with alcohol abstention should be normal.

If necessary, the low-dose dexamethasone suppression test may document true hypercortisolism. Dexamethasone 0.5mg orally is administered every 6 hours for 48 hours, while a 24-hour urinary free cortisol including 17-hydroxysteroids (17-OHCS) is collected before and on the second day of dexamethasone. Failure to suppress 24-hour urine 17-OHCS to less than 4mg or the urinary free cortisol to less than 25μg suggests pathologic hypercortisolism, although pseudo-Cushing’s states occasionally cannot be suppressed. The urine 17-OHCS level is less essential because of the advent of the urinary free cortisol. Once true Cushing’s syndrome has been documented, a corticotropin level separates corticotropin-dependent from corticotropin-independent disease.

The corticotropin-dependent hypercortisol diseases and syndromes are:

The corticotropin-independent hypercortisol diseases and syndromes are:

A low corticotropin level prompts CT of the adrenal to look for a tumor or nodules. A normal or elevated corticotropin value suggests Cushing’s disease or ectopic corticotropin production; these can be differentiated by the high-dose (8mg) overnight dexamethasone suppression test. If a morning cortisol level suppresses by 50% in response to 8mg of dexamethasone the evening before, the diagnosis is presumed to be Cushing’s disease. However, the specificity is not 100%. Many occult bronchial carcinoid tumors with corticotropin secretion can suppress in response to high-dose dexamethasone.

Magnetic resonance imaging is not a definitive means for distinguishing pituitary from nonpituitary tumors, because 50% of Cushing’s disease patients have occult pituitary adenomas. Furthermore, up to 10% of patients may have false-positive pituitary scans (pituitary “incidentaloma”). Inferior petrosal sinus sampling (enhanced with CRH) may be necessary; an elevated sinus-to-peripheral corticotropin gradient suggests Cushing’s disease.

Treatment

It should be apparent that the diagnostic workup for Cushing’s syndrome can have many pitfalls. False-positive screening tests, pseudo-Cushing’s states, modest specificity of the high-dose dexamethasone suppression test, and limitations of pituitary imaging can all lead to an erroneous diagnosis. It is important to correctly diagnose Cushing’s disease because the most appropriate treatment is transsphenoidal pituitary adenomectomy performed by an experienced neurosurgeon, although radiation therapy, ketoconazole (Nizoral), or bilateral adrenalectomy may be needed in some cases. Resection of the underlying tumor or chemotherapy is the treatment for adrenal neoplasia and ectopic corticotropin production.

Cushing’s Syndrome and Pregnancy

Although the clinical diagnosis may be difficult during pregnancy, one should seek out catabolic signs. There is also a greater likelihood of diabetes, worsening hypertension, cardiomyopathy, and psychological and muscular symptoms. The diagnostic testing, such as low- and high-dose dexamethasone testing, remains the same. One should remember that with higher cortisol binding globulin levels, the usual serum (total) cortisol levels may be falsely high.²⁶

Poor wound healing should be anticipated as well as prolonged bleeding from any surgical procedures.

Treatment is the same as for the nonpregnant state although surgical intervention such as adrenalectomy, if required, should be performed early in the second trimester. Occasionally, ketoconazole²⁷ has been used to medically control the hypercortisolism without adverse effects on the mother or the baby. Adrenal insufficiency can occur postoperatively and therefore preventive therapy should be initiated.²⁸

Clinical Presentation

The triad of headaches, palpitations, and diaphoresis in the presence of hypertension is classic for pheochromocytoma. Other signs and symptoms are listed in Table 22-8. More frequently recognized are silent pheochromocytomas presenting as adrenal incidentalomas. Cocaine abuse may be mistaken for pheochromocytoma.

Table 22-8 Signs and Symptoms of Pheochromocytoma

Diagnosis

Screening for pheochromocytoma consists of a 24-hour urine collection for catecholamines and metanephrines. Plasma catecholamines may also be useful; plasma norepinephrine levels greater than 2,000 pg/mL are specific for pheochromocytoma. Borderline or indeterminate results require further testing. The clonidine (Catapres) suppression test is used to confirm the diagnosis in patients with indeterminate urine or plasma studies. The test involves the measurement of plasma catecholamines before and 3 hours after 0.3mg of oral clonidine. A normal response is a plasma norepinephrine level less than 500pg/mL or a 50% decrease from baseline. Plasma metanephrines is also an excellent screening tool.

The glucagon stimulation test may also be used. An increase in blood pressure and plasma catecholamines strongly suggests pheochromocytoma. However, the sensitivity of this test is limited, and it is potentially dangerous (hypertensive crisis). Chromogranin A, a neuropeptide secreted with the catecholamines, is sensitive for pheochromocytoma but has poor specificity. It is elevated with even minor degrees of renal insufficiency and cosecreted with many hormones.

Once the diagnosis is biochemically established, radiographic localization is indicated. Although CT is the initial choice, MRI may be especially useful because pheochromocytoma can be markedly hyperintense (white) on T2-weighted images. Scanning with iodine-131-labeled metaiodobenzylguanidine (MIBG) is most specific and is particularly useful for extra-adrenal (10%) and malignant metastatic tumors (10%).

Treatment

Treatment of a pheochromocytoma is resection after appropriate operative preparation (volume loading and adrenergic receptor blockade). Calcium channel blockers may also be effective.

Pheochromocytoma and Pregnancy

Pheochromocytoma in a pregnant woman is life-threatening, but the prognosis appears to be improving. Maternal and fetal mortality rates of 48% and 54.4%, respectively, in the late 1960s³⁵ dropped to 17% and 26%, respectively, by the late 1980s.³⁶ In a 1999 review of patients with pheochromocytoma in pregnancy, the maternal and fetal mortality rates were 4% and 11%, respectively. Antenatal diagnosis of pheochromocytoma reduced the maternal mortality rate to 2%.³⁷

Pregnant patients with pheochromocytoma usually present with severe and fluctuating hypertension. The most common associated symptoms are headache, perspiration, palpitation, and tachycardia. Other signs and symptoms may include arrhythmias, postural hypotension, chest or abdominal pain, visual disturbance, convulsions, and sudden collapse. A history of multiple endocrine neoplasia type II (MEN II), familial pheochromocytoma, von Hippel-Lindau syndrome, or retinal angiomatosis should increase clinical suspicion.

Preoperative management with alpha-adrenergic blockade (e.g., phenoxybenzamine) is safe in pregnancy. Combined alpha and beta blockers (e.g., labetalol) have also been used in pregnancy without adverse fetal effects. Beta blockade should not be used without prior alpha blockade because unopposed alpha-adrenergic activity may lead to vasoconstriction and a hypertensive crisis.

Surgical intervention should be performed before 24 weeks’ gestation, after achieving adequate alpha blockade. After 24 weeks’ gestation, uterine size makes abdominal exploration and access to the tumor difficult. Optimum results are obtained if surgery is delayed until fetal maturity is reached.³⁸ At that time, with adequate alpha blockade, elective cesarean delivery may be performed, followed immediately by adrenal exploration. Vaginal delivery appears to be higher risk than cesarean delivery. Some authors have reported success with alpha and beta blockade from the beginning of the second trimester to term, with good fetal outcomes. Malignant pheochromocytoma may recur in pregnancy. Lifelong monitoring is necessary in all patients, with extra caution in those who are pregnant.

Thyroid Physiology

Physiologic Effects of Thyroid Hormone

Thyroid hormone influences almost all tissues of the body, and some consider them tissue growth factors. Protein synthesis and catabolism is stimulated, and this is probably responsible for some of the calorigenic effect of thyroid hormone. Thyroid hormone also affects carbohydrate metabolism, increasing epinephrine effects in stimulating glycogenolysis and gluconeogenesis and enhancing the rate of intestinal glucose absorption.

Thyroid hormone affects catabolism of all lipoproteins. Hypothyroidism can thus lead to increased levels of any of the lipoproteins, including low-density, very low-density, intermediate-density, and high-density lipoproteins.

Prevalence of Thyroid Disease

The National Health and Nutrition Examination Survey (NHANES III)⁴³ measured serum thyrotropin, total serum T₄, and antithyroid antibodies in a sample representative for geographic distribution of U.S. population. The prevalence of hypothyroidism was 4.3% (0.3% clinical and 4.0% subclinical) and the prevalence of hyperthyroidism was 1.3% (0.5% clinical and 0.7% subclinical). It should be noted that mean serum thyrotropin in a healthy population was 1.5mU/L. Thyrotropin levels were higher in females compared to males, higher in the white population than African Americans or Mexican Americans. Women were also more likely to have antithyroid antibodies.

In 2004, the U.S. Preventive Health Task Force⁴⁴ felt that there was insufficient “good strength” evidence to support testing or routine screening of thyroid function in the general population (Table 22-10). Most experts agree that although controversial, screening is warranted in women over age 35, men over age 65, and as routine screening in women at their first prenatal visit.^45,46 The main areas of disagreement between the U.S. Preventive Task Force in 2004 and the joint statement by several endocrine associations in 2005⁴⁷ are

Table 22-10 Screening Recommendations for Thyroid Disease

Until more evidence is gathered through major clinical trials, patient preference will also have an important role in the decision making together with the best clinical judgment from the practicing physician.

Thyroid Disease and Fertility

Menometrorrhagia may be evident in mild to moderate hypothyroidism, and amenorrhea may be observed with severe hypothyroidism. There may be disorders of ovulation or conception with hypothyroidism. Occasionally, with severe hypothyroidism, prolactin levels may be elevated, resulting in reduced LH and FSH secretion, leading to absent menses. Autoimmune ovarian problems can coexist with hypothyroidism, which may result in premature ovarian failure. Endometriosis has also been reported in antibody-positive women. Hyperthyroidism may also be associated with irregular or absent menses, and infertility is common.

Thyroid disease should be considered in patients undergoing investigation for menstrual problems⁴⁸ or infertility.⁴⁹ A recent prospective study by Poppe and colleagues of more than 400 infertile women showed a higher prevalence of autoimmune thyroid disease (18%), determined by the presence of antimicrosomal antibodies, compared with controls (8%).⁵⁰ A Finnish study reported an overall prevalence of hypothyroidism of 4% in infertile women.⁵¹ Fortunately, once treated adequately, neither hypothyroidism nor hyperthyroidism has a major impact on fertility.

The potential effect of treatment of relative thyroid hormone deficiency on infertility is unknown.⁵² One intervention trial in women with recurrent abortions, mild thyroid dysfunction, and positive antimicrosomal antibodies⁵³ showed that early supplementation with thyroid hormone favorably affects the outcome of pregnancy. It is unknown whether treatment of women with antithyroid antibodies but normal thyrotropin levels can lead to better outcomes. Systematic screening⁵⁴ should be considered in all women with a female cause of infertility.⁵⁵

Subclinical Hypothyroidism

Subclinical hypothyroidism is defined as an elevated serum thyrotropin level associated with normal total or free levels of T₄ and T₃ in the absence of symptoms. The thyrotropin level is usually less than 10μU/mL. It has been also called mild hypothyroidism, preclinical hypothyroidism, mild thyroid failure, and compensated hypothyroidism⁵⁶

The natural history of subclinical hypothyroidism is variable.⁵⁷ In some individuals, the thyrotropin level will be normal several months later or may remain unchanged. This may be due to laboratory error or to transient silent thyroiditis. The patient may also develop overt hypothyroidism, which occurs at a rate of about 5% per year in patients with raised thyrotropin levels and detectable antithyroid antibodies.⁵⁸ In some subjects with high titers of antithyroid antibodies, the risk of progression to overt disease may be closer to 20% per year.⁵⁹ Consideration of these possible outcomes⁶⁰ affects the decision about whether to treat or to observe without treatment.⁶¹

Subclinical Hyperthyroidism

Subclinical hyperthyroidism is defined as a suppressed serum thyrotropin level associated with normal total or free levels of T₄ and T₃. The prevalence (2%) is much lower compared with subclinical hypothyroidism. With or without a goiter, it is often difficult to make a definitive diagnosis, even with additional tests.

If the thyrotropin level is not detectable or is at the lowest limit of normal, it is unlikely that the patient is hyperthyroid. If the thyrotropin level is only slightly below the normal range (i.e., 0.1 to 0.3μU/mL), this is most likely a transient abnormality and should be monitored rather than treated. If the individual is truly hyperthyroid, there will be potential increased risk of atrial fibrillation, osteoporosis, and changes in heart contractility.

Nevertheless, the abnormal test results may be a result of nonthyroidal illness and concomitant medication, underlying autonomous thyroid function, or the initial phase of thyroiditis. It would be reasonable to repeat thyroid function tests in 8 to 12 weeks. Normalization would indicate likely recovery from nonthyroidal illness or thyroiditis. If the initial pattern persists, the choice should be made between a trial of antithyroid drugs and close clinical follow-up. Antithyroid drugs would be preferable to radioactive ablation, because they do not cause permanent hypothyroidism and thus would constitute a therapeutic/diagnostic trial.

Hypothyroidism

Hypothyroidism is a common disease, especially in women, with a 1% to 2% prevalence (up to 10% in those older than age 65).^43,56,65 Congenital hypothyroidism is one of the most frequent congenital diseases, with an incidence of 1/4000 newborns. Table 22-11 lists the causes of hypothyroidism.

Table 22-11 Causes of Hypothyroidism

Clinical Features

The symptoms are generally related not only to the pathogenesis of hypothyroidism, duration, and severity, but also to the age of the patient. The symptoms and signs of thyroid disease are ubiquitous and often nonspecific. Armed with a high index of suspicion, one can more easily document the clinical manifestations of thyroid disease. Hypothyroidism may manifest as modest weight gain; cold intolerance; fatigue; dry, falling hair; facial puffiness; macroglossia; slow, guttural speech; muscle aches; depression; reduced memory; somnolence; sleep apnea; constipation; galactorrhea; and a menstrual disorder such as menorrhagia.

Clinical signs include dry and yellow skin, eyelid edema, puffy hands and swelling of feet, cold extremities, dry skin and brittle nails, coarse hair, slow speech, delayed relaxation phase of deep tendon reflexes, bradycardia, and serous cavity effusions. Despite popular belief weight gain is minimal and is due mostly to fluid retention. Since autoimmune processes play a major role in thyroid disorders, one should often look for other autoimmune disorders in the patient and enquire about family history of thyroid and other autoimmune disorders, especially in female relatives. Smoking increases the metabolic effects of hypothyroidism in a dose-dependent way.

Thyroid gland examination should include the size, symmetry, consistency, tenderness, nodularity, mobility, vascularity, and any associated lymphadenopathy. The presence of goiter is not essential for diagnosis.

Laboratory Tests

The best screening test for both hypothyroidism and hyperthyroidism is the level of thyrotropin (TSH). The thyrotropin response to decreasing free T₄ levels is hyperbolic. Once the patient is hypothyroid, thyrotropin rises beyond the normal range, but subsequent drops in free T₄ levels can result in exponential rise in thyrotropin levels. Although the thyrotropin level is helpful in making the diagnosis of hypothyroidism, the levels of TSH do not correlate with the severity of the hypothyroidism.

Once an abnormal TSH level is detected, one should confirm the diagnosis with measurement of free T₄ or T₃ levels. Total T₄ reflects bound and free T₄. T₄ uptake is an estimate of binding that correlates with the amount of TBG. The free thyroxine index is a calculated value (product of total T₄ and the T₄ uptake). The free T₄ is a direct immunoassay detecting unbound T₄. This is a more economical method compared to the more accurate but laborious dialysis assay. Total T₃ and free T₃ are additional tests that are not immediately necessary for thyroid evaluation.

Thyroglobulin levels may be high, indicating inflammation or damage to the thyroid gland, and may be low in situations of excessive exogenous thyroid hormone administration.

Antithyroid Antibodies

Microsomal antibodies (or thyroid perioxisomal antibodies) usually represent underlying Hashimoto’s thyroiditis. Approximately 5% to 15% of euthyroid women and up to 2% of euthyroid men have antithyroid antibodies and these patients have an increased risk of developing thyroid dysfunction.

Thyroglobulin antibodies may also be present in Hashimoto’s thyroiditis (autoimmune thyroiditis). In scenarios where thyroglobulin levels are being monitored, the presence of thyroglobulin antibodies may interfere with the thyroglobulin assay, resulting in falsely low or falsely high levels of thyroglobulin.

Thyrotropin receptor antibodies are antibodies that bind to the thyrotropin receptor. Their presence signifies Graves’ disease. Some antibodies may be stimulatory, such as thyroid-stimulating immunoglobulin; others may be inhibitory (thyroid binding inhibitory immunoglobulin. Antithyroid antibodies may cross the placenta and can cause transient thyroid dysfunction in the fetus.

Other Diagnostic Methods

The thyroid ultrasound examination is now widely available and is the best delineator of thyroid structure. A radioactive iodide scan can determine which areas of the thyroid are able to trap and organify iodide. Radioactive iodide uptake is a numerical (not visual) measure, describing the percentage of iodide that is being taken up specifically by the thyroid tissue. Measurements can be typically made 4 hours or later after the isotope (¹³¹I or ¹²⁵I) is administered.

Treatment

The thyroid hormone replacement preparations available are:

The most commonly used preparation is levothyroxine, usually with a daily replacement of 1.6μg/kg. Thyroid function tests should be assessed at 2 months, then 6 months, and then annually to monitor compliance and dosage requirements. The dosage is smaller if the patient still has residual thyroid function.

Due to its short half-life, T₃ is used before some diagnostic tests. There are some data indicating that adding T₃ to T₄ treatment will improve mood and quality of life, but other studies don’t show any beneficial effect.⁶⁹ The medication should be taken at least 1 hour from a meal. Medications such as calcium, soy, iron, aluminum, and cholestyramine can interfere with the absorption or metabolism of levothyroxine, and they should be separated by 4 hours from the thyroid hormone. In elderly patients, with or without cardiac disease, a lower dose (12.5 to 25μg/day) is started and increased slowly, by 25μg/day every 4 to 6 weeks.

Special consideration should be taken when treating pregnant women with preexistent hypothyroidism (see “Thyroid Disease in Pregnancy” in this chapter) and to treat adrenal insufficiency first in secondary hypothyroidism.

The interchangeability of thyroxine products has been closely watched for several decades, but in 2004, the American Association of Clinical Endocrinologists, The Endocrine Society (TES), and the American Thyroid Association issued a joint statement addressing the introduction to the market of several generic levothyroxine products that had been approved by the U.S. Food and Drug Administration (FDA).⁷⁰ The main concern was related to the FDA’s method in determining bioequivalence. Bioequivalence establishes therapeutic equivalence; this would be better reflected with an endocrine endpoint, such as serum thyrotropin, but this measurement was not used by the FDA. Thus the difference in some preparations was large (33% [uncorrected] and 12.5% to 25% [corrected for baseline values]). The panel recommended not substituting thyroxine preparations for one another, but if it is clinically indicated, then it suggested monitoring thyrotropin at 6 weeks.

Estrogen Therapy

In women with hypothyroidism, estrogen therapy may increase thyroxine requirements.⁷¹ The serum TBG concentration increases at 6 weeks in response to estrogen, reaching a peak at 12 weeks. Serum T₄ level rises in parallel.

Estrogen increases serum TBG levels by increasing hepatic biosynthesis. Androgens decrease serum TBG levels.

Clinical Examination

Hyperthyroidism may manifest as involuntary weight loss; occasional hyperphagia; thin, brittle hair; reduced ability to concentrate; personality change; initial hypomanic symptoms followed by fatigue; insomnia; increased sweating; heat intolerance; fine tremor; proximal muscle weakness; tachyarrhythmia; more frequent bowel movements; lighter menses with reduced rate of ovulation; thin, brittle nails; and eye stare and lid lag.

The presence of proptosis on ocular examination or pretibial myxedema (a nonpitting edema of the shins) strongly suggests Graves’ disease⁷² (Table 22-13). The differential diagnosis is listed in Table 22-14.

Table 22-13 Symptoms and Signs of Thyrotoxicosis

Italicized items are more specific for Graves’ disease.

Table 22-14 Differential Diagnosis of Hyperthyroid Symptoms

Laboratory Evaluation

Finding a suppressed thyrotropin level with an elevated T₄ or T₃ level confirms the diagnosis of hyperthyroidism. New generations of thyrotropin assays can detect levels as low as 0.002IU/mL. Truly hyperthyroid patients will have low thyrotropin levels that are in this range or most likely undetectable. The presence of thyrotropin receptor antibodies indicates Graves’ disease but by themselves do not indicate hyperthyroidism.

Radioactive iodine uptake can help determine if the thyroid is autonomously overactive. This procedure can be performed in a nonpregnant woman but is not an option in a pregnant woman.

Antithyroid Drugs

Thionamides, including propylthiouracil (PTU) and methimazole, are approved by the FDA for the treatment of hyperthyroidism. Both inhibit thyroid hormone synthesis by interfering with thyroid peroxidase-mediated iodination of tyrosine residues in thyroglobulin, an important step in the synthesis of T₄ and T₃. PTU has an additional effect in blocking the conversion of T₄ to T₃. The medications may also have direct immunosuppressive effects in the thyroid, accounting for some of their effects in Graves’ disease.⁷³

Personal preference has usually determined the initial choice of antithyroid medication. Recently methimazole has become the treatment of choice due to its better side effect profile and once-a-day schedule. The usual starting dose of methimazole is 15 to 30 mg; of PTU is 300 mg daily. After starting the treatment, close follow-up testing at 4 weeks is recommended and then every 4 to 6 weeks until euthyroidism is achieved. Some authors prefer using high doses first to block the gland and supplement with exogenous thyroid hormones,⁷⁴ but these benefits have not been replicated in North America.⁷⁵ There do not appear to be any good predictors of clinical remission or response to antithyroid drugs. Typically antithyroid medication is used for between 12 and 18 months. Once the medication is stopped, relapse occurs, usually within the first 3 to 6 months, but remission may last as much as 40 years.

Side Effects of Antithyroid Drugs

Antithyroid drugs have a variety of minor side effects, such as skin reactions, arthralgias, gastrointestinal effects, and sialadenitis. Almost all patients taking antithyroid drugs will have transient elevation of liver transaminases within the first 2 to 6 weeks. The most fearful side effect is agranulocytosis, thought to occur in 0.3% of cases, mostly at the beginning of the treatment (first 3 months). A complete blood count is recommended after initiating therapy, but follow-up tests are not helpful because the agranulocytosis is idiosyncratic. However, all patients should be aware of this risk and should be told to stop the drug and seek urgent medical therapy if they develop sudden fever or sore throat without explanation. Rarer side effects include hepatic necrosis, vasculitis, and cholestasis.⁷⁶

Radioactive Iodine

Radioactive iodine is used to definitively treat patients with hyperthyroidism.⁷⁷ This will result in subsequent hypothyroidism. Radioiodine has not been shown to cause infertility or birth defects but certainly can cause fetal hypothyroidism, especially if given after the first trimester.

Thyroid Function in Pregnancy

Thyroid disorders are observed 4 to 5 times more frequently in women than in men. Consequently, physicians should be aware of the physiologic changes of thyroid function in pregnancy.

Pregnancy results in a number of physiologic changes⁸¹:

Total thyroid hormone (T₄) is increased mostly in the first half of gestation due to a profound increase in TBG. Serum T₄ levels increase between 6 and 12 weeks and slowly after that; T₃ rise is more progressive. Serum T₄ has a 20-fold higher affinity for TBG than T₃, so the ratio between T₄ and T₃ is constant. The changes in TBG imply that the extrathyroidal T₄ pool must increase to ensure the same free hormone level. The daily increased secretion is between 1% and 3 % until it reaches a steady state and then returns to previous levels. The free levels of T₃ and T₄ are maintained usually in a normal range. The indirect calculated free T₄ indices are not very reliable in pregnancy. The hormonal output is regulated through the normal pituitary–thyroid feedback by thyrotropin stimulation that is minor in a patient with a normal thyroid gland.⁸² However, these physiologic adjustments can be “stressed” in women with any predisposition to thyroid disease.

Human chorionic gonadotropin is a weak thyroid stimulator that can bind to the thyrotropin receptor. If hCG is markedly elevated (as may happen normally in a twin pregnancy) or is a more potent molecular variant, serum free T₄ concentrations may increase to hyperthyroid range with temporary thyrotropin suppression.⁸³

Immunology of Normal Pregnancy

It has been observed that most immune disorders improve during pregnancy. One cause has been postulated to be the absence of expression of the classic class I or II major histocompatibility complex (MHC) antigens on the placenta. These MHC antigens are needed to present antigenic peptides to cytotoxic cells and T-helper cells. The placenta produces human leukocyte antigen G, which binds natural killer cells and activates CD8+ T cells. The placental trophoblast cells express a Fas ligand that mediates apoptosis of Fas-expressing maternal lymphocytes, resulting in protection of the fetus.

There are many conflicting data regarding the effect of pregnancy on T cells and B cells, with a profound interest in the Th2/Th1 ratio, which seems to be elevated in pregnancy.⁸⁴ During pregnancy, there is also there is a large drop in antibody levels with no parallel reduction in B-cell number. Their reduced activity is correlated to the sex steroids. Within 6 months of delivery, total imunoglobulin G as well as autoantibodies rise above prepregnancy levels and we see an exacerbation of almost all autoimmune disorders.

Fetal Thyroid Function

The fetal thyroid begins to function after 10 to 12 weeks of pregnancy. Thyroid hormones (mostly from the fetal thyroid and a negligible amount from the mother’s thyroid) are important for development of the fetal nervous system. Iodine in the mother’s diet readily crosses the placenta and is used by the fetal thyroid gland to make thyroid hormone. Iodine deficiency can cause newborn hypothyroidism or mental retardation (cretinism) and is a major world health problem in underdeveloped countries. Because there is an overabundance of iodine in the American diet, disorders caused by a lack of dietary iodine rarely occur here. Low thyroid hormone concentrations in early gestation may be associated with lower IQ in children age 5 to 7.⁸⁵ Some of the altered physiological development⁸⁶ was also found in biochemically euthyroid women with elevated antimicrosomal antibodies.⁸⁷

Planning Pregnancy for Women with Thyroid Disease

In patients with hypothyroidism the therapeutic aim is to maintain the thyrotropin level in the normal range, preferable close to 1 to 2μU/mL.⁸⁸ If a woman is hyperthyroid before pregnancy, medical treatment with PTU should be started.⁸⁹ Clearly, radioactive iodine is contraindicated in pregnancy, and nonpregnant women should be advised to avoid conception for 6 to 12 months after the treatment. If a woman conceives while taking PTU the medication can be continued but adjusted to allow the thyroid hormone levels to be at the upper end of normal.

Hypothyroidism in Pregnancy

Overt hypothyroidism is present in 0.3% to 0.7% of pregnancies and subclinical hypothyroidism in up to 2.5%. L-thyroxine is safe and is well absorbed during pregnancy. Some women require higher doses during their pregnancy. Physicians generally monitor the thyrotropin level two or three times during the pregnancy to detect even mild hypothyroidism and increase the L-thyroxine dose, if necessary. Several publications have shown that 35% to 62% of women with autoimmune hypothyroidism and up to 70% to 100% of athyroid women require an increase of levothyroxine dosage. A prospective study of 19 women found that an increase in the levothyroxine dose was necessary during 17 pregnancies.⁹⁰ The mean levothyroxine requirement increased 47% during the first half of pregnancy (median onset of increase, 8 weeks’ gestation) and plateaued by week 16. This increased dose was maintained and required until delivery.

Hyperthyroidism in Pregnancy

Thyrotoxicosis (hyperthyroidism) during pregnancy, most often due to Graves’ disease, presents a challenge for diagnosis and treatment because of unique fetal and maternal considerations. The risk of miscarriage and stillbirth is increased if thyrotoxicosis goes untreated, and the overall risks to mother and baby further increase if the disease persists or is first recognized late in pregnancy.⁹¹

The main disorders that present with symptoms and signs of hyperthyroidism in pregnancy include Graves’ disease, silent thyroiditis, hyperemesis gravidarum, and molar pregnancy (Table 22-15). The diagnosis of hyperthyroidism is suggested by specific physical signs, such as prominent eyes, enlarged thyroid gland, and exaggerated reflexes, and is confirmed by markedly elevated serum thyroid hormone levels and a suppressed thyrotropin level. Radioactive investigations are not performed. However, because there is no fetal thyroid activity until after the end of the first trimester, there is very little iodide trapping by the fetus in early pregnancy. Later in pregnancy radioactive iodine can destroy the fetal thyroid, but this is probably not a sufficient reason to end the pregnancy, because recognition and treatment of hypothyroidism shortly after delivery usually ensures normal growth and development in the child.

The treatment of choice for thyrotoxicosis during pregnancy is antithyroid medication, either PTU or methimazole,⁹² because radioactive iodine cannot be used. PTU remains the drug of choice, because methimazole has been associated with rare cases of aplasia cutis in some infants.⁹³

The initial goal is to control the hyperthyroidism and then use the lowest medication dose possible to maintain serum thyroid hormone levels in the high normal range. In this way smaller doses of medications are used and thus are less likely to cause fetal hypothyroidism. If a mild allergy to one of these medications develops, the other medication may be substituted. If there is a problem with taking pills or more severe drug allergy, thyroidectomy may be performed during the second trimester but is rarely necessary.

The natural course of hyperthyroidism in pregnancy is for the disease to become milder or remit totally near term.⁹⁴ In many patients antithyroid medications can be tapered to low levels or even discontinued. For those patients who are not so fortunate, it is important to maintain control of the hyperthyroidism throughout pregnancy to avoid severe thyrotoxicosis (thyroid storm) developing during labor and delivery.⁹⁴ If this does develop, additional acute treatment with beta-adrenergic blockers such as propranolol (Inderal) and high doses of nonradioactive iodine are used. Long-term treatment with these agents is not advised in pregnancy, because beta blockers have been associated with fetal bradycardia and occasionally intrauterine growth retardation.⁹⁵

In lactating mothers, both PTU and methimazole can be safely used, their concentration in breast milk being small, with no effects on thyroid functions in the breastfed infant.⁹⁶

Fetal Thyroid Disease

Antithyroid medications, nonradioactive iodine, and maternal thyroid antibodies can all cross the placenta and cause hypothyroidism in the fetus. Nonradioactive iodine, which is present in some medications, including some cough medications, can cause a goiter in the fetus, making delivery difficult or causing respiratory obstruction. For this reason, iodine-containing drugs should never be used in pregnancy except in the case of thyroid storm. Unfortunately, there is no simple blood test to assess fetal thyroid function, although measurements of thyroid hormone or thyrotropin levels in the amniotic fluid sac have been used in research studies.⁹⁷ Plain X-rays sometimes show delayed bone development in fetal hypothyroidism, but this test is usually not recommended. Screening for hypothyroidism at birth, now done routinely in North America on all babies, identifies the need for early short- or long- term thyroxine treatment, with excellent long-term follow-up results.

Fetal thyrotoxicosis (hyperthyroidism) occurs occasionally due to transfer of maternal thyroid-stimulating antibodies across the placenta. Most often, the mother herself has hyperthyroidism, which is being treated with antithyroid drugs that also passively treat the baby by crossing the placenta. Sometimes, however, the mother’s thyrotoxicosis occurred in the past and was controlled by either radioactive iodine treatment or an operation in which the mother’s thyroid gland was removed. In such a situation the mother has less thyroid tissue and cannot be hyperthyroid, even though she continues to have thyroid-stimulating antibodies in her blood. Because the mother is well, fetal thyrotoxicosis may not be suspected.

Clues to the presence of fetal hyperthyroidism are fetal heart rate consistently above the normal limit of 160 beats per minute and the presence of high levels of thyroid-stimulating antibodies in the mother’s blood. Recently, it has been suggested that ultrasonography of the fetal thyroid gland may be helpful in assessing fetal thyroid size.⁹⁸

All women with a history of Graves’ disease should be tested for thyroid-stimulating antibodies late in pregnancy.⁹⁹ The consequences of untreated fetal thyrotoxicosis include low birth weight and head size, fetal distress in labor, and neonatal heart failure and respiratory distress. Administration of antithyroid drugs to the mother during pregnancy can treat the baby in this situation. Close follow-up and continued treatment is required after delivery.

Preexisting Thyroid Disease

For preexisting hypothyroidism, thyroid hormone treatment is continued after delivery and breastfeeding is encouraged. Thyroid hormones do not pass into breast milk in significant amounts. Graves’ disease is prone to relapse or worsen in the postpartum period. If that happens, antithyroid drugs can be started or their dose increased, or radioactive iodine can be given if the mother is not breastfeeding. Women taking PTU may breastfeed, because little of this drug crosses into the milk. Nursing is also possible for women who take methimazole, although more of this drug is secreted into breast milk. In both cases the baby’s thyroid function should be monitored. Definitive therapy with radioactive iodine should be considered, although many breastfeeding women will wish to postpone this, because some of the mother’s radioiodine crosses into her baby through the breast milk.

Postpartum Thyroiditis

Postpartum thyroiditis may occur in 8% to 10% of women.¹⁰⁰ Thyroiditis also occurs in the nonpostpartum period, as well as in men, and is probably an autoimmune thyroid disease related to Hashimoto’s thyroiditis.¹⁰¹

Typically, it consists of a temporary period of hyperthyroidism lasting from 6 weeks to 3 months postpartum, followed by hypothyroidism occurring between 3 and 9 months after delivery. Women at risk include those with a previous history of postpartum thyroiditis or those who can be shown to have thyroid autoantibodies.¹⁰² Usually, no treatment or only symptomatic treatment is required for the hyperthyroid phase, and a short course of thyroxine treatment for 6 to 12 months is sufficient for the hypothyroid phase. Some women who do not recover from the hypothyroid phase will require long-term thyroid replacement therapy.¹⁰³

During the first 3 months after delivery, symptoms of fatigue, depression, and impairment of memory and concentration are common and often unrelated to a woman’s thyroid hormone level. Symptoms can mimic postpartum depression and thus a high index of suspicion is needed to rule out hypothyroidism.¹⁰⁴ It is reasonable to perform a thyrotropin level in those women who do experience emotional disorders following pregnancy.