Endocrinology

Chapter 35 Endocrinology

George Wilson, Arshag Mooradian, Irene Alexandraki, George Samrai

Adrenal Glands 777

Disorders of Cortical Hypofunction 778

Disorders of Cortical Hyperfunction: Hypercortisolism 780

Disorders of Hyperfunction: Adrenal Medulla 783

Mixed Disorder: Congenital Adrenal Hyperplasia 784

Ovarian and Testicular Disorders 784

Normal Sexual Development 784

Abnormal Puberty 785

Delayed Puberty 787

Problems of the Testicle and Other Male Endocrine Issues 789

Problems of the Ovary and Other Female Endocrine Issues 790

Disturbances in Calcium and Phosphate 796

Hypercalcemia 796

Hypocalcemia 799

Hyperphosphatemia 799

Hypophosphatemia 800

Osteoporosis and Osteomalacia 800

Pituitary Disorders

• The hypothalamic-pituitary axis orchestrates the hormonal secretions of the other endocrine glands.

• The pituitary is composed of the adenohypophysis (anterior lobe) and neurohypophysis (posterior lobe).

• The hormonal secretions of the anterior pituitary are regulated by hypothalamic releasing hormones and inhibitory molecules.

• The posterior pituitary lobe is where nerve endings, originating in the paraventricular and supraoptic nuclei, project as the supraopticohypophyseal tract.

Hypothalamic-Pituitary Axis

The hypothalamus affects several nonendocrine functions, including appetite, sleep, body temperature, and activity of the autonomic nervous system. In addition, the hypothalamus modulates the pituitary hormone secretions. The pituitary gland is often referred to as the “master gland” in recognition of its role in orchestrating the hormonal secretions of the other endocrine glands (Mooradian and Korenman, 2007; Mooradian and Morley, 1988). The pituitary gland is located in the anterior fossa, in the sella turcica, close to the optic chiasm. The pituitary is composed of the adenohypophysis, or anterior lobe, and the neurohypophysis, or posterior lobe, and is connected to the hypothalamus by the pituitary stalk.

The hormonal secretions of the anterior pituitary (the adenohypophysis) are regulated by a number of hypothalamic releasing hormones and inhibitory molecules. These factors reach the pituitary through the portal circulation and, on interaction with specific receptors, either stimulate or inhibit the secretion of the anterior pituitary hormones. The main releasing hormones include thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (GnRH), corticotropin-releasing hormone (CRH), and growth hormone–releasing hormone (GHRH). The two major inhibitory factors are dopamine, which principally inhibits prolactin release, and somatostatin, a potent inhibitor of growth hormone (GH), and to a lesser extent, thyrotropin (TSH). Other factors have an important regulatory effect on anterior pituitary function. The kisspeptin hormones are a family of peptides encoded by the KiSS-1 gene and are thought to play a critical role in reproduction. Kisspeptin receptors stimulate GnRH release and activation of the mammalian reproductive axis. Mutations in kisspeptin receptor GPR-54 cause idiopathic hypogonadotropic hypogonadism, characterized by delayed or absent puberty (Jayasena and Dhillo, 2009).

The portal circulation also allows pituitary hormones to flow backward to the hypothalamus and provide feedback on their own releasing hormones to create a short-loop regulatory system. The control of the pituitary hormonal secretion is the result of interplay between the effects of hypothalamic releasing hormones and the long-loop negative feedback on the pituitary and hypothalamus by hormones secreted by endocrine glands in the periphery. For example, a rise in plasma thyroid hormone level “feeds back” and suppresses pituitary TSH and hypothalamic TRH secretion.

The posterior lobe (pars nervosa) of the pituitary is essentially an extension of the hypothalamus where the nerve endings, originating in the paraventricular and supraoptic nuclei, project as the supraopticohypophyseal tract. The posterior pituitary hormones vasopressin and oxytocin are directly controlled by neural impulses and are released into the inferior hypophyseal veins and then into the systemic circulation (Mooradian and Morley, 1988).

Approach to Pituitary Disease

• Pituitary disease may manifest with pituitary hormone excess or deficiency or symptoms of mass expansion, including headaches and visual disturbances.

• Pituitary adenoma is the most common cause of pituitary dysfunction in adults.

• Hypothalamic-pituitary axis function should be assessed in patients with a mass in the sella turcica.

• Evaluation of pituitary dysfunction involves serum measurements (prolactin, GH, IGF-1, FT₄, TSH), free cortisol or dexamethasone suppression test, and imaging.

The most common cause of pituitary disease is the development of benign tumors. Adenomas can cause symptoms because of excessive production of hormones such as prolactin, GH, or adrenocorticotropic hormone (ACTH), or can cause pituitary hormone insufficiency secondary to tissue destruction. The pituitary hormones that can be lost early during the gradual destruction of pituitary tissue include GH and GnRH, followed by TSH and lastly ACTH. Occasionally, however, the autoimmune destruction of the pituitary can be cell specific and cause selective pituitary hormone deficiency.

Pituitary tumors can expand into the optic chiasm and hypothalamus and cause visual field defects and symptoms of hypothalamic disease, respectively. The classic symptom of optic chiasm compression is bitemporal hemianopsia (inability to see either side). Early manifestations of optic chiasm impingement can be subtle and include seeing images that float apart or seeing one half of the face higher than the other half (Picasso effect, or hemifield slide phenomenon). These symptoms emerge when the patient is tired or anxious and are the result of failure to fuse the images from both eyes because of the lack of nasal fields. Expansion of tumors into the hypothalamus can cause disturbances in sleep, appetite, temperature regulation, sweating, water balance, and memory (Mooradian and Morley, 1988).

In children, pituitary adenomas are less common, and hypothalamic pituitary dysfunction is typically the result of hypothalamic tumors, notably craniopharyngiomas.

When microadenoma (<10 mm) is discovered incidentally, the initial evaluation should seek hormone hypersecretion by measuring levels of serum prolactin, insulin-like growth factor type 1 (IGF-1), TSH, and free thyroxine (FT₄) levels and 24-hour urine free cortisol or a 1-mg overnight dexamethasone suppression test (Mooradian and Korenman, 2007). More extensive workup is required for pituitary masses larger than 10 mm (macroadenoma), regardless of symptoms. Overall workup and management of pituitary disease should include identifying and treating hormonal deficiency and excess as well as diagnosing and managing mass effects of the tumors.

Hypopituitarism

• Hypopituitarism refers to total or partial deficiency of one or more pituitary hormones.

• Hypopituitarism can result from a genetic disorder or releasing factor deficiency but more often results from pituitary tissue destruction secondary to mass expansion, infiltrative process, autoimmune or infectious disease, vascular accidents, radiation injury, or trauma.

• Pituitary apoplexy may result in life-threatening hypocortisolism.

• Lymphocytic hypophysitis is a rare autoimmune pituitary disease occurring in women in late pregnancy or postpartum that may mimic pituitary tumor but does not require resection.

• Kallmann syndrome is characterized by an isolated defect in GnRH secretion.

• Approximately 10% of patients with empty sella syndrome have clinically apparent hypopituitarism, and some may have pituitary adenomas.

• Systemic disease, including end-stage liver disease or chronic renal failure, is associated with variable degrees of hypopituitarism without significant histopathologic changes in the pituitary.

Hypopituitarism refers to total or partial deficiency of one or more pituitary hormones resulting in end-organ changes or reduced hormonal secretion of target endocrine glands (Toogood and Stewart, 2008). The deficiencies could be the result of primary disease of the pituitary or could be secondary to failure of hypothalamic hormone synthesis or transport. There are no good estimates of the incidence of hypopituitarism because the disease is often subclinical.

Causes

Hypopituitarism may result from a genetic disorder or deficiency in hypothalamic releasing factor but more often is the result of pituitary tissue destruction secondary to mass expansion, infiltrative process, autoimmune or infectious disease, vascular accidents, radiation injury, or trauma. In some patients the etiology of hypopituitarism cannot be identified and is considered idiopathic. Most idiopathic cases are sporadic, although there are well-described familial causes of hypopituitarism.

The most common cause of hypopituitarism in the adult population is intrasellar pituitary tumors. Occasionally, hypopituitarism is resolved with surgical or medical treatment of the pituitary mass. Parasellar masses that cause hypopituitarism include craniopharyngiomas, meningiomas, optic nerve gliomas, teratomas, germinomas, chordomas, metastatic cancers, and lymphomas.

The second most common cause of hypopituitarism is postpartum pituitary necrosis (Sheehan’s syndrome). The portal system of the anterior pituitary vascular supply, increased oxygen demand of an enlarged pituitary gland during pregnancy, excessive blood loss, and possibly increased intravascular coagulation combine to cause ischemic pituitary injury. Other ischemic causes of pituitary necrosis can occur in systemic vascular diseases such as diabetes mellitus, temporal arteritis, and sickle cell disease. These diseases can also result in hemorrhagic infarction (apoplexy) of the pituitary, with acute onset of severe headache, visual impairment, altered mental status, and hypopituitarism. The sudden decline in ACTH and thus hypocortisolism may be the most life-threatening consequence of hypopituitarism, requiring emergency treatment with corticosteroids. Although pituitary adenomas are the most common cause of pituitary apoplexy, it may often be related to complications of diabetes, radiotherapy, or open heart surgery (Toogood and Stewart, 2008).

Rarely, infectious diseases can lead to hypopituitarism. Examples include meningitis, intracranial abscess, septic shock, fungal infections of the central nervous system (CNS), tuberculosis (TB), malaria, and syphilis.

Infiltrative diseases of the pituitary, and more frequently of the hypothalamus, can cause hypopituitarism. Sarcoidosis can present with hypopituitarism along with polydipsia and polyuria. Histiocytosis X may present as a suprasellar tumor. Lipid storage diseases and hemochromatosis can cause hypopituitarism, often with hypogonadotropin deficiency.

Lymphocytic hypophysitis is a rare autoimmune disease of the pituitary occurring in women during late pregnancy or in the postpartum period. Lymphocytes and plasma cells infiltrate the pituitary gland, which results in the destruction of anterior pituitary cells. This disease may mimic pituitary tumor but does not require resection, making the correct diagnosis especially important. Lymphocytic hypophysitis cannot be distinguished from tumor except by biopsy. The diagnosis is suspected in women who develop hypopituitarism during or immediately after pregnancy, in the absence of a history of hemorrhage during delivery or previous history of infertility or menstrual disorders.

Mutations in the genes coding for specific anterior pituitary hormones have also been described, the most common being isolated GH deficiencies manifesting as short stature, beginning in infancy or childhood. Kallmann syndrome is characterized by an isolated defect in GnRH secretion. Young men develop a eunuchoid appearance and testosterone deficiency, and women have amenorrhea or oligomenorrhea. The syndrome may also be associated with hyposmia or anosmia (Oliveira et al., 2001). Mutations in the PROP-1 gene are the most common causes of congenital hypopituitarism and present as deficiencies of GH, prolactin, TSH, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Older adults with PROP-1 gene mutations may present with ACTH deficiency (Wu et al., 1988). Iatrogenic causes of hypopituitarism include surgical ablation and radiotherapy. Hypothalamic and pituitary deficiency may occur after several years, with GH and gonadotropin deficiencies the most common. Prolactin level may be mildly elevated.

Approximately 10% of patients with empty sella syndrome have clinically apparent hypopituitarism, and some may have pituitary adenomas (Mooradian and Morley, 1988). The empty sella syndrome occurs when a defect in the sellar diaphragm allows the subarachnoid space to herniate into the pituitary fossa. It is a relatively common disorder found in 5% to 8% of autopsies.

Systemic disease, including end-stage liver disease and chronic renal failure, is associated with variable degrees of hypopituitarism without significant histopathologic changes in the pituitary (Mooradian, 2001; Nowak and Mooradian, 2007).

Clinical Manifestations

• Progressive loss of hormones occurs in pituitary injury, starting with loss of GH and gonadotropin and followed by TSH and ACTH deficiency.

• ACTH deficiency results in cortisol deficiency, leading to hypotension, shock, and cardiovascular collapse.

• TSH deficiency results in signs and symptoms of hypothyroidism.

• Gonadotropin deficiency results in the signs and symptoms of hypogonadism.

• GH deficiency causes short stature in children and may be asymptomatic in adults.

The clinical manifestations of hypopituitarism are highly variable and depend on age and gender of the patient as well as on the etiology of the pituitary disease (Toogood and Stewart, 2008). Patients can be completely asymptomatic for many years or present with dramatic symptoms of nausea, vomiting, headache, and vascular collapse. Symptoms are more common in pituitary apoplexy, when the sudden withdrawal of ACTH and ensuing adrenal insufficiency cause hemodynamic instability. It is believed that at least 75% of the glandular tissue must be destroyed before an individual becomes clinically symptomatic. If the etiology is a space-occupying lesion, such as expanding adenoma or carotid aneurysm, the clinical manifestations will include headache and visual field defects, which are classically bitemporal hemianopsia. Other, subtle changes in vision involve color perception, patchy scotomas, and difficulty in passing a thread through the eye of a needle (Mooradian and Morley, 1988).

Failure to lactate may be the first clinical sign of Sheehan’s syndrome (postpartum pituitary necrosis). Lethargy, anorexia, and weight loss; failure to resume normal menstrual periods; and loss of sexual hair may also be present later in the postpartum period. On the other hand, symptoms and signs of pituitary infarction may be subtle and not recognized for years.

Patients with panhypopituitarism (Simmonds’ syndrome) are usually pale and lethargic, have dry skin and low blood pressure, and rarely may look cachectic (Toogood and Stewart, 2008). These patients have lost all the anterior pituitary hormones, and the clinical manifestations are caused by a mixture of hypogonadism, hypothyroidism, adrenal insufficiency, and GH deficiency. The clinical manifestations depend on whether the deficiency is partial or complete. Individual signs and symptoms reflect the biologic actions of various hormones secreted by the pituitary.

Growth hormone deficiency manifests as growth retardation in children. The body proportion and primary teeth are normal, but secondary tooth eruption is delayed. In up to 10% of children with GH deficiency, symptomatic hypoglycemia may occur. In adults, GH deficiency may be asymptomatic. Subtle changes may occur in insulin sensitivity, manifested by reduced insulin requirements in diabetic patients, decreased muscle and bone mass and increased adiposity, delayed wound healing, and fasting hypoglycemia, and may contribute to anemia of hypopituitarism. Additional adverse effects associated with GH deficiency in adults include increased low-density lipoprotein (LDL) and decreased high-density lipoprotein (HDL) cholesterol, decreased cardiovascular function and increased risk of cardiovascular events, and a diminished sense of well-being. Life expectancy is reduced in these patients compared with age-matched controls (Svensson et al., 2004).

Gonadotropin deficiency will result in hypogonadotropic hypogonadism (HH) or secondary hypogonadism. In prepubertal children, HH manifests as failure to achieve pubertal changes along with lack of pubertal growth spurt. Girls will have primary amenorrhea and lack of breast development or widening of the pelvis. In boys, testicular size will remain small, scrotal skin will not thicken, and penile growth, muscle development, and hoarseness of voice will not appear. In adults, HH presents as infertility, loss of libido, decreased facial hair and muscular mass in men and amenorrhea, and decreased breast size and atrophic vaginal mucosa in women. If left untreated, men and women with HH will develop osteoporosis.

A deficiency in TSH will cause secondary hypothyroidism unless the patient has concomitant Graves’ disease or an autonomously functioning thyroid nodule. The classic clinical manifestations of hypothyroidism include lethargy, easy fatigability, dry skin, cold intolerance, constipation, fine silky hair, slow mentation, and slow relaxation phase of deep tendon reflexes. Other features include anemia and hyponatremia secondary to increased antidiuretic hormone (ADH) secretion. In general, these symptoms are less severe in patients with TSH deficiency compared with patients with primary thyroid failure, and other findings, such as hypercholesterolemia, hypercarotenemia, myxedema and effusions in body cavities, may occur less frequently (Toogood and Stewart, 2008).

A deficiency in ACTH will result in deficiency of cortisol secretion and is referred to as secondary adrenal insufficiency. The clinical features resemble primary adrenal disease, such as Addison’s disease. In both entities, anorexia, lethargy, nausea, vomiting, abdominal pain, postural hypotension, and vascular collapse may occur. Hyponatremia is more common in ACTH deficiency, whereas hyperkalemia is seen only in primary adrenal insufficiency and loss of aldosterone secretion, primarily regulated by the renin-angiotensin system and serum potassium/sodium concentrations. Hyperpigmentation of the skin and vitiligo are features of primary adrenal insufficiency, whereas patients with ACTH deficiency have difficulty tanning on exposure to sunlight. Mild ACTH deficiency may be asymptomatic and may go undiagnosed for a long time.

Diagnosis

• If one pituitary hormone insufficiency is documented, the other pituitary hormones should be tested.

• An 8 am plasma cortisol level less than 5 μg/dL strongly suggests hypocortisolism; a level greater than18 μg/dL excludes ACTH deficiency.

• Serum free T₄ must be used with serum TSH concentration in assessing thyroid function.

• Normal or subnormal LH level in menopausal or amenorrheic women, in the presence of a low estradiol level, indicates secondary hypogonadism (in men, low testosterone level).

• Diagnosis of GH deficiency requires provocative testing.

Since the presenting complaints can be subtle, clinicians should have a high index of suspicion to diagnose hypopituitarism (Toogood and Stewart, 2008). If the clinical manifestations fit hypogonadism, hypothyroidism, or adrenal insufficiency, those hormonal tests should be ordered to confirm the diagnosis. If one pituitary hormone insufficiency is documented, every attempt should be made to test the status of the other pituitary hormones as well. The underlying etiology of the disease should be determined by computed tomography (CT) or magnetic resonance imaging (MRI) of the hypothalamic-pituitary area. Occasionally, angiography is needed when carotid artery aneurysm is suspected, or to define the blood supply of the tumor. Formal ophthalmologic examination with visual field evaluation should be ordered if the patient is symptomatic or has a pituitary mass lesion.

Pituitary hormone secretion is episodic, and in general, dynamic testing is more valuable than single, baseline hormone measurements. For practical reasons, however, the screening can be done with pituitary hormone and target hormone measurements simultaneously. For evaluating suspected hypopituitarism, tests include thyroid function, LH, serum testosterone in men and estradiol in women, IGF-1 (because GH has a short half-life in blood), prolactin, and morning cortisol. Provocative testing for GH and ACTH reserve may be required as well. Patients with known pituitary disease and deficiency of ACTH, TSH, or gonadotropins have a 95% chance of a subnormal provocative stimulus for GH. Also, patients with known pituitary disease and a serum IGF-1 concentration lower than normal can be presumed to have GH deficiency (Gharib et al., 2003). Provocative tests for GH are either physiologic (sleep or exercise) or pharmacologic such as insulin-induced hypoglycemia, GHRH with arginine, and levodopa with arginine tests (Biller et al., 2002). GH deficiency is diagnosed when GH does not rise above 5 ng/mL in response to two or more stimuli.

A plasma cortisol level less than 5 μg/dL at 8 am on two occasions in the patient with a disorder known to cause hypopituitarism strongly suggests hypocortisolism, and in the presence of normal or low serum ACTH concentration, it establishes the diagnosis of secondary adrenal insufficiency. Conversely, a cortisol level of 18 μg/dL or greater virtually excludes the diagnosis of ACTH deficiency.

To evaluate ACTH reserve, insulin hypoglycemia test (0.1-0.15 U/kg IV) should be done. A normal cortisol response to adequate hypoglycemic stimulus (blood glucose <50 mg/dL) is either an incremental level of 6 to 10 μg/dL or an absolute level greater than 20 μg/dL. The test allows for concomitant evaluation of GH reserve; however, it is contraindicated in elderly patients and those with coronary artery disease or epilepsy (Nowak and Mooradian, 2007). An alternative is the metyrapone test, 750 mg orally every 4 hours for six doses, which assesses the sensitivity of the pituitary to the negative inhibition by cortisol. Metyrapone blocks 11β-hydroxylase, an enzyme that catalyzes the final step in cortisol biosynthesis. The decrease in cortisol secretion after metyrapone is given should result in a compensatory increase in the ACTH level. The level of the precursor steroid 11-deoxycortisol should also increase. A normal response is an increase in serum 11-deoxycortisol level greater than10 μg/dL, when serum cortisol level is reduced to less than 8 μg/dL, indicating adequate suppression of glucocorticoid synthesis. In the more convenient overnight test, metyrapone, 30 mg/kg orally, is administered at midnight. An increase in the 8 am serum 11-deoxycortisol level to more than 7 μg/dL is found in healthy persons. If symptomatic postural hypotension occurs after metyrapone administration, hydrocortisone should be administered exogenously.

Cosyntropin, 250 μg intramuscularly (IM) or intravenously (IV), should result in an increase in the serum cortisol level of 18 μg/dL or greater at 60 minutes in normal subjects. The test may not reliably determine the ACTH reserve, especially in those with recent ACTH deficiency, in whom the adrenal glands may not be sufficiently atrophied. Some controversy surrounds whether the 1-μg cosyntropin stimulation test (IV only) may be more sensitive for the diagnosis of subtle secondary adrenal insufficiency.

Thyrotropin (TSH) deficiency is diagnosed when low baseline free T₄ and low or normal TSH is documented on more than one measurement. Gonadotropin deficiency in men is tested with measurements of baseline LH, FSH, and total testosterone. Serum samples are drawn between 8 and 10 am, and low concentrations should be confirmed with a second serum sample. The 8 to 10 am serum testosterone concentration generally should be 300 to 1000 ng/dL. A low testosterone value (<200 ng/dL) with low or normal LH is indicative of hypogonadotropic hypogonadism. For serum total testosterone levels between 200 and 400 ng/dL, free testosterone level should also be ordered (Mooradian and Korenman, 2006). The presence of amenorrhea in premenopausal women, along with low estrogen level (<30 pg/mL), establishes the diagnosis of HH. In menopausal women the absence of elevated FSH and LH is sufficient for the diagnosis.

Elevated serum prolactin level in a hypogonadal patient suggests a pituitary adenoma. Prolactin deficiency often indicates severe intrinsic pituitary disease and is uncommon without concomitant deficiencies of other anterior pituitary hormones.

Conditions known to mimic hypopituitarism should be excluded when evaluating patients, including anorexia nervosa, protein-calorie malnutrition, systemic illness, chronic renal failure, and liver cirrhosis.

Treatment

• Hydrocortisone is given to ACTH-deficient adults at 20 to 30 mg/day and increased twofold to threefold during times of illness and other stresses.

• The goal of thyroid replacement is to achieve a normal serum free thyroxine concentration and clinical euthyroidism.

• Thyroid replacement will increase the clearance of cortisol, so ACTH status is assessed; if deficient or uncertain, glucocorticoid replacement is indicated before replacing thyroid hormone.

• Treatment of secondary hypogonadism depends on gender and whether fertility is desired.

• Serum IGF-1 concentration and growth rate in children are used for monitoring the effectiveness of GH replacement.

The treatment of hypopituitarism depends on the etiology and the particular hormonal deficiency. Surgical and medical interventions may be necessary for treatment of pituitary masses, infiltrative diseases, and carotid aneurysms.

Growth hormone deficiency is treated with recombinant human GH (somatotropin) preparations (Gharib et al., 2003). The recommended GH dose in children with GH deficiency is 0.04 mg/kg/day. In adults, recombinant human GH is administered subcutaneously (SC) at 0.001 to 0.008 mg/kg/day. The usual starting dose is 0.1 to 0.3 mg/day for a 70-kg man, with a typical maintenance dose of 0.3 to 0.6 mg/day. In general, women require higher doses than men because estrogen increases GH resistance. Serum IGF-1 concentration should be monitored to maintain it at the midnormal range. Side effects that should be monitored include edema, carpal tunnel syndrome, arrhythmias, paresthesias, and glucose intolerance.

Levothyroxine (l-thyroxine) is the hormone of choice for the treatment of patients with TSH-deficient hypothyroidism (Oiknine and Mooradian, 2006). A typical replacement dose in adults is approximately 1.6 μg/kg/day. The daily requirements should be individually determined based on clinical and biochemical evaluations. The free T₄ level should be in the middle to upper third of the normal range. Since thyroid replacement will increase the clearance of cortisol and uncover a subclinical adrenal insufficiency, the ACTH status should be assessed, and if deficient or uncertain, glucocorticoid replacement is indicated before thyroid hormone is replaced.

Treatment of secondary hypogonadism depends on the patient’s gender and whether or not fertility is desired. Estradiol and progesterone replacement is the treatment of choice for secondary hypogonadism in premenopausal women who have an intact uterus and do not desire fertility. These hormones can be given cyclically or daily in fixed-dose combinations. In women with hysterectomy, estrogen replacement is sufficient, to maintain vulvar and vaginal lubrication, relieve symptoms of vasomotor instability, and reduce bone loss. Women wanting to restore fertility should be referred to specialized centers for pharmacologic induction of ovulation with exogenous pulsatile GnRH and exogenous FSH and LH treatment. GnRH can be used to restore fertility when hypothalamic disease and tertiary hypogonadism are present. Women over age 50 with secondary hypogonadism should be treated as menopausal, taking into consideration the risk/benefit ratio of estrogen replacement therapy in this age group.

Secondary hypogonadism in men is treated with testosterone replacement. Fertility can be restored in men with pituitary disease using gonadotropin replacement or human chorionic gonadotropin (hCG) therapy. GnRH can be used when hypothalamic disease is the cause of hypogonadism.

Many preparations are available for testosterone replacement. Traditional oral androgens, including 17α-methyltestosterone, fluoxymesterone, and other 17α-alkylated steroids, may cause hepatic toxicity and should be avoided. The current injectable testosterone esters, such as testosterone enanthate or testosterone cypionate, act similarly. The usual replacement dose is 200 mg IM every 2 weeks. In older men, it may be prudent to start at 50 to 75 mg weekly. Testosterone undecanoate is available as an oral preparation that does not have hepatotoxicity; because of its short half-life, however, it must be taken three times daily. Transdermal preparations can be given as patches or gels. Some androgen skin patches are associated with a high incidence of skin reactions. The commercially available transdermal gel preparations (Androgel 1%, Testim 1%) are applied over the trunk daily. Sublingual and buccal preparations of testosterone (e.g., Striant) are also available for replacement therapy (Mooradian and Korenman, 2006).

Side effects of testosterone replacement should be monitored carefully. Digital rectal examination (DRE), hematocrit (Hct), and prostate-specific antigen (PSA) should be measured at 3, 6, and 12 months follow-up, then annually or semiannually. Bone density measurements should be obtained at baseline and if low, at 2-year intervals to monitor improvement. In addition to monitoring clinical response, serum testosterone levels should be measured with the goal of achieving a midnormal range at 7 days after injection of testosterone enanthate or cypionate, at 3 to 10 hours after application of a testosterone patch, or at any time after application of a testosterone gel.

Absolute contraindications to testosterone therapy are prostate or breast cancer, Hct of 55% or more, or sensitivity to ingredients of the testosterone preparation (Mooradian and Korenman, 2006). Relative contraindications include obstructive sleep apnea, congestive heart failure, obstructive symptoms of prostatic hyperplasia, and Hct of 52% or greater. However, there are no data to suggest that testosterone replacement aggravates subclinical prostate cancer.

Patients with ACTH deficiency should be treated with glucocorticoids, preferably hydrocortisone, which the adrenals produce. Hydrocortisone replacement should be given orally as 20 to 30 mg/day divided into two doses, with two thirds of the daily dose given in the morning and one third given in the early afternoon or evening (Coursin and Wood, 2002; Toogood and Stewart, 2008). Alternatively, prednisone is given at a total daily dosage of 5 to 7.5 mg/m²/day in one to two doses. Clinical evaluation is the primary modality to assess the adequacy of cortisol replacement. It is important to increase the dose of hydrocortisone twofold to threefold during illness and other stresses. All patients should carry medical alert tags or cards to identify the need for high-dose glucocorticoids in an emergency. Those with secondary adrenal insufficiency usually do not require mineralocorticoid replacement because ACTH is not essential for aldosterone secretion.

Hyperfunctioning Pituitary Adenomas

• Pituitary adenomas may present with visual impairment, headache, or hormonal abnormalities.

• Prolactinomas are the most common type of functioning pituitary adenoma and manifest with galactorrhea and hypogonadism.

• Nonpathologic causes of hyperprolactinemia are sought, and primary hypothyroidism is excluded.

• MRI is the imaging modality of choice for the anatomic evaluation of the hypothalamus and pituitary gland.

• Prolactin level over 150 ng/mL and pituitary adenoma not identified on imaging suggest macroprolactinemia.

• A dopamine agonist (bromocriptine or cabergoline) is first-line treatment of prolactinomas.

Pituitary adenomas can arise from any cell type and can be functioning or nonfunctioning. The precise pathogenesis of these adenomas is not known but mutations found in several genes can play a role in the development of many adenomas. With prolactinomas the most common type, other functioning pituitary adenomas include gonadotropic, thyrotropic, somatotropic, and corticotropic adenomas.

Hyperprolactinemia and Prolactinomas

Diagnosis

Prolactin is a polypeptide secreted from the lactotrophs of the anterior pituitary (Leung and Pacaud, 2004; Mancini et al., 2008). The main function of prolactin is the development of breast tissue in preparation for milk production and maintenance of lactation postpartum. Unlike other pituitary hormone regulation, prolactin release is predominantly under inhibitory control. Dopamine is the principal inhibitor, and prolactin stimulators such as TRH and estrogen have minor roles.

Hypersecretion of prolactin may be physiologic or pathologic in origin. Physiologic stimulators include exercise, pain, breast stimulation, sexual intercourse, general anesthesia, and pregnancy. Pathologic causes of hyperprolactinemia include prolactinomas, decreased dopaminergic inhibition of prolactin secretion through pharmacologic agents, and decreased clearance of prolactin. Early manifestation of prolactin hypersecretion is galactorrhea and menstrual irregularities, notably amenorrhea, in women and erectile dysfunction or loss of libido in men. Rarely, galactorrhea with gynecomastia can occur in men. These patients are at risk of developing osteoporosis secondary to hypogonadism as well as a result of the direct inhibitory effect of prolactin on bone formation. Galactorrhea is rarely found in postmenopausal women with hyperprolactinemia, in whom mass effect of prolactinomas may cause the principal presenting symptom, such as headache or visual disturbance (Mancini et al., 2008). Similarly, the diagnosis of prolactinomas in men is often delayed because the clinical signs and symptoms of hyperprolactinemia are less obvious.

Clinical evaluation of patients with suspected prolactinomas should include a thorough evaluation of medication history and presence of comorbidities. Many drugs are known to cause hyperprolactinemia, including phenothiazines, haloperidol, metoclopramide, H₂ antagonists, imipramines, selective serotonin reuptake inhibitors (SSRIs), calcium channel blockers, and hormones. The physical examination may reveal galactorrhea and visual field defects. Women may have mild hirsutism and men decreased facial hair growth.

Laboratory tests include serum prolactin and thyroid function. Primary hypothyroidism is associated with hyperprolactinemia secondary to elevated TRH that induces prolactin secretion. Testing should also seek systemic illnesses with increased prolactin levels, such as liver or renal failure. MRI is the imaging modality of choice for the anatomic evaluation of the hypothalamus and pituitary gland. Complete pituitary hormone evaluation should be performed when an adenomatous mass is noted in the region of the pituitary.

Features to distinguish hyperprolactinemia associated with pituitary tumors include (1) prolactin levels greater than 150 ng/mL, (2) loss of normal sleep-associated increases in prolactin levels, and (3) failure of prolactin levels to rise in response to exogenous TRH. No test is absolute, and diagnosis of prolactinoma depends on radiologic studies.

Clinicians should be aware of two prolactin assay–related conditions that may cause diagnostic confusion. In macroprolactinemia, large-molecular-weight prolactin, aggregated with globulins, is recorded as elevated levels of prolactin in the absence of any physiologic or pathologic cause of hyperprolactinemia (Mancini et al., 2008). Macroprolactinemia is suspected in the patient with very high prolactin level and no galactorrhea or tumor on pituitary MRI. The second area of confusion occurs when extremely high concentrations of serum prolactin overwhelm the assay reagents such that the measurements underestimate the true concentration of prolactin. This is referred to as the “hook effect.”

Treatment

The treatment of hyperprolactinemia depends on the etiology, presence or absence of mass effects (e.g., visual changes), presence of bothersome galactorrhea or associated pituitary hormone deficiencies, and whether fertility is desired (Leung and Pacaud, 2004; Mancini et al., 2008). If possible, drugs known to cause prolactin elevation should be discontinued and serum prolactin concentration remeasured. Persistent hyperprolactinemia requires pituitary-hypothalamus imaging.

Treatment of prolactinomas includes dopamine agonists as first-line treatment. In select subgroups, surgical excision is recommended, usually through the transsphenoidal approach. Rare patients with large, residual tumor mass after surgery not responsive to medical therapy may be offered radiation therapy. Associated hormone deficiency should also be targeted. Often, as the prolactin levels are normalized, symptoms of hypogonadism can be reversed.

Bromocriptine and cabergoline are U.S. Food and Drug Administration (FDA)–approved dopamine agonists used to treat hyperprolactinemia. Cabergoline has greater tolerability than bromocriptine and is more effective in achieving normalization of prolactin levels in 90% of patients with prolactinomas. Because of long-standing experience, however, bromocriptine is the preferred agent in women who want to become pregnant. Bromocriptine should be discontinued once pregnancy has been confirmed, even though the risk of teratogenicity is small. Pregnant women with prolactinomas should be warned to report any visual disturbances or headaches, because up to 10% of microprolactinomas and 30% of macroprolactinomas increase in size sufficient to cause symptoms. During pregnancy, prolactin levels should be monitored periodically, but interpretation of the results may be difficult. Pregnant women with macroadenomas should receive similar advice and have serial visual field testing.

Pergolide is an alternative but non-FDA-approved medication for hyperprolactinemia. Caution should be exercised with all these ergot derivatives because of rare case reports of valvular heart damage in patients taking the drug at very high doses for prolonged periods.

Withdrawal of the drug may lead to recurrent prolactin hypersecretion and adenoma growth, although the microadenomas have resolved after a few years of treatment in some patients. The dosage of the dopamine agonist may be reduced when prolactin levels have been normalized for 1 year and tumor size has been significantly reduced. Medication withdrawal may be considered after 2 years in those with normal prolactin levels and an MRI scan showing no tumor, or tumor reduction more than 50% and more than 5 mm from the optic chiasm, with no invasion of the cavernous sinus. Pituitary MRI and serum prolactin levels should be monitored closely thereafter.

Indications for transsphenoidal surgery in patients with prolactinomas include medical treatment failure or medication intolerance, very large tumors threatening visual pathways, or hemorrhagic infarcts (apoplexy). Approximately 30% of macroadenomas can be successfully removed surgically.

Acromegaly and Gigantism

See the discussion online at www.expertconsult.com.

Cushing’s Disease

• Cushing’s syndrome is categorized into ACTH-dependent or ACTH-independent cases. Pituitary ACTH-dependent Cushing’s syndrome is Cushing’s disease.

• The diagnosis is established when the clinical findings of Cushing’s syndrome are associated with laboratory documentation of excess cortisol production.

• Measurement of 24-hour urinary cortisol excretion is a good screening tool.

• Comparison of serum ACTH concentration with serum cortisol level can help determine the cause of hypercortisolism.

• Treatment of Cushing’s syndrome is directed at the cause of hypercortisolism. The treatment of choice for Cushing’s disease is selective transsphenoidal resection.

Hypercortisolemia (also hypercortisolism, hyperadrenocorticism), caused by either exogenous administration of cortisol or other synthetic glucocorticoids or endogenous overproduction of cortisol, leads to a constellation of clinical and biochemical findings referred to as Cushing’s syndrome (Arnaldi et al., 2003; Findling and Raff, 2005). The multiple causes include pituitary adenomas, excess production of CRH leading to hyperplasia of corticotropes in the pituitary, ectopic production of ACTH and CRH, and adrenocortical adenomas and carcinomas. The term Cushing’s disease specifically refers to pituitary-dependent cortisol hypersecretion (Biller et al., 2008). Pituitary, ACTH-dependent Cushing’s disease accounts for at least 70% of endogenous cases, while the most common cause of ACTH-independent Cushing’s syndrome is prolonged glucocorticoid therapy.

Patients who have undergone bilateral adrenalectomy for hypothalamic-pituitary–dependent Cushing’s syndrome may develop pituitary tumors associated with marked skin pigmentation. This condition is known as Nelson’s syndrome. The skin hyperpigmentation occurs because of excess production of melanocyte-stimulating hormone (MSH), a product of the gene that also encodes ACTH and beta endorphin.

Diagnosis

A high index of suspicion is required to make the diagnosis of Cushing’s syndrome because manifestations of the disease are insidious and develop over months.

The clinical features include weight gain with centralized obesity distributed in the face, neck, trunk, and abdomen with facial rounding and plethora. The thinning of the skin and loss of subcutaneous tissue result in easy bruisability and violaceous abdominal striae. Patients with ectopic ACTH-dependent Cushing’s syndrome have extreme ACTH increases that cause rapid hyperpigmentation and are more likely to demonstrate features of mineralocorticoid excess, such as hypokalemia and metabolic alkalosis. Gonadal dysfunction is associated with decreased testosterone levels in men and decreased serum estradiol levels and menstrual disorders, notably amenorrhea, in women. Virilization and androgen excess are more common in patients with Cushing’s syndrome caused by adrenal carcinomas.

Glucocorticoid excess also interferes with calcium and bone metabolism and leads to osteoporosis. Catabolic effects of excess glucocorticoid on muscles cause proximal muscle weakness. Glucose intolerance is found in 30% to 60% of those with hypercortisolism. Other complications of hypercortisolism include risk of opportunistic infections, including Pneumocystis jiroveci (formerly carinii) pneumonia, hypercoagulable state, and thromboembolic events secondary to increased plasma concentration of clotting factors and neuropsychiatric changes (Arnaldi et al., 2003; Findling and Raff, 2005).

Establishing the Cause

The diagnosis is established when the clinical findings of Cushing’s disease are associated with laboratory documentation of excess cortisol production, loss of diurnal variation of plasma cortisol level, and more than 50% suppression of plasma and urine cortisol after administration of 2 mg of dexamethasone every 6 hours (high-dose dexamethasone suppression test). Measurement of 24-hour urinary cortisol excretion is a good screening tool. Alternatively, impaired suppression of cortisol after an overnight 1-mg dexamethasone suppression test can be used as a screen in nonobese individuals. Plasma ACTH concentration less than 5 pg/mL and serum cortisol concentration greater than 15 μg/dL suggest an ACTH-independent cause. Plasma ACTH concentration greater than 15 pg/mL in a patient with hypercortisolism likely indicates ACTH-dependent Cushing’s syndrome (Arnaldi et al., 2003; Findling and Raff, 2005).

The vast majority of ACTH-dependent Cushing’s syndrome patients have a pituitary adenoma as the cause. The few patients who have an ectopic source of ACTH must be identified with high-resolution CT scanning of chest, abdomen, and pelvis.

Suppression of urinary cortisol excretion, after administration of high-dose dexamethasone, is consistent with the diagnosis of Cushing’s disease, whereas urinary cortisol excretion in cases of ectopic ACTH syndrome is usually not suppressible. When the high-dose dexamethasone suppression test fails to differentiate an ectopic source from a pituitary source of ACTH, and radiographic imaging is not conclusive, further CRH testing and petrosal sinus sampling of ACTH are indicated to localize the tumor to the pituitary.

Treatment

The treatment of choice for Cushing’s disease is selective transsphenoidal resection of the pituitary adenoma. The cure rate for this procedure is 70% to 80% for microadenomas at experienced centers. In some patients, total hypophysectomy is considered when the disease recurs after transsphenoidal resection. Many postsurgical patients require low-dose cortisol replacement for up to 12 months, until their endogenous adrenal function recovers.

Bilateral adrenalectomy with or without pituitary irradiation is offered to patients who have recurrence of hypercortisolemia or severe disease. For poor surgical candidates, adjunctive medical therapy is offered and includes metyrapone (blocker of 11β-hydroxylase), mitotane (O′P′DDD), and cyproheptadine. These treatment options have variable efficacy.

Craniopharyngiomas; Thyrotropin-Secreting Pituitary Adenomas; Gonadotropic and Other Adenomas

See the discussions of these pituitary tumors online at www.expertconsult.com.

Posterior Pituitary Disorders

Arginine vasopressin (AVP) and oxytocin are the principal hormones secreted from the posterior pituitary. The two major stimuli of oxytocin secretion are suckling during lactation and dilation of the cervix during labor. Although not essential for initiation of labor, oxytocin can be used pharmacologically to initiate labor or control postpartum hemorrhage and uterine atony. Rarely, it has been used to induce milk ejection. The physiologic role of oxytocin in males is not known. AVP differs from oxytocin by only one amino acid. AVP is found in all mammals except pigs and related species, in which lysine vasopressin replaces AVP. In humans and many mammals, AVP and oxytocin are associated with two neurophysins, the exact roles of which are not known, except as carrier proteins in storage and transport of posterior pituitary hormones (Mooradian and Morley, 1988).

Antidiuretic hormone (vasopressin) is synthesized in the hypothalamus and migrates down into the posterior lobe of the pituitary to be stored and later secreted. Some ADH is secreted directly into the cerebrospinal fluid (CSF) rather than the posterior pituitary. Thus, pathologic lesions affecting the hypothalamus below the median eminence may preserve some functional ADH that migrates from the CSF into the systemic circulation. The half-life of AVP in circulation is only 20 minutes because of its susceptibility to peptidases. Loss of the terminal amino group in position 1 makes this peptide resistant to degradation, whereas substitution of the levo analog of arginine for dextroarginine in position 8 reduces presser effect without altering its antidiuretic properties. The resultant peptide deamino-8-d-argenine vasopressin (DDAVP) is currently the treatment of choice for central diabetes insipidus.

The biologic effects of AVP are initiated at two receptors, V1 and V2. The V1 receptors are located in the vascular system, and their stimulation results in vasoconstriction. The V2 receptors are located in the kidneys, and their stimulation results in free-water reabsorption (Korbonits and Carlsen, 2009). Plasma osmolality, blood volume, and blood pressure are the most important physiologic stimuli of AVP secretion. Other factors that modulate AVP secretion include pain, stress, nausea, hypoglycemia, hypercapnea, angiotensin II, atrial natriuretic hormone, and drugs. Many stimuli of AVP release also promote thirst. Thirst is less sensitive than AVP release in response to these stimuli and therefore is a second-line defense against dehydration.

Central Diabetes Insipidus

• Diabetes insipidus is characterized by excessive dilute urine with thirst and polydipsia and results from decreased ADH secretion.

• Differential diagnosis of hypotonic polyuria includes neurogenic DI (vasopressin sensitive), nephrogenic DI (vasopressin resistant), and primary polydipsia.

• The water restriction test assists in diagnosis.

• Desmopressin is the primary treatment for central DI.

Clinical Features

Diabetes insipidus (DI) is characterized by the production of excessive dilute urine with secondary thirst and polydipsia. Polyuria is defined as 3 L or more of urine daily in adults and 2 L or more in children. Central DI may be familial or sporadic and is caused by head trauma, neurosurgery, neoplasms, granulomas, infections, inflammation, chemical toxins, vascular disorders, congenital malformations, and genetic disorders. Other causes include hypoxic encephalopathy; infiltrative disorders, notably histiocytosis X (Hand-Schuller-Christian disease); anorexia nervosa; acute fatty liver of pregnancy; and Wolfram syndrome (central DI, diabetes mellitus, optic atrophy, and deafness) (Reddy and Mooradian, 2009). An autoimmune process is probably the cause of idiopathic DI and accounts for 30% to 50% of cases of central DI (de Bellis et al., 1999).

Thickening or enlargement of the posterior pituitary on MRI may represent lymphocytic infiltration and inflammation. Classically, DI after head trauma or neurosurgery has three phases: polyuria in the first 1 to 2 days after surgery, oliguria for 3 to 4 days, and culminating in a polyuric phase. These phases reflect the early paralysis of vasopressin-producing cells, followed by neuronal degeneration and massive ADH release, with subsequent permanent loss of vasopressin production.

Vasopressin-resistant DI is usually a familial disorder, although sporadic causes are recognized, as in chronic medullary kidney disease associated with sickle cell disease, multiple myeloma, amyloidosis, Sjögren’s syndrome, and renal medullary cystic disease. In addition, prolonged primary polydipsia can wash out the normal medullary concentration gradient and may mimic ADH-resistant nephrogenic DI.

Diagnosis

Although a variety of diseases may present as polyuria and polydipsia, thorough history and routine laboratory evaluation can narrow the differential diagnosis of hypotonic polyuria to three possibilities: neurogenic DI (vasopressin sensitive), nephrogenic DI (vasopressin resistant), or primary polydipsia (Mooradian and Morley, 1988).

Serum sodium concentrations less than 137 mEq/L and polyuria are usually manifestations of primary polydipsia. Patients with serum sodium concentration less than 143 mEq/L should have a water deprivation test after an overnight fast, with hourly measurement of body weight, urine volume, and osmolality. In severe cases the dehydration test can be started at 6 am. When the urine osmolality remains constant during three consecutive measurements, or if the patient loses more than 5% total body weight, plasma osmolality, ADH, and sodium concentrations are determined, and aqueous vasopressin (0.1 U/kg SC) or 10 μg of nasal desmopressin is administered and the response evaluated. An increase in urine osmolality of 150 mOsm/kg above baseline will exclude nephrogenic DI. In central DI, 10 μg of nasal desmopressin will result in increases in urine osmolality of as much as 800%. The response to desmopressin in partial central DI may result in urine osmolality increases of 15% to 50%. Patients with nephrogenic DI continue to have urine osmolality levels that remain below isosmotic. Primary polydipsia responds to the water deprivation test with urine concentrating to 500 mOsmol/kg or higher, compared with urine osmolality increasing to 800 mOsmol/kg or higher in normal subjects. Administration of exogenous vasopressin produces no further concentration in cases of primary polydipsia.

When the water suppression test yields equivocal results, the serum AVP concentration at baseline and after the water restriction test should be measured. However, the results of these tests may still be misleading because primary polydipsia will result in submaximal secretion of AVP, mimicking the pattern of AVP secretion in partial central DI.

Treatment

The treatment of choice for central DI is desmopressin. DDAVP can be administered IV, SC, nasally, or orally. An initial nasal inhalation of 5 μg is given at bedtime and increased by 5-μg increments until nocturia is resolved, when a morning dose is given. The total daily dosage of nasal desmopressin is 5 to 20 μg daily. Oral desmopressin should be given on an empty stomach; absorption can be reduced by up to 50% when taken with food. A 0.1-mg tablet is equivalent to 2.5 to 5.0 μg of nasal spray (de Bellis et al., 1999).

Patients with partial DI will benefit from oral agents that potentiate AVP action or stimulate the release of AVP. These agents include chlorpropamide, carbamazepine, and clofibrate. In such cases, desmopressin requirements may be lower than available preparations can provide. Patients with nephrogenic DI benefit from thiazide diuretics or indomethacin. Patients with DI should wear a medical alert bracelet. When the ability to drink fluids is impaired, intravenous hydration will be required to avoid dehydration and hypernatremia.

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

• Laboratory evaluation of plasma osmolality, urine osmolality, and urine sodium concentration assist in determining the cause of hyponatremia.

• Water restriction and salt replacement are the most important treatments in hyponatremia. The underlying cause should be identified and treated, when possible.

• Vasopressin antagonists are currently indicated for the treatment of euvolemic and hypervolemic hyponatremia.

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is associated with plasma ADH concentrations that are inappropriately high for the plasma osmolality. Laboratory and clinical features of SIADH include (1) euvolemic hyponatremia; (2) decreased measured plasma osmolality (<275 mOsm/kg); (3) urine osmolality >100 mOsm/kg; (4) urine sodium usually >40 mEq/L; (5) normal acid-base and potassium balance; (6) blood urea nitrogen (BUN) <10 mg/dL; (7) hypouricemia <4 mg/dL; (8) normal thyroid and adrenal function; and (9) absence of advanced cardiac, renal, or liver disease (Reddy and Mooradian, 2009). Conditions or factors associated with SIADH include CNS trauma and infections, tumors, drugs, major surgery, pulmonary disease (e.g., TB), hormone administration, human immunodeficiency virus (HIV) infection, hereditary SIADH, idiopathic causes, and cerebral salt wasting (Box 35-1).

Box 35-1 Select Causes of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

Modified from Reddy P, Mooradian AD. Diagnosis and management of hyponatremia in hospitalized patients. Int J Clin Pract 2009;63:1494-1508.TB, Tuberculosis; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; MAOIs, monoamine oxidase inhibitors; ACE, angiotensin-converting enzyme; MDMA, 3,4-methylenedioxymethamphetamine.

Nonosmotic stimuli

Nausea, pain, stress

Human immunodeficiency virus (HIV)

Acute psychosis

Pregnancy (physiologic)

Congestive heart failure exacerbation

Drug induced

Antipsychotics

Antidepressants

SSRIs, TCAs, MAOIs

Anticonvulsants

Carbamazepine, oxcarbazepine

Sodium valproate

Analgesics and recreational drugs

Morphine (high doses)

MDMA (“ecstasy”)

Nonsteroidal anti-Inflammatory drugs

Colchicine, venlafaxine

Duloxetine (Cymbalta)

Antidiabetic drugs

Tolbutamide, glipizide

Lipid-lowering agent

Antineoplastic agents

Cyclophosphamide

Vincristine, vinblastine

Cisplatin, hydroxyurea

Immunosuppressives

Tacrolimus, methotrexate

Interferon α and γ, levamisole

Monoclonal antibodies

Antibiotics

Azithromycin, ciprofloxacin

Trimethoprim-sulfamethoxazole

Cefoperazone/sulbactam, rifabutin

In some cases it is difficult to differentiate SIADH from mild to moderate depletional hyponatremia. The response of urinary and plasma sodium concentration to an infusion of 1 to 2 L of 0.9% (isotonic) saline may help in the differential diagnosis. In the patient with SIADH who is at equilibrium, the saline will be excreted, and therefore urinary sodium will increase while plasma sodium concentration will either not change or decrease slightly. If the patient has depletional hyponatremia from renal losses, sodium from the administered saline is retained and the excess water excreted. Urinary sodium decreases, whereas plasma sodium concentration increases.

A reset osmostat may be suspected when mild hyponatremia persists despite changes in fluid and salt intake. A reset osmostat may be confirmed by giving the patient a fluid bolus of 10 to 15 ml/kg. Normal patients, or those with a reset osmostat, should excrete 80% of this bolus in 4 hours, which does not occur with SIADH. Cerebral salt wasting induces SIADH-like symptoms. Salt wasting, followed by volume depletion, occurs in some patients with cerebral disease. This leads to a secondary rise in ADH levels. The mechanism underlying cerebral salt wasting is unclear.

Treatment

Management of SIADH should begin with water restriction and treatment or elimination of the underlying etiology. In all patients with hyponatremia, free-water intake from all sources should be restricted to less than 1 to 1.5 L daily. In patients with mild symptoms, the rate of urinary solute excretion, the main determinant of urine output, can be increased by a high-salt, high-protein diet or supplementation with urea (30-60 g/day) or salt tablets (200 mEq/day) (Reddy and Mooradian, 2009). However, salt therapy is generally contraindicated in patients with hypertension and edema because it leads to exacerbation of both conditions. In addition, water restriction is contraindicated in subarachnoid hemorrhage with hypovolemia, in which water restriction may result in hypotension, creating a risk for cerebral infarction. This risk is more pronounced if the patient has cerebral salt wasting, which must be treated first, with isotonic or hypertonic saline solution, until adequate volume status is demonstrated.

In general, plasma sodium concentration should be corrected at a rate of 1 mEq/L/hr until the reversal of neurologic symptoms. The correction rate is then reduced to 0.5 mEq/L/hr until the plasma sodium has reached a level of 120 to 125 mEq/L. This approach effectively prevents the devastating neurologic consequences of acute hyponatremia and is associated with reduced risk of osmotic demyelination of pontine and extrapontine neurons.

The most specific treatment for SIADH is to block the V2 receptors in the kidney that mediate the diuretic effect of ADH. Vasopressin antagonists are currently indicated for the treatment of euvolemic and hypervolemic hyponatremia (Loh and Verbalis, 2008). For hospitalized patients, conivaptan is given as an intravenous (IV) loading dose of 20 mg delivered over 30 minutes, then as 20 mg continuously over 24 hours. Subsequent infusions may be administered every 1 to 3 days at 20 to 40 mg daily by continuous infusion (Reddy and Mooradian, 2009). More recently, an orally active vasopressin receptor antagonist, tolvaptan, became available. Rapid correction of hyponatremia has been reported in patients receiving these agents; therefore, frequent checks of plasma sodium are needed. Chronic SIADH can occur in patients with ectopic ADH-producing tumors and in whom antipsychotic drugs cannot be discontinued. If water restriction and salt tablet therapy is ineffective, attempt (1) administration of loop diuretic along with salt tablets; (2) demeclocycline; (3) lithium carbonate; and (4) orally active vasopressin antagonists such as tolvaptan (cost limits its utility). Demeclocycline is nephrotoxic in patients with cirrhosis and is contraindicated in children because of interference with bone development and teeth discoloration. Lithium carbonate may induce interstitial nephritis and renal failure. Therefore, lithium should be considered for use only in patients in whom demeclocycline is contraindicated.

KEY TREATMENT

Hydrocortisone is given to ACTH-deficient adults at 20 to 30 mg daily, increased twofold to threefold during illness and other stresses (Coursin and Wood, 2002; Toogood and Stewart, 2008) (SOR: A).

The goal of thyroid replacement should be to achieve a normal serum free-thyroxine concentration and clinical euthyroidism (Oiknine and Moordian, 2006) (SOR: A).

A dopamine agonist is first-line treatment of prolactinomas (Mancini et al., 2008) (SOR: A).

Transsphenoidal surgery to remove the pituitary adenoma is usually the treatment of choice in individuals with acromegaly (Melmed et al., 2009) (SOR: A).

Octreotide (Sandostatin) is often effective in normalizing GH and IGF-1 levels. Pegvisomant is a GH receptor antagonist also approved for treatment of acromegaly (Melmed et al., 2009) (SOR: A).

Treatment of Cushing’s syndrome should be directed at the cause of hypercortisolism. The treatment of choice for Cushing’s disease is selective transsphenoidal resection (Biller, 2008) (SOR: A).

Desmopressin is the primary treatment for central diabetes insipidus (Loh and Verbalis, 2008; Reddy and Mooradian, 2009) (SOR: A).

Water restriction and salt replacement are the most important treatment modalities in hyponatremia. The underlying cause should be identified and treated, when possible (Reddy and Mooradian, 2009) (SOR: A).

Vasopressin antagonists are currently indicated for the treatment of euvolemic and hypervolemic hyponatremia (Loh and Verbalis, 2008; Reddy and Mooradian, 2009) (SOR: A).

Thyroid Disorders

• Primary thyroid disorder is caused by abnormal function of the thyroid gland.

• Secondary thyroid disorder is the result of abnormalities at the level of the pituitary.

• Tertiary thyroid disorder results from malfunction at the level of the hypothalamus.

Thyroid disorders include processes that affect function (physiology) as well as structure (anatomy). Extraglandular causes include metastatic neoplasia, pituitary disorders, dietary issues, autoimmune diseases, infections, and genetic or familial diseases, such as multiple endocrine neoplasia IIA and familial medullary thyroid carcinoma. Other causes are intrinsic to the thyroid and include cysts, nodules, and goiter. In either case, all thyroid diseases exist in one of three functional states: euthyroid, hyperthyroid, or hypothyroid; each is defined by the level of total bound and free, circulating thyroid hormone. The presence of any one of these states in an individual can be transient, static, or progressing. Laboratory abnormalities of circulating thyroid hormone, at any point in time, do not prove disease and do not depend on the etiology of thyroid dysfunction. All three states may exist at different times during the course of an illness, and each state can exist with or without disease or clinical findings. In addition, the various thyroid structures can reflect disease independent of endocrinologic function.

Accurate assessment of thyroid function, with determination of presence or absence of disease, requires data in addition to levels of circulating thyroid hormones. These data include serum free and total thyroid hormone levels, thyrotropin (TSH) levels, and in some cases, antithyroid antibody (ATA) titers. This battery of tests will provide diagnosis in the majority of common thyroid disorders. When imaging studies and fine-needle aspiration are added, 90% to 95% of patients with thyroid disease who present in the primary care setting can be diagnosed and appropriately managed.

Thyroid disorders affect 60 to 80 per 1000 adults worldwide and up to 8.9% of the adult U.S. population (Bagchi et al., 1990; Vanderpump et al., 1995). Since most have an insidious onset or closely mimic other, more common disorders, thyroid disorders are easily missed and, although rarely fatal, can cause significant morbidity. Early recognition is critical to minimizing morbidity. With the exception of conditions such as simple goiter or visible nodule, patients who ultimately are diagnosed with thyroid disease rarely present to the family physician with complaints suggesting thyroid disorder.

Anatomy and Physiology

• Thyroxine (T₄) is the major product of the thyroid gland.

• Triiodothyronine (T₃) is the active hormone at the cellular level.

• The majority of circulating T₃ is formed in the peripheral circulation by deiodination of T₄.

• Thyroxine serves as a reservoir (prohormone) for T₃.

• Serum thyrotropin (sTSH) is required in all evaluations of dementia or depression.

Histologically, the thyroid gland consists of five primary elements: follicular cells, colloid, interstitial tissue, “C” cells, and lymphoid cells. The most prominent element is the follicular cell, which produces colloid. The thyroid follicle is the functional unit of the gland and the site where colloid is stored. It is within the follicle where thyroid hormone (thyroxine, or T₄) synthesis occurs. The remaining cellular elements are C cells and lymphoid cells. The few C cells are located in the intrafollicular space and produce calcitonin. Lymphoid cells are found scattered throughout the gland stroma in small, isolated clusters.

Circulating Thyroid Hormones

Biosynthesis of thyroid hormone is unique among endocrine glands because final assembly occurs extracellularly in the follicular lumen. The source of thyroid hormones (T₄ and triiodothyronine, or T₃) is thyroglobulin (Tg), an iodoprotein produced by thyroid follicular cells. Thyroglobulin is the major portion of intraluminal colloid and is the most important protein of the thyroid gland (Kopp, 2005). Thyroglobulin provides a matrix for the synthesis of thyroid hormones and a vehicle for subsequent storage. Stored thyroglobulin is oxidized by thyroid peroxidase (TPO), adding an iodine molecule to tyrosine to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). MIT and DIT are then assembled into the final products, tetraiodothyronine (T₄) and triiodothyronine (T₃), which are stored in the follicular colloid for future use. When stimulated by serum thyrotropin (sTSH), thyroglobulin within the colloidal space is internalized by thyroid cells and enzymatically degraded to release T₄ and T₃ into the peripheral circulation. Approximately one third to one half of T₄ released into the peripheral circulation is deiodinated to form T₃.

In the peripheral circulation, T₄ and T₃ are bound to thyroid-binding globulin (TBG). Thyroxine is bound to TBG in concentrations 10 to 20 times greater than T₃, and neither bound T₄ nor bound T₃ is directly available to tissues. Only unbound or “free” portions of T₄ and T₃ are metabolically available at the cellular level. The free portion of T₄ represents 0.02% to 0.05% of total serum T₄ and the free portion of T₃ represents 0.1% to 0.3% of total serum T₃ (Benvenga, 2005; Meier and Burger, 2005; Toft and Beckett, 2005). Most T₃ (>99.5%) is bound to TBG, but T₃ is not as tightly bound as T₄, allowing easier release into the free state.

Thyroid hormones exert their effect by binding to thyroid receptors (TRs) within cells. At the cellular level, T₃ is about twice as biologically active as T₄, partly because T₃ binds to TRs 10 to 15 times more than T₄ (Yen, 2005). T₃ is the biologically active form of thyroid hormone. Thyroxine’s role in this process appears to be that of a prohormone, providing a readily accessible reservoir for conversion to T₃; otherwise, its exact purpose is unknown (Bianco and Larsen, 2005).

Thyroid hormones (T₄ and T₃) regulate growth, development, and metabolism by affecting oxygen consumption and protein, carbohydrate, and vitamin metabolism. Around puberty, the effect on growth and development begin to wane, and in adults, thyroid hormones essentially affect only metabolism (Yen, 2005).

Normal thyroid function, in terms of circulating levels of T₄, T₃, free T₄ (FT₄), free T₃ (FT₃), and the thyrotropin feedback system, appears to remain stable throughout life. Without intrinsic disease of the hypothalamic-pituitary-thyroid axis, age does not appear to have an adverse effect on the function of the thyroid gland or its component parts, in terms of serum concentration of T₄ and T₃ (Oiknine and Mooradian, 2006). Although changes in measurable levels of total serum T₄ and T₃ do result from changes in transport protein concentrations, FT₄ and FT₃ levels remain mostly constant (Hassani and Hershman, 2006).

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Tags: Textbook of Family Medicine

Oct 3, 2016 | Posted by admin in MANUAL THERAPIST | Comments Off

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