Pituitary Hormones	Hypothalamic Hormones	Other Regulatory Factors
Thyrotropin	TRH	T₄, T₃, dopamine, Pit-1
Corticotropin	CRH	ADH, adrenaline, cortisol
Luteinizing hormone	LH-RH	Estrogen, progesterone, testosterone
Follicle-stimulating hormone	LH-RH	Activin, estrogen, inhibin, follistatin, testosterone
Growth hormone	GH-RH	Somatostatin, estrogens, T₄, Pit-1
Prolactin	PRF	Dopamine, TRH, Pit-1, estrogen, serotonin, vasoactive intestinal peptide, GnRH-associated peptide

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 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

	Endocrine Effects
Mass Effects	Hyperpituitarism	Hypopituitarism
Headaches	GH: acromegaly	GH: short stature in children, increased fat mass, decreased strength and well-being in adults
Chiasmal syndrome	Prolactin: hyperprolactinemia	Prolactin: failure of postpartum lactation
Hypothalamic syndrome	Corticotropin: Cushing’s disease Nelson’s syndrome	Corticotropin: hypocortisolism
Disturbances of thirst, appetite, satiety, sleep, and temperature regulation	LH/FSH: gonadal dysfunction or silent α-subunit secretion	LH or FSH: hypogonadism
Diabetes insipidus	Thyrotropin hyperthyroidism	Thyrotropin: hypothyroidism
SIADH
Obstructive hydrocephalus
Cranial nerves III, IV, V₁, V₂, and VI dysfunction
Temporal lobe dysfunction
Nasopharyngeal mass
CSF rhinorrhea

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

PITUITARY ADENOMAS

Approximately 50% of pituitary adenomas are prolactinomas, 15% are growth hormone (GH)-producing, 10% are corticotropin-producing, and less than 1% secrete thyrotropin. Nonfunctioning pituitary adenomas, or more appropriately named nonsecretory adenomas represent about 25% of pituitary tumors. Most of these adenomas on morphologic examination reveal granules containing hormones, typically components of glycoprotein hormones. Autopsy studies suggest that up to 20% of normal individuals harbor incidental pituitary microadenomas that are pathologically similar in distribution to those that present clinically.³

Impingement on the optic chiasma or its branches by pituitary pathology may result in visual field defects, with the most common being bitemporal hemianopsia. Lateral extension of the pituitary mass to the cavernous sinuses may result in diplopia, ptosis, or altered facial sensation. Among the cranial nerves, palsy of CN III is the most common.

Premenopausal women often present with smaller pituitary tumors because they seek medical attention once altered menses are noted. The initial workup for most suspected adenomas should be limited and should include a serum prolactin and insulin-like growth factor-I (IGF-I) level. Other screening tests may be performed depending on clinical features.

Prolactinoma

Prolactin Physiology

The pituitary content of prolactin is approximately 100μg but can increase 10- to 20-fold during pregnancy and lactation. Although breast tissue is the most important target organ for prolactin, prolactin receptors have been identified in various tissues, including the liver, kidney, ovaries, testes, prostate, and seminal vesicles. Dopamine is the major inhibitor of prolactin secretion, and any mechanisms that interrupt dopamine transport from the hypothalamus or reduce dopamine activity in the pituitary can lead to elevated levels of serum prolactin. Estrogens, TRH, and serotonin increase prolactin levels. Whereas H₂ receptors inhibit prolactin secretion, H₁ receptors stimulate its secretion.

Hyperprolactinemia

Hyperprolactinemia is the most common pituitary disorder. Estrogen therapy in the past was suggested as a cause of prolactinoma formation, but careful case-cohort studies have found no evidence that oral contraceptives induce development of prolactinomas. Clonal analysis of tumor DNA indicates that prolactinomas are monoclonal in origin.

Hyperprolactinemia impairs pulsatile gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) release, likely through alteration in hypothalamic luteinizing hormone-releasing hormone (LHRH) secretion. Women of reproductive age usually present with oligomenorrhea, amenorrhea, galactorrhea, and infertility. Those with longstanding amenorrhea are less likely to have galactorrhea secondary to longstanding estrogen deficiency. Postmenopausal women and men usually come to medical attention because of a mass effect, such as headaches and visual field defects.⁴

Many men with hyperprolactinemia do not report any sexual dysfunction, but once treated effectively for hyperprolactinemia, the majority realize the presence of problems, including decreased libido and erectile dysfunction. Men with longstanding hypogonadism may have decreased beard and body hair, with soft but usually normal-size testes. If hypogonadism starts before completion of puberty, testes will be small. Patients with microadenomas have higher frequency of headaches compared to control subjects.

Drug history is an important part of the initial evaluation of patients with elevated prolactin level, because some medications are associated with hyperprolactinemia and their discontinuation (if possible) will avoid any further, often expensive, workup. Other common conditions associated with elevated prolactin levels include pregnancy and hypothyroidism (Table 22-3).

Table 22-3 Differential Diagnosis of Hyperprolactinemia

Physiologic	Pathologic	Pharmacologic
Pregnancy	Prolactinoma	TRH
Postpartum	Acromegaly (25%)	Psychotropic medications
Newborn	Hypothalamic disorders	Phenothiazines
Stress	“Chiari-Frommel”	Reserpine
Hypoglycemia	Craniopharyngioma	Methyldopa
Sleep	Metastatic disease	Estrogen therapy
Postprandial hypoglycemia	Pituitary stalk secretion or compression	Metoclopramide, cimetidine (especially intravenous)
Intercourse	Hypothyroidism	Opiates
Nipple stimulation	Renal failure	Verapamil
	Liver disease	Some SSRIs, including fluoxetine and fluvoxamine
	Chest wall trauma (burns, shingles)

SSRI = Selective serotonin reuptake inhibitor.

The prolactin level usually correlates well with the size of the tumor. Serum prolactin level above 200μg/L is almost always indicative of a prolactin-producing pituitary tumor. However, a serum prolactin level below 200μg/L can be seen in the presence of a large pituitary adenoma, because stalk compression from an adenoma that does not secrete prolactin can also cause hyperprolactinemia. Stimulatory tests, including the TRH stimulation test, which are performed to determine whether an elevated prolactin is a result of a prolactinoma, are nonspecific and cannot be used to diagnose or exclude a tumor. Large prolactinomas may be associated with a falsely low prolactin level. Dilution of serum will reveal the markedly elevated prolactin levels.

Observational studies in patients with microadenomas indicate that serum prolactin concentration or adenoma size increases in only a minority of patients; indeed, serum prolactin deceases in a majority of patients over time. Details of the relationship between prolactin adenomas and amenorrhea are found in Chapter 16.

Treatment

Dopamine agonists are now the first-line treatment for prolactinoma, because surgical resection is curative only in a minority of patients and is associated with a high risk of side effects and recurrence in all patients. Bromocriptine mesylate (Parlodel), pergolide mesylate (Permax), and cabergoline (Dostinex) are potent inhibitors of prolactin secretion, and their use often results in tumor shrinkage.

Suppression of prolactin secretion by dopamine agonists depends on the number and affinity of dopamine receptors on lactotrope adenoma. There is usually a substantial decrease in prolactin level even when serum prolactin levels do not normalize. These medications should be initiated slowly, because side effects often occur at the beginning of treatment.

The most common side effects of dopamine agonists include nausea, headache, dizziness, nasal congestion, and constipation. In men treated for prolactinomas, it may take up to 6 months before testosterone increases and normal sexual function is restored. Prolactin appears to have an independent effect on libido in men, because exogenous testosterone works poorly in restoring libido in those who continue to have elevated prolactin levels.

Although patients with microadenomas or those without evidence of a pituitary tumor can sometimes be followed without therapy, patients with macroadenomas always need to be treated. Occasionally a patient with microadenoma or no definite pituitary tumor has no increase in prolactin concentration once the dopamine agonist is discontinued. For this reason, it would be reasonable to try a “drug holiday” after several years of therapy with close follow-up.

Medical therapy during pregnancy often stirs debate about the continuation of bromocriptine. Tumor-related complications are seen in about 15% of pregnancies and in only 5% of women with microadenomas. A sensible approach would be to stop bromocriptine when pregnancy begins, and then follow the clinical status with serum prolactin levels and visual field examinations. If there is significant worsening in clinical status, bromocriptine could be reinstituted. The adenoma can be followed yearly by MRI, increasing the duration between imaging studies if size is stable.⁵

Transsphenoidal surgery is reserved for patients with disease refractory to medical therapy. Even in patients with a mass effect, including visual field defects, dopamine agonists are the first line of therapy, because a rapid improvement in symptoms is observed in the majority of patients. The main advantage of surgery is avoidance of chronic medical therapy. Radiation therapy may be considered for patients who poorly tolerate dopamine agonists and who will likely not be cured by surgery (e.g., tumor invasion of cavernous sinuses).

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

Coarsening of facial features

Prominent jaw and frontal sinus

Broadening of hands and feet

Hyperhidrosis

Macroglossia

Signs of hypopituitarism

Diabetes mellitus (10%–25%)

Skin tags (screening for colonic polyps required)

Hypertension (25%–30%)

Cardiomyopathy (50%–80%)

Carpal tunnel syndrome

Sleep apnea (5%)

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.

Treatment

The primary aims of treatment include relief of the symptoms, reduction of tumor bulk, normalization of IGF-I and GH dynamics, and prevention of tumor regrowth. Medical treatment of acromegaly has gained significance since the limitations of radiation and surgical therapy have become evident.

Somatostatin analogues are the most effective medical therapy available for acromegaly. Octreotide therapy has significantly changed the management of acromegaly with lowering and normalization of IGF-I in 90% and 65% of patients, respectively. Octreotide is usually given as a subcutaneous injection three times per day. The long-acting octreotide (Sandostatin LAR) has been approved by the U.S. Food and Drug Administration (FDA) for medical therapy of acromegaly as a monthly intramuscular injection.

Long-term observations of patients on somatostatin analogues have shown no evidence for tachyphylaxis. Some degree of tumor shrinkage is expected in up to 50% of patients, although in most cases there is less than 50% shrinkage in tumor size. The most common side effects are gastrointestinal, including diarrhea, abdominal pain, and nausea. The most serious side effect of somatostatin analogues is cholelithiasis, seen in up to 25% of patients. Its long-term management is similar to that for cholelithiasis in the general population, and routine ultrasonographic screening is not indicated. There have been very few reports of the use of a somatostatin analogue during pregnancy.^7,⁸

Normalization of IGF-I is seen in only 10% to 15% of patients treated with dopamine agonists and is more likely with pituitary tumors secreting both GH and prolactin. Surgical approach is the treatment of choice in those presenting with pituitary microadenoma or when tumor is confined to the sella, with cure rates up to 90%. However, patients with acromegaly who have a macroadenoma will have a surgical cure less than 50% of the time. Even in those not cured by surgery, tumor debulking usually results in improvement of symptoms and lowering of IGF-I levels.

Radiation therapy almost always induces a decrease in size of the tumor and GH level but often fails to normalize IGF-I levels. In view of its low efficacy, high risk of hypopituitarism, and the lack of knowledge about its long-term effect on neuropsychiatric functions, radiation therapy should be reserved for those not responsive to other treatment modalities. Radiosurgery (gamma knife) seems to be superior to conventional radiation therapy, but large studies on efficacy and long-term safety profile are lacking.

The most important recent development in the treatment of acromegaly is the introduction of a novel GH receptor antagonist. This is a recombinant modified GH molecule conjugated with polyethyleneglycol (PEG), which prevents the GH receptor from dimerization. In clinical practice, although pituitary-derived GH levels increase by a third, serum IGF-I levels are normalized in more than 90% of patients. This drug (Pegvisomant) is currently administered as a daily subcutaneous injection of approximately 1mL. Theoretical concerns exist for pituitary tumor growth but have not been substantiated.

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

Clinical Feature	Approximate Prevalence (%)
Obesity
General	80–95
Truncal	45–80
Hypertension	75–90
Menstrual disorders	75–95
Osteopenia	75–85
Facial plethora	70–90
Hirsutism	70–80
Impotence/decreased libido	65–95
Neuropsychiatric symptoms	60–95
Striae	50–70
Glucose intolerance	40–90
Weakness	30–90
Bruising	30–70
Kidney stones	15–20
Headache	10–50

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.

Ectopic Corticotropin Syndrome

The most important differential diagnosis of Cushing’s disease is ectopic production of corticotropin. Ectopic ACTH syndrome is the most frequent and best studied of the ectopic hormone syndromes. Most tumors associated with ectopic corticotropin syndrome are carcinomas and have a poor prognosis. They usually present as a rapid-onset syndrome (within 6 months) associated with profound muscle weakness, hyperpigmentation, hypertension, hypokalemia, and edema. Hyperpigmentation is thought to be due to cosecretion of β-melanocyte-stimulating hormone, one of the byproducts of corticotropin synthesis.

Some benign tumors, such as carcinoids or islet cell tumors, have been shown to cause ectopic corticotropin syndrome and are difficult to differentiate from pituitary causes of Cushing’s syndrome. This difficulty is increased by radiologic investigations of the sella that are often negative or show a microadenoma, which is seen in up to 20% of autopsy series in normal individuals.

Treatment

Surgical (transsphenoidal) removal of corticotropin-secreting pituitary tumor is the treatment of choice. Availability of an experienced surgeon is crucial, with an 80% to 90% remission rate after surgery. An undetectable postoperative cortisol level with the patient not taking steroids is considered to be an excellent marker for long-term cure. A period of temporary adrenal insufficiency follows successful surgery, usually lasting 6 to 8 months, but possibly as long as 2 years. For those not cured by the surgery, other options include second operation and radiation therapy.

Patients whose tumor is unresponsive to these therapies may then be offered medical or surgical adrenalectomy. Ectopic corticotropin-producing tumors should be resected if possible. Octreotide may inhibit ectopic corticotropin secretion. Mitotane (Lysodren) is perhaps the most effective adrenolytic agent. Other medications, such as aminoglutethimide (Cytadren), ketoconazole (Nizoral), or metyrapone (Metapyrone), are useful as temporizing agents only. The glucocorticoid antagonist mifepristone (RU-486) is a promising therapy that appears to have few side effects. One difficulty is that one cannot rely on cortisol measurements to follow the effect of mifepristone. This agent blocks cortisol action but may be associated with actual higher levels of circulating cortisol.

Nonsecretory and Glycoprotein-Secreting Pituitary Adenomas

HYPOPITUITARISM

Pituitary adenomas are the most common cause of hypopituitarism, but other causes, including parasellar diseases, pituitary surgery, or radiation therapy, are possible. Head injury must also be considered.

Pituitary hormone deficiency secondary to a mass effect usually occurs in the following order: GH, LH, FSH, thyrotropin, corticotropin, and prolactin. Prolactin deficiency is uncommon except in those with pituitary infarction. Isolated deficiencies of various anterior pituitary hormones have also been described.

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

Lymphocytic Hypophysitis

Lymphocytic hypophysitis is an autoimmune disease often presenting in women during or after pregnancy. The clinical manifestations are secondary to hypopituitarism or adrenal insufficiency or are due to a pituitary mass effect. Serum prolactin is elevated in half of patients but may be decreased. Antipituitary antibodies are present in some patients, and other autoimmune endocrine disorders, including Hashimoto’s thyroiditis and Addison’s disease, have been seen by others.¹²

The diagnosis may be suspected on clinical grounds in a pregnant or postpartum woman. However, surgical biopsy is needed for confirmation of diagnosis.

The natural history of lymphocytic hypophysitis is variable, worsening or improving spontaneously. Some patients recover fully, while others may need selective hormone replacement. For this reason, patients need to be assessed at regular intervals to determine the necessity of continued hormone replacement. Adequate hormone replacement therapy is crucial.

Although lymphocytic hypophysitis is a chronic inflammatory process, probably of autoimmune etiology, anti-inflammatory corticosteroid treatment has not been systematically used so far. Thirteen patients in the literature were treated with a mean daily dose of 27.5mg methylprednisolone equivalent for a mean time of 4.75 months. Lasting improvements, both endocrinologic and neuroradiologic, occurred in 15%. Transient improvements, primarily neurologic, occurred in 62% of cases. Relapse of symptoms occurred days to a few months after discontinuation of corticosteroid therapy.

Recent experience from Germany suggests that one should be cautiously optimistic about high-dose steroid therapy. MRI findings improved in 88% of patients treated with high-dose steroids, but clinical normalization was quite variable, with none achieving complete recovery.¹³

Surgery for mass effect in lymphocytic hypophysitis can lead to rapid relief of neurologic symptoms, but endocrinologic improvement was seldom reported. Indications for surgery are the presence of gross chiasma compression, ineffectiveness of corticosteroid therapy, and the impossibility of establishing the diagnosis of lymphocytic hypophysitis with sufficient certainty by conservative evaluation.¹⁴

Empty Sella Syndrome

The diagnosis of empty sella syndrome has become increasingly more common, owing to the prevalent use of CT and MRI of the brain for headaches or other symptoms. Pituitary fossa enlargement is secondary to communication between the pituitary fossa and subarachnoid space, which causes remodeling and enlargement of the sella. Primary empty sella syndrome is the result of a congenital diaphragmatic defect; secondary empty sella syndrome may result from previous surgery, irradiation, or infarction of a preexisting tumor.

Most patients have no pituitary dysfunction, but a wide spectrum of pituitary deficiencies have been described, especially in those with secondary empty sella syndrome. Coexisting tumors may occur.

Management is usually with reassurance and hormone replacement, if necessary. Surgery is only necessary if visual field defects occur or if cerebrospinal fluid rhinorrhea is present.

Pituitary Apoplexy

Pituitary apoplexy is an endocrine emergency resulting from hemorrhagic infarction of the pituitary usually associated with a preexisting pituitary tumor. A variety of predisposing conditions, including bleeding disorders, diabetes mellitus, pituitary radiation, pneumoencephalography, mechanical ventilation, and trauma, have been described.

The clinical manifestations of this syndrome are related to rapid expansion and compression of the pituitary gland and the perisellar structures leading to hypopituitarism, visual field defect, and cranial nerve palsies. Extravasation of blood or necrotic tissue into the subarachnoid space may cause clouding of consciousness, meningismus, and fever.

If pituitary apoplexy is suspected, anterior pituitary insufficiency should be presumed and the patient must be treated accordingly. The glucocorticoid dose must be adequate for the degree of stress and presumptive cerebral edema. Any evidence of sudden visual field defects, oculomotor palsies, hypothalamic compression, or coma should lead to immediate surgical decompression. The recovery of a variety of pituitary hormone deficiencies after surgery has been documented; all patients should be reevaluated for possible recovery of their pituitary hormone axes.

Sheehan’s Syndrome

Sheehan’s syndrome is the result of ischemic infarction of the normal pituitary gland, leading to hypopituitarism secondary to postpartum hemorrhage and hypotension.¹⁵ Patients have a history of failure to lactate postpartum, failure to resume menses, cold intolerance, or fatigue. Some women may have an acute crisis mimicking apoplexy within 30 days postpartum. There is often subclinical central diabetes insipidus.¹⁶

ADRENAL GLAND DISORDERS

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

Etiology

Clinical adrenal insufficiency results from hypofunction of the adrenal cortex. This may be due to destruction of the adrenal gland itself, referred to as Addison’s disease or primary adrenal insufficiency. Alternatively, it may be due to a lack of either corticotropin (i.e., secondary adrenal insufficiency) or CRH.¹⁸

The most common cause of Addison’s disease in adults (80%) is autoimmune destruction of the adrenal gland. This is often seen in association with other autoimmune diseases, including Hashimoto’s thyroiditis, Graves’ disease, or type 1 diabetes mellitus. Adrenal insufficiency in this setting is known as type II autoimmune polyglandular syndrome. Type I autoimmune polyglandular syndrome, more commonly seen in children, consists of Addison’s disease, hypoparathyroidism, and mucocutaneous candidiasis.

Other causes associated with adrenal insufficiency are listed in Table 22-6. Currently, acquired immunodeficiency syndrome is the most common cause of infectious adrenal destruction, and the antiphospholipid syndrome (lupus anticoagulant) is increasingly being recognized as a cause of adrenal hemorrhage.

Table 22-6 Other Causes of Primary Adrenal Insufficiency in Adults

Infection

Viral

Human immunodeficiency virus (HIV)

Mycobacterial

Fungal

Hemorrhage/infarction Anticoagulants/coagulopathy Sepsis Thrombosis Metastatic cancer: breast, lung, gastrointestinal, renal Infiltrative disorders: amyloidosis, sarcoidosis, hemochromatosis

Adrenoleukodystrophy/adrenomyeloneuropathy

Disorder seen in young men (X-linked)—abnormal accumulation of very-long-chain fatty acids in adrenal cortex, brain, testes, and liver

Central nervous system demyelination

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