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

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).

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.

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 Adenomas

Nonsecretory or glycoprotein-secreting tumors are usually clinically silent because they are inefficient in secreting hormones and lack a clinically recognizable syndrome. They usually come to attention because of manifestations of a mass lesion, including headache and visual field defect. Patients may present with varying degrees of hypopituitarism due to the mass effect.

Glycoprotein-secreting Adenomas

Rarely, pituitary adenomas can secret glycoproteins, including FSH, LH, or thyrotropin. An FSH adenoma may cause amenorrhea in a woman, or an LH adenoma may cause precocious puberty in a boy. Diagnosis is confirmed by measurement of either intact glycoprotein hormones or their α and β subunits. Levels of the α subunit tend to be inappropriately elevated, compared with those of the intact hormone itself.¹¹

Thyrotropin-secreting Pituitary Adenomas

The clinical picture in patients with thyrotropin-secreting pituitary adenoma includes pituitary mass lesion, hyperthyroidism, and goiter. Their most important biochemical feature is elevation of thyroid hormone levels in the presence of normal or elevated thyrotropin level. For this reason, any patient presenting with endogenous hyperthyroidism and an elevated or normal thyrotropin level should be further evaluated for the presence of a thyrotropin-secreting pituitary adenoma. Elevations in serum prolactin and α subunit of thyrotropin are in favor of a thyrotropic adenoma and against thyroid hormone resistance syndrome, which can also elevate the thyrotropin level.

Treatment

The transsphenoidal surgical approach is standard for this type of adenoma, especially if visual function is abnormal. Surgery is rarely curative because of the size of adenoma on presentation, and usually radiation therapy is needed as an adjunct. Octreotide may be helpful in reducing hormone secretion, but further studies are required to assess if it has any effect on tumor size. Dopamine agonists such as bromocriptine have been used in high doses, but clinical responses (i.e., changes in tumor size or visual symptoms) occur in less than 10% of patients.

Long-acting gonadotropin-releasing hormone (GnRH) agonists and antagonists may reduce secretion of FSH and LH by tumors but do not reduce tumor size. In summary, the efficacy of medical therapy in patients with nonfunctional or glycoprotein-secreting pituitary adenoma is not established but is used in an attempt to reduce tumor hypersecretion and size after unsuccessful surgery.

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

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

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

Diagnosis

The diagnosis of adrenal insufficiency is made by demonstrating diminished responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to stimulation. A morning cortisol value less than 3μg/dL (assuming normal cortisol-binding globulin) can be sufficient to make the diagnosis. However, the cosyntropin (Cortrosyn or corticotropin) stimulation test is usually required and is the gold standard. In this test a baseline serum cortisol is obtained and then cosyntropin 250μg is given intramuscularly or intravenously. The serum cortisol level is drawn again after 30 to 60 minutes. A rise in the cortisol level to 18μg/dL is a normal response. If an abnormal response is obtained, a corticotropin level then determines primary (high corticotropin) versus secondary disease (normal or low corticotropin).

In secondary adrenal insufficiency, however, the corticotropin stimulation test is not always abnormal. Adequate corticotropin may be present to prevent adrenal gland atrophy, thereby resulting in a response to the supraphysiologic dose of corticotropin used in the test. However, the HPA axis may not be able to respond to stress. In patients with suspected secondary adrenal insufficiency and a normal corticotropin stimulation test, CRH is now available to assess corticotropin response. In addition, the insulin tolerance test or the metyrapone test evaluate the integrity of the HPA axis by its response to hypoglycemia or inhibited cortisol synthesis, respectively. Although not widely used, some investigators find that a 1μg corticotropin stimulation test may be more sensitive at detecting mild adrenal insufficiency.²⁰

Treatment

The treatment of adrenal insufficiency is replacement of the deficient hormones. The following agents may be used in treating adrenal insufficiency:

Cortisol 20mg in the morning and 10mg in the evening, or prednisone, 5 to 7.5mg daily, provides dramatic relief of symptoms. However, to prevent Cushing’s syndrome, the smallest dose needed to control the patient’s symptoms should be used. For a minor illness, the glucocorticoid dose should be doubled for as short a time as needed. For a major stress, parenteral hydrocortisone, 200 to 400mg daily, is given initially and then rapidly tapered. Aldosterone replacement is required in primary adrenal insufficiency only and is given as fludrocortisone acetate (Florinef Acetate), 0.05 to 0.2mg daily. The dose is adjusted according to the blood pressure and potassium level. Renin levels may be required to assess plasma volume. Adrenal androgens are not replaced.²¹

In undiagnosed patients with suspected adrenal crisis, dexamethasone, 2 to 4 mg intravenously or intramuscularly, should be given along with saline and glucose. Dexamethasone does not interfere with the cortisol assay. The corticotropin stimulation test should then be done as soon as possible.

In the management of secondary adrenal insufficiency caused by previous exogenous steroids, glucocorticoids with short half-lives (usually cortisone) should be given. Typically larger doses are used in the morning and smaller doses in the evening. The evening doses are gradually tapered, as symptoms permit, to allow overnight hypothalamic-pituitary “desuppression” and a rise in corticotropin level. This leads to a return of adrenal gland function. When morning cortisol reaches 10μg/dL, replacement glucocorticoid can generally be discontinued. Stress glucocorticoids, however, should be given until result of the corticotropin stimulation test is normal. Recovery of the HPA axis from glucocorticoid suppression generally requires 6 to 12 months.

Pregnancy and Adrenal Insufficiency

Because the excess estrogens in pregnancy can result in increased synthesis of cortisol binding globulin, the doses of cortisone or prednisone may need to be increased modestly. Dosing is empiric since there is no good blood test to titrate the steroid replacement. One must avoid overreplacement as well.