Neuroendocrine Aspects of Endoscopic Skull Base Surgery: Chapter 3


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Endoscopic Skull Base Surgery
Chapter 3: Neuroendocrine Aspects of Skull Base Surgery
By Hrayr K. Shahinian, M.D., FACS

Abstract:

In this chapter the neuroendocrine aspects of skull base surgery are discussed, with special emphasis on the pituitary gland and the various tumors and/or disorders that may affect it. The different pathological conditions that may result from pituitary tumors, such as Cushing's syndrome, acromegaly, and others, are also reviewed. The chapter explains the clinical effects of pituitary hormonal deficiencies and overproduction and the methods used in the neuroendocrine evaluation of patients with pituitary tumors, such as blood tests and bilateral inferior petrosal sinus sampling in Cushing's syndrome. In addition, the chapter provides insight into perioperative neuroendocrine management of pituitary tumor patients, including the various drugs and drug categories that are used, hormonal supplementation therapy for pituitary failure, and long-term management and out patient care of pituitary tumor patients.

1. Introduction

1.1. The Pituitary Gland

The pituitary gland is considered the master gland of the body and it lays at the base of the skull in the sella turcica. It secretes several hormones that regulate other endocrine organs throughout the body and its proper function is vital for the well-being of an individual. The hormones that the pituitary gland secretes include adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), and prolactin (PRL). These hormones are made in the anterior pituitary gland. In addition, the posterior pituitary gland makes arginine vasopressin (AVP), which is also known as antidiuretic hormone (ADH), and oxytocin. The pituitary hormones are all regulated by hypothalamic hormones. ACTH secretion is regulated by corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). Growth hormone secretion is regulated by growth hormone releasing hormone (GHRH). LH and FSH secretions are regulated by gonadotropin releasing hormone (GnRH). TSH and prolactin secretions are positively regulated by thyrotropin releasing hormone (TRH) and additionally prolactin secretion is inhibited by dopamine. In addition, somatostatin (SMS) inhibits secretion of growth hormone and TSH. There are distinct cells in the pituitary gland that secrete each of the pituitary hormones. ACTH is secreted by corticotroph cells, LH and FSH are secreted by gonadotroph cells, growth hormone is secreted by somatotroph cells, prolactin is secreted by lactotroph cells, and TSH is secreted by thyrotroph cells. These pituitary hormones go to peripheral end organs to stimulate hormone release. For example, TSH stimulates the thyroid gland to secrete thyroxine and triiodothyronine. Prolactin acts on the breast to allow for milk release. Growth hormone acts on the liver to secret insulin-like growth factor-1 (IGF-1). LH acts on the ovaries and the testes to stimulate the secretion of estrogen and testosterone. FSH also acts on the ovaries and the testes, and is involved in follicle stimulation and spermatogenesis as well as increasing the secretion of the hormone inhibin. ACTH acts on the adrenal glands to stimulate the stress hormone, cortisol, and to a lesser extent, the salt regulating hormone, aldosterone. In addition, the posterior hormones also affect peripheral target tissues. Vasopressin has three receptors, in the kidney to regulate free water uptake, in the pituitary to regulate ACTH secretion, and in the smooth vessels to regulate vasoconstriction. Oxytocin acts in the uterus and the breast (Figure 1).

Figure 1: The Pituitary as a Master Gland

1.2. Skull Base Tumors and other Disorders that affect the Pituitary Gland

Disorders of the pituitary gland can be caused by pituitary tumors that produce excessive hormones or from tumors that cause decreased hormone production leading to hormonal deficiencies. Larger tumors can have mass effect and may affect peripheral vision or cause headaches and elevated intracranial pressure (ICP). Rarely, pituitary tumors can become malignant invading surrounding tissues and leading to metastases. Tumors and disorders that affect the pituitary gland include:

Prolactin-producing pituitary tumors
ACTH-producing pituitary tumors
Growth hormone-producing pituitary tumors
Thyroid hormone- producing pituitary tumors
Non-functioning pituitary tumors
Pituitary carcinomas

Other pathologies:

Meningiomas - tuberculum sellae, planum sphenoidale, olfactory groove
Craniopharyngiomas
Rathke's cleft cysts
Chordomas
Epidermoid tumors (epidermoid cysts)
Inflammatory and other rare conditions: Hypophysitis, sarcoidosis, Histiocytosis, Pituitary abcess, hypothalamic gliomas, tuberculomas, germinomas and others

2. Pituitary Tumors

2.1. Prolactinomas

Prolactin-secreting tumors are the most common pituitary tumors. Most prolactinomas are relatively small in females, although they can be quite large in males. The clinical effects of prolactinomas in females include galactorrhea (breast milk discharge) and irregular (oligomenorrhea) or absent (amenorrhea) periods. Prolactinomas inhibit the GnRH-LH-estradiol axis which leads to estrogen deficiency. Estrogen deficiency, if untreated, can lead to osteoporosis. Prolactinomas are very responsive to medical treatment with dopamine agonists

Besides prolactinomas, there are other causes of elevated prolactin and these include other large lesions that affect the hypothalamic-pituitary axis. This is called "stalk effect". Additionally, stimulation of the breasts, pregnancy and primary hypothyroidism (by the stimulation of TRH, which increases prolactin secrtetion) leads to elevated prolactin. Psychiatric medicines that have dopamine antagonist activity also raise prolactin. These classically include the psychotropic medicines such as Haldol used for schizophrenia, but also include the newer SSRIs and some antidepressants.

Figure 2: Clinical Effects of Prolactinomas

In female patients presenting with galactorrhea and/or oligomenorrhea or amenorrhea, a prolactin level should be measured, and, if elevated, the other causes of elevated prolactin besides prolactinoma need to be excluded. This includes a careful review of all medications. An MRI should be performed to exclude a large pituitary lesion. If the patient has a microadenoma or a macroadenoma that is not compressing the optic nerves, the patient should be treated medically with dopamine agonists. Though classically bromocriptine has been the agent used to treat prolactinomas, the use of this drug has been largely replaced by the use of cabergoline (dostinex) which is a specific D2 agonist. This medicine has much fewer side effects compared to bromocriptine and is usually given once or twice a week. Cabergoline and other dopamine agonists are also effective at reducing the size of the tumor so in most patients with a prolactinoma, medical treatment should be initiated. Surgical treatment is indicated for patients that fail to have a response to dopamine agonists or cannot tolerate the side effects (Figure 2).

2.2. Cushing's disease

The second most common hormone-secreting pituitary tumor is an ACTH-secreting tumor. This condition is called Cushing's disease. Cushing's disease results in elevated cortisol levels and a wide range of clinical symptoms and signs. These manifestations include rapid and unexplained weight gain, central obesity, stretch marks (striae), bruising, round plethoric face, a buffalo hump, thinning of extremities, acne, and hirsutism. Decreased libido and severe fatigue are also noted. Muscle weakness and psychiatric problems including mania, anxiety, and depression are common. Diabetes or high blood pressure usually occur in patients with more severe disease.

The causes of hypercortisolism can be divided into endogenous and exogenous. Exogenous hypercortisolism comes from patients being given steroids, and this is quite common. Of the endogenous causes of hypercortisolism, Cushing's disease is the most common, it occurs between 80% and 90% of patients with Cushing's syndrome and is much more common in females than males. Other causes of endogenous hypercortisolism are adrenal tumors secreting cortisol, and ectopic tumors, most likely bronchial or lung tumors that secrete ACTH. Additionally, an entity called pseudo-Cushing's exists in which disorders such as depression, alcoholism, and alcohol withdrawal lead to elevated cortisol secretion without the stigmata of Cushing's syndrome. However, pseudo-Cushing's appears to be decreasing in frequency, possibly due to more sensitive urinary free cortisol assays that only detect cortisol and not cortisol metabolites. Nevertheless, it is important to distinguish between exogenous Cushing's syndrome due to steroid use or abuse, endogenous Cushing's syndrome due to Cushing's disease, and pseudo-Cushing's syndrome.

Cushing's syndrome is now more recognized by both patients and endocrinologists and is diagnosed much earlier with patients having milder signs and symptoms. With the recognition of mild cases, the occurrence of Cushing's syndrome is probably much more frequent than previously thought. Because of this, a high degree of suspicion for Cushing's syndrome is needed, and multiple testing needs to be performed. Additionally, some patients with Cushing's syndrome have what is described as episodic or periodic type in that they have higher cortisol secretion rates at some times rather than at other times. Again, multiple testing is needed and a single normal test cannot be used to exclude Cushing's syndrome (Figure 3).

Figure 3: Clinical Effects of Cushing's syndrome

The most common tests used for the diagnosis of Cushing's syndrome are 24-hour urinary-free cortisol measurements, nighttime blood cortisol measurements, dexamethasone suppression tests, and nighttime salivary cortisol measurements. A 24-hour urinary cortisol collection involves collecting all urine for 24 hours, and a creatinine should also be measured to determine that collection was complete. A 24-hour urinary collection should have both a urinary free cortisol (UFC) and a 17-hydroxysteroid collection as the latter may be positive in some patients with normal urinary-free cortisol collection. Because patients with Cushing's syndrome can be periodic, it is important that the collection be done at the time when they have signs and symptoms of high cortisol production.

Nighttime blood cortisol levels are usually done between 11:00 PM to 1:00 AM. A value greater than 7 g/dL is consistent with Cushing's syndrome. This test has been somewhat replaced by salivary cortisols which reflect free cortisol in the blood. Salivary cortisols are convenient and can be mailed off. They should be done between 11:00 PM and 12:00 midnight. Each laboratory has a different normal range.

Dexamethasone suppression tests were widely used to screen and diagnose patients with Cushing's syndrome. The most common test to screen for Cushing's syndrome is an overnight dexamethasone test in which the patient takes 1 mg of dexamethasone at midnight, and an 8:00 AM cortisol is drawn. The recommended cutoff for the cortisol has been decreasing, and it is now recommended to use a value between 1.8 g/dL and 3 g/dL. This lower cut-off may pick up more patients with Cushing's syndrome but will also detect more patients without it. Additionally, many patients do suppress to the overnight dexamethasone test so this test is no longer recommended to exclude patients from having Cushing's syndrome. Additionally, there is a low-dose dexamethasone suppression test in which the patient takes dexamethasone 0.5 mg every six hours for two days. This dose of dexamethasone should suppress cortisol levels in normal patients but not in patients with Cushing's syndrome of any type. However, patients with Cushing's disease have been found to quite readily suppress to this two-day dexamethasone suppression test, and this test is also unlikely to be of much use. Therefore, the recommended tests for the diagnosis of Cushing's syndrome include multiple measurements of 24-hour urines for urinary-free cortisol and 17-hydroxysteroids, nighttime salivary cortisol, and nighttime blood cortisol.

Although traditionally imaging tests have not been performed at the initial evaluation of a patient with Cushing's syndrome, the high quality of new pituitary MRIs, has allowed the early detection of most tumors. Additionally, dynamic pituitary MRIs have focused on the slow infusion and diffusion of gadolinium into and out of the pituitary gland further refining the detection of very small lesions typical of ACTH secreting tumors. Thus, the MRI has become a valuable technique for the initial evaluation of the disease and could be performed at the time that the diagnosis is being entertained. A negative MRI makes pituitary Cushing's disease very unlikely, although it is possible that the patient could still have ectopic or adrenal Cushing's. A positive pituitary MRI does not diagnose Cushing's disease as there are pituitary incidentalomas in which the patient has a pituitary tumor that is not secreting any hormone. Thus, all patients with symptoms of cortisol excess that have a positive MRI for a microadenoma should be evaluated with 24-hour urines for urinary-free cortisol and 17-hydroxysteroids, and nighttime salivary or blood cortisols.

Once the diagnosis of Cushing's syndrome is made, the next step is determining whether the patient has ACTH-dependent (pituitary Cushing's disease or ectopic ACTH syndrome) or ACTH-independent (adrenal) Cushing's syndrome. The distinction is made by measuring a morning plasma ACTH level. If this value is low (<10 pg/mL), the patient likely has adrenal Cushing's syndrome, and the patient should have an adrenal CT or MRI. If the ACTH level is above 100 pg/mL, the patient most likely has ectopic Cushing's syndrome, while if the patient has an ACTH between 10 and 100 pg/mL pituitary Cushing's is more likely. However, the ACTH levels between ectopic and pituitary Cushing's do overlap so further investigation is needed. In most patients, the ectopic Cushing's syndrome is more severe than pituitary Cushing's syndrome, and these patients can usually be detected by failure to suppress to an overnight or low-dose dexamethasone suppression test. Additionally, a high-dose dexamethasone suppression test can also be done; patients with pituitary Cushing's disease suppress to high-dose dexamethasone, while patients with ectopic Cushing's do not.

Once the diagnosis of pituitary Cushing's disease is obtained, surgical intervention should be recommended. Most patients can be cured of their disease with selective pituitary surgery, either thru traditional transphenoidal techniques or more recently thru a minimally invasive endoscopic endonasal approach.. Postoperatively, many patients become hypocortisolemic due to the fact that before surgery the normal pituitary corticotrophs were suppressed by the elevated cortisol levels. However, some patients have episodic and mild Cushing's disease, and they do not have suppression of the normal pituitary corticotrophs, and therefore they do not have low cortisol values postoperatively. Although this is the case, most patients do become mildly hypocortisolemic after surgery and do require cortisol replacement for a period between three months and one year. The cortisol replacement should be tapered off, and within a year the patient is usually off cortisol supplementation. Additionally, during surgery, the pituitary may be damaged, and postoperatively it is quite common for patients to require growth hormone replacement. Patients may also require thyroid hormone, estrogen, or testosterone replacement and occasionally develop diabetes insipidus and require DDAVP.

In those patients that fail initial pituitary surgery, another MRI should be performed. Our approach is that patients who have a visible lesion on MRI should undergo a second pituitary surgery. If no lesion is seen, we usually recommend bilateral adrenalectomy to cure the hypercortisolism. Although pituitary radiation can also be done at this stage, the effects are quite delayed. Additionally, most patients that receive pituitary radiation develop hypopituitarism and require pituitary hormone replacement.

2.2.1. Bilateral inferior petrosal sinus sampling in Cushing's disease

If the patient has biochemical evidence of pituitary Cushing's disease and a pituitary tumor, the patient should proceed to pituitary surgery. However, if the patient has biochemical evidence supporting ectopic Cushing's syndrome, and a pituitary microadenoma, or the patient does not have a pituitary tumor yet has biochemical evidence of pituitary Cushing's disease, petrosal sinus samplings should be performed. In this procedure, also called bilateral inferior petrosal sinus sampling (BIPSS), blood in the petrosal sinuses which drain each side of the pituitary is sampled for ACTH. This is usually done before and after corticotropin-releasing hormone (CRH) is given, and this is usually measured at 0, 2, 5, and 10 minutes afterwards. In pituitary Cushing's disease, the ACTH is much higher in the petrosal blood than in a simultaneously drawn peripheral sample. In contrast, in ectopic ACTH the values between petrosal and peripheral blood are similar. A rise in ACTH with CRH is also indicative of Cushing's disease, and the lateralization may help determine what side of the pituitary the tumor is on. In tumors that are large, the blood drainage is often compromised, and therefore the ACTH levels between the two petrosal sinuses may not be valid for lateralization.. However, in patients with small microadenomas the petrosal sinus sampling is most useful and the lateralization is often effective. Petrosal sinus sampling cannot be used to distinguish pituitary Cushing's disease from normal individuals as normal individuals and patients with pituitary Cushing's disease have very similar petrosal ACTH values. Both normal individuals and patients with pituitary Cushing's disease respond to CRH and both have lateralization of ACTH. However, it is reassuring to see petrosal sinus sampling show lateralization that is on the same side as the pituitary tumor seen on MRI. This helps confirm that the pituitary tumor seen on MRI is indeed secreting ACTH. Most importantly, petrosal sinus sampling is very good at distinguishing between pituitary and ectopic Cushing's (Figure 4).

2.3. Acromegaly

Excess growth hormone in adults is called acromegaly, and growth hormone secreting pituitary tumors are the third most common types of hormone secreting pituitary tumors. Patients with acromegaly have traditionally had large pituitary tumors as the signs and symptoms of acromegaly are relatively nonspecific, and there has often been delay in seeking treatment and diagnosis. However, more recently, acromegaly has been recognized earlier as a condition, and now many of the tumors are smaller. Women usually seek medical attention before men, and this is often the case with acromegaly.

Patients with acromegaly usually have multiple slow changes in the body habitus. These include increase in ring and foot size, increase in tongue size, a wide forehead, widening of the nose, enlarged and sweaty hands, and gaps between the teeth. They also have arthritis, cardiac problems including congestive heart failure, and increased instance of polyps in the GI tract.

The initial workup for acromegaly usually involves measuring a serum IGF-1 level which is almost always elevated in patients with acromegaly. In patients with an elevated IGF-1, an oral glucose tolerance test is obtained. In the normal population glucose should suppress plasma growth hormone levels. In patients with acromegaly, the suppression is blunted, and patients usually have a growth hormone value following glucose of >1 ng/mL. In general, measuring random growth hormone is not helpful for the diagnosis of acromegaly, due to pulsatility of growth hormone.

Once the diagnosis of acromegaly is made, pituitary imaging should be obtained. If the patient can be cured with pituitary surgery, surgery should be done, and no other treatment is needed. If the patient cannot be cured with surgery because the tumor is invading the cavernous sinus or other brain regions, the usual approach is to undergo pituitary surgery for reduction of the tumor mass and decreasing of the growth hormone. Following this, medical treatment is initiated with one or two drugs. One family of drugs are somatostatin analogs which act to both decrease the IGF-1 level caused by the excess growth hormone as well as control the tumor size. The somatostatin analogs are based on the structure of an octreotide and are modified to be long-lasting. The side effects of octreotide-based drugs include nausea, vomiting, gallstones, or gallbladder sludge formation. A newer drug is pegvisomant, also called Somavert, which acts as a growth hormone antagonist. This drug prevents endogenous growth hormone from binding at the growth hormone receptor and stimulating IGF-1 and is very effective at decreasing IGF-1 levels. However, it does not have any affect on tumor size. In some patients, the use of pegvisomant plus octreotide analogs in combination is effective. Radiation therapy can be used but is only a third-line approach (Figure 5).

2.4. TSH-secreting tumors

TSH-secreting tumors are extremely rare and manifest with symptoms of hyperthyroidism with an elevated TSH and free T4 levels. Patients usually have a goiter. This can be distinguished from thyroid hormone resistance where there is also an elevated TSH and T4 level, by a positive pituitary MRI. Patients with TSH-secreting pituitary tumors should be aggressively treated with surgery.

2.5 LH- and FSH-secreting tumors

Patients with LH- and FSH-secreting tumors are also rarely identified clinically, although many nonsecreting pituitary tumors when examined by immunohistochemistry, do secrete small amounts of LH and FSH, patients with true LH- and FSH-secreting tumors are usually males who present with either mass effect or low testosterone levels. They may have erectile dysfunction and decreased libido. Females would have irregular or no periods, and in postmenopausal women the diagnosis is extremely difficult to make. Sometimes these tumors secrete high levels of alpha subunits of LH and FSH, and these can be measured.

2.6. Nonfunctioning pituitary tumors

Another very frequent type of tumor that secretes no hormones is known as a silent or nonfunctioning pituitary tumor. These tumors affect the pituitary because of their mass effect. Tumors usually larger than 1.5-2.0cms that cause visual field cuts are surgically resected.

3. Hormonal deficiencies caused by pituitary tumors

Any tumor that is large enough to compress the pituitary gland can give rise to pituitary hormonal deficiencies. However, it is increasingly recognized that small pituitary tumors such as microadenomas which are defined as tumors <10 mm in size can also give pituitary dysfunction. The pituitary hormone that is most easily affected by pituitary damage, and therefore by relatively small pituitary tumors, is growth hormone. This susceptibility is followed by LH, FSH and TSH. ACTH is the last hormone affected. Therefore, in all patients with pituitary damage (tumors, or prior surgery or radiation), growth hormone deficiency should be tested. Additionally, testosterone in females is due to secretion of ACTH and gonadotropins. Thus, testosterone deficiency may be an early sign of decreased pituitary function in patients with relatively small pituitary tumors or other pituitary damage. All patients with large pituitary tumors deserve a complete hormonal workup. To test for hyperfunction, we recommend measuring an IGF-1 for growth hormone, thyroid function tests, and a 24-hour urine for urinary-free cortisol.

3.1. Growth hormone deficiency

Diagnosing growth hormone deficiency is becoming more important as it is realized that growth hormone deficiency plays a crucial role in adults. Patients with growth hormone deficiency have relatively nonspecific complaints, but these symptoms have been shown to be due to growth hormone and improve with growth hormone therapy. These include severe fatigue, trouble sleeping, joint and muscle pains, depression and other mood disturbances.. Patients with growth hormone deficiency also have decreased lean muscle mass and increased body fat and also have osteopenia or osteoporosis. A screening test for growth hormone deficiency is an IGF 1. However, IGF-1 levels can be normal in patients with growth hormone deficiency and can be low in patients without growth hormone deficiency. An IGF-1 level also needs to be adjusted for age and gender. IGF-1 levels that are within one standard deviation of the median for age argue against growth hormone deficiency. Patients that have very low IGF-1 levels and also have other pituitary deficiencies are very likely to have growth hormone deficiency. Patients with a low normal or mildly low IGF-1 should be tested with growth hormone stimulation testing to determine the ability of the pituitary to secrete growth hormone. The most common of these is called an arginine-GHRH test in which arginine and GH are given and response to growth hormone is measured. We use a growth hormone measured by RIA of 9 ng/dL as a cutoff any time following arginine-GHRH stimulation.

3.2. Central hypothyroidism

To assess central hypothyroidism, which is hypothyroidism caused by pituitary problems, we measure a free T4 and a TSH. A free T4 below or at the lower limit of normal coupled with a low TSH in a patient with a pituitary problem is consistent with central hypothyroidism, and that patient should be treated with thyroid hormone replacement.

3.3. Gonadotropin deficiency

Female patients with irregular or no periods are likely to be estrogen deficient. Thus, for those patients a physician should measure estradiol, LH, and FSH levels; and, if consistent with low LH, FSH, and estradiol, a pituitary cause of hypogonadism is likely. The patient should be treated with an estrogen replacement, especially if the patient is premenopausal. Female patients can also have androgen deficiency, and testosterone levels should be measured, with the caveat that many commercially available assays for testosterone lack precision and sensitivity in the range of female testosterone levels. However, in a patient with low testosterone levels and signs of testosterone deficiency such as decreased libido and decreased muscle mass, testosterone replacement may be indicated. There is no FDA-approved form of testosterone replacement for women. One option is to give over-the-counter DHEA which gets converted to testosterone. Alternatively, compounding pharmacies can compound testosterone in doses suitable for females.

Hypogonadism in men is manifested as erectile dysfunction and decreased libido. In these patients, total and free testosterone levels should be measured as well as an LH and FSH to determine if the cause is pituitary in nature. Patients with a low testosterone benefit from testosterone replacement. The forms of testosterone replacement include AndroGel which is testosterone cream, Androderm which is a testosterone patch, buccal testosterone preparation (Striant), and testosterone injections. Additionally, HCG injections which stimulate the testes to make testosterone are also an option.

3.4. ACTH deficiency

ACTH is the last hormone to be affected in case of pituitary damage, and most patients have an intact ACTH-cortisol axis. Chronic ACTH deficiency leads to cortisol deficiency. Our approach in patients suspected of ACTH and cortisol deficiency is to measure a morning cortisol level. If this level is <4 g/dL, it is pretty certain that the patient has cortisol deficiency and needs to be placed on cortisol. If the cortisol is >12 g/dL, then it is unlikely that the patient has cortisol insufficiency. If the cortisol level is between 4 and 12 g/dL, then a cosyntropin test should be done. Cosyntropin is ACTH1-24 and it is given by IM or subcutaneous injection, and cortisol is drawn at 0, 30, and 60 minutes. We recommend a 1-mcg cosyntropin test as this is more sensitive to pick up pituitary insufficiency. A cortisol at 30 minutes of >18 g/dL is considered normal. If the value comes out between 12 and 18 g/dL, the patient should have cortisol replacement in stresses such as surgery or accident. If the cortisol value is <12 g/dL, the patient most likely needs daily cortisol replacement.

3.5. Diabetes Insipidus

Another complication of pituitary surgery or radiation that patients can develop in terms of hypopituitarism is diabetes insipidus. Diabetes insipidus is due to a deficiency of the antidiuretic hormone (ADH) also called arginine vasopressin (AVP). AVP is made in the posterior pituitary, so only when this portion of the pituitary is damaged, does diabetes insipidus occur. Manifestations of diabetes insipidus are polyuria, polydipsia, and hypernatremia. Immediately following pituitary surgery, there is occasionally a transient diabetes insipidus. This can be followed by episodes of hyponatremia due to excess ADH secretion at around day 7 postoperatively. This can resolve, or it can lead to permanent diabetes insipidus. The diagnosis of diabetes insipidus is usually made by noticing increased urinary volume. Our cutoff is that a 24-hour urinary volume of >3 liters is abnormal, and diabetes insipidus should be considered. We also perform a modified water deprivation test and have the patient fast for 12-hours including no liquids. A normal individual should have an elevated urine osmolality. However, patients with diabetes insipidus fail to have a concentrated urine and have a urine with low osmolality. Usually after a 12-hour fast, their spot urine osmolality is <500 mOSM/kg, with normals being greater than this cut-off. With an increased 24-hour urine volume and dilute urine following a 12-hour fast, a formal water deprivation test is usually not needed.

The treatment for diabetes insipidus is to give the AVP analogue, DDAVP, it can either be given orally or intranasally The goal would be to eliminate nighttime awakenings due to urination and still have the patient retain a normal fluid balance. The urine volume, urine and serum osmolality and serum sodium should be monitored after initiation of DDAVP treatment (Figure 6).

3.6. Other causes of hypopituitarism

Any lesion around the hypothalamic stalk or pituitary can give hypopituitarism. These include craniopharyngiomas, meningiomas, chordomas, and Rathkes' cysts. Additionally, other lesions in the hypothalamus including sarcoidosis, hemochromatosis, tuberculosis, and histiocytosis X can also lead to hypopituitarism. Head trauma can lead to hypopituitarism, as can other lesions in the pituitary including lymphomas, and other space-occupying lesions. All of these patients should be evaluated for each pituitary hormone as discussed above.

4. Long-term Follow-up of Pituitary Tumor Patients

Following pituitary surgery the patients are seen within a few days for clinical evaluation. The postoperative evaluation of pituitary function is carried out weeks after surgery. Endocrinologically active adenomas are followed by regular testing of marker homones. As long as the endocrine data is within the normal limits no imaging studies are required. In Acromegaly, the easiest parameter to follow is IGF-1, prolactinomas are followed by serum PRL level and so forth. In our practice, the initial examination is performed 8-12 weeks after surgery and repeated annually for the next 5 years.

Medications are given based on hormonal abnormalities. For instance, dopaminergic agents are used for hyperprolactinemia and somatostatin analogues are used for acromegaly. Patient education including diet, daily activity and awareness to the symptoms of recurrence are all part of a long term follow up plan. Of note that in patients who received radiotherapy or radiosurgery for their pituitary tumors, pituitary dysfunction may occur years following therapy. These patients are monitored for development of hypopituitarism and long-term evaluation of pituitary hormones is necessary. In case of endocrine inactive adenomas, the follow-up depends essentially on serial MRIs and visual studies (Table 1).

Legends:
Figure 1: The Pituitary as a Master Gland
Figure 2: Clinical Effects of Prolactinomas
Figure 3: Clinical Effects of Cushing's syndrome
Figure 4: Inferior Petrosal Sinus Sampling
Figure 5: Clinical Effects of Acromegaly and Gigantism
Figure 6: Physiology and Effects of Antidiuretic Hormone
Table 1: Pituitary-Target Organ Hormone Axis