Where is the Pituitary Gland Located? 

The pituitary gland is located at the base of the skull in a bony structure called the sella turcica (turkish saddle). It is composed of two parts: an anterior lobe and a posterior lobe, which are connected to a higher brain center (the hypothalamus), by the pituitary stalk (the infundibulum).

Why is the Location of the Pituitary Gland Important?

Critical brain structures are adjacent to the pituitary gland and may be adversely affected by large tumors in the sella. These important structures include the optic chiasm (located above) which contains nerve fibers for vision. The cavernous sinuses (located laterally) contain the internal carotid arteries (which carry blood supply to the brain), and cranial nerves (which are important for eye movement). The sphenoid sinus, a facial air space, is located below the pituitary gland.

What Does the Pituitary Gland Normally Do?

The pituitary is an endocrine gland that secretes hormones into the bloodstream in response to stimulatory and inhibitory factors from the hypothalamus and the body. These hormones act on tissues throughout the body to regulate several important functions including: reproduction, lactation, growth, stress responses and metabolism (energy utilization).

The anterior portion makes up most of the pituitary gland (>60%) and is composed of five distinct cell types that secrete six unique hormones. These anterior pituitary hormones include: 

• Thyrotropes secrete Thyroid Stimulating hormone (TSH)-which stimulates the thyroid gland to produce thyroid hormone (T4 and T3).
• Corticotropes secrete Adrenocorticotropin (ACTH)-that stimulates the adrenal glands to release cortisol and sex steroids (DHEA).
• Lactotropes secrete Prolactin (PRL)-which stimulates milk production from the mammary glands.
• Somatotropes secrete Growth hormone (GH), which stimulates the liver to produce Insulin-like growth Factors (IGF-1). IGF-1, in turn, causes bone/cartilage and muscle growth, glucose production, and fat breakdown.
• Gonadotropes secrete Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) that stimulate the gonads to produce sex steroid (testosterone-♂, and estrogen/progesterone-♀) and mature gametes (sperm and eggs).

The posterior pituitary lobe contains nerve endings from the hypothalamus and releases two hormones:

• Vasopressin  (Anti-diuretic Hormone [ADH])-acts on the kidneys and vascular smooth muscle to conserves body free water and regulate blood pressure, respectively.
• Oxytocin-stimulates the uterus during parturition (childbirth) and milk let-down during lactation.

Can Adults Live Without a Pituitary Gland?

Yes. The pituitary gland is critical for normal body functions, but fortunately all of its hormones can be readily replaced by medications (except prolactin).

                                                                                                                          

What are Pituitary Adenomas?

Pituitary adenomas are benign (non-cancerous) tumors of the pituitary gland.

How Common are Pituitary Adenomas?

Pituitary adenomas are common brain tumors, with an estimated prevalence of 10-15% in the general adult population, although most adenomas are small (<5 mm), and are not clinically apparent.

How are Pituitary Adenomas Characterized?

Pituitary Adenomas are classified by:

Size 

<1 cm = microadenomas
>1 cm = macroadenomas,      AND

Hormone Production (Functional Status), as determined by physical exam, laboratory testing, and pathology testing (in some surgical cases). Pituitary adenomas that secrete excess hormones are called ‘functional’ or ‘hypersecretory,’ whereas tumors not associated with excess hormone secretion are called ‘non-functional.’

What are the Different Types of Pituitary Adenomas? How Do They Present?

Clinically-apparent pituitary adenomas, estimated at 1:10,000 population, usually comes to medical attention because of symptomatic hormone excess and/or mass effects on the normal pituitary gland and adjacent brain structures (see pituitary gland introduction). Such compressive effects include: headaches, pituitary gland dysfunction (hypopituitarism), vision loss (classically peripheral vision loss) and/or double vision.

Pituitary adenomas can be derived from all 5 pituitary cell types, with the lactotrope (PRL-secreting), corticotrope (ACTH-secreting), somatotrope (growth hormone secreting) and the rare thyrotrope (TSH-secreting)-derived tumors typically producing syndromes of excess hormones. Conversely, gonadotrope (LH/FSH-secreting) tumors, and null cell tumors (which do not secrete any pituitary hormone) are typically clinically silent, but are often large and cause problems related to mass effects. 

Pituitary Adenomas	Relative Frequency	Common Presentation
PRL	30-40%	Galactorrhea/Irregular menses (♀) Low Testosterone/Mass Effects ( ♂)
FSH or LH-tumor	15-20%	Mass Effects
Null cell tumors	5-10%	Mass Effects
GH tumor	15-20%	Acromegaly/Mass Effects
ACTH-tumor	10-15%	Cushing's Disease
TSH-tumor	<1%	Hyperthyroidism/Mass Effects

What Causes Pituitary Adenomas?

Adenomas are caused by a mutation in a single cell that subsequently undergoes unregulated growth. The etiology for tumor formation has been identified in only a subset of adenomas, most notably GH tumors which harbor an activating (oncogene) mutation in ~ 40% of cases. Various other mutations have been detected in other pituitary adenoma sub-types, but do not account for most mutations.  

 Are Pituitary Adenomas Inherited?

Inheritable forms of pituitary tumors are uncommon, and account for <5% of all adenomas.       

Are Pituitary Adenomas Ever Cancerous?

Very rarely are pituitary adenomas malignant (<0.1%), although pituitary adenomas can be locally invasive (i.e., the cavernous sinus and sphenoid bone).

What Are the Indications for Treating an Adenoma?

In general, adenomas with excess hormone secretion (of any size), and macroadenomas associated with mass effects require treatment. Small tumors, not associated with hormone excess, or significant interval tumor growth, do not require treatment.

How Are Pituitary Adenomas Treated? 

The treatment approach to pituitary adenomas varies by tumor type, size, and evidence of invasion. Medical therapy, surgical resection and radiation therapy are used either alone or in combination to control tumor growth and/or excess hormone secretion. Prolactinomas (micro- and macroadenomas) are the only functional tumors that are preferentially treated with medical therapy. Surgical resection is indicated for all other functional and non-functional pituitary tumors.

What is a Prolactinoma?

A prolactinoma is a benign tumor of pituitary lactotrope (prolactin-secreting) cells.

How Common are Prolactinomas? Who is Commonly Affected

Prolactinomas are the most common tumors of the pituitary gland (40-50%). 

• Incidence of 20-50:10,000 population
• Female predominance (Female: male ratio-10:1)
• Typically presents between the ages of 20-50 yrs.

How Do Prolactinomas Typically Present?

Hormone Effects-Elevated prolactin (PRL) levels (hyperprolactinemia) typically result in:

• Low sex steroids (estrogen and testosterone) from PRL inhibition of gonadotropes (FSH and LH).
• Females-present with menstrual irregularities/amenorrhea, reduced sex drive (libido), vaginal dryness, pain on intercourse, reduced fertility/infertility, bone loss (osteopenia/osteoporosis), increased hair growth (hirsutism)
• Males-present with low libido, erectile dysfunction, reduced fertility/infertility, bone loss, anemia and gynecomastia (rarely)
• Low sex drive (independent of low sex steroid levels)
• Inappropriate breast milk discharge (galactorrhea)-common in females, rare in males

Tumor Size-Macroprolactinomas are more common in men than women at the time of diagnosis and can additionally cause problems of mass effect, such as:

• Headaches
• Vision loss from compression of the optic nerve
• Double vision from compression of the cranial nerves
• Loss of normal pituitary function (hypopituitarism) from compression of normal pituitary gland and/or hypothalamus. 

How is Hyperprolactinemia Diagnosed?

An elevated prolactin level is determined by a blood test, using gender-normative ranges, because females have slightly higher PRL levels than males.

Is Hyperprolactinemia Caused by a Pituitary Tumor in All Cases?

No, importantly a number of other conditions and medications can cause hyperprolactinemia and need to be considered, including:

• Pregnancy or Nursing
• Hypothyroidism 
• Kidney or Liver dysfunction
• A Large Pituitary Mass (of any cause) by inhibiting normal dopamine delivery  to the pituitary gland (called stalk effect)
• Medications 
• Anti-depressants (e.g., tricyclics, MAO inhibitors, some SSRIs)
• Anti-psychotic agents (e.g., haldol, risperadol, olanzapine)
• H2-blockers (cimetidine) 
• Anti-emetics (e.g., reglan, domperidone)
• Estrogens
• Opiates
• Anti-hypertensive (e.g., verapamil, methyldopa)

Is There a PRL Levels that Helps to Distinguish a PRL-secreting Tumor from other Causes of Hyperprolactinemia?

In general, prolactin levels >100-150 ng/dl are most consistent with a PRL-secreting tumor, and the tumor size generally correlates with the prolactin levels. 

How are Prolactinomas Localized?

Prolactinomas are best localized by a pituitary-dedicated, gadolinium contrast-enhanced magnetic resonance imaging (MRI). 

How are Prolactinomas Treated?

Prolactinomas are unique among the pituitary adenomas, in that they are best treated with medications. Dopamine agonists are very effective in normalizing prolactin levels and decreasing tumor size in the vast majority of patients (>90%). Medication options include:

• Cabergoline (Dostinex) is the preferred drug because of its higher efficacy, better side effect profile, and ease of dosing (twice weekly). 
• Bromocriptine (Parlodel) has the advantages of slightly lower cost and greater safety data during pregnancy. This dug, however, requires twice daily dosing and is generally less well-tolerated. Common side effects include: nausea, headaches, dizziness with standing (postural hypotension).

What are the Indications for Prolactinoma Treatment?

The primary indications for treating prolactinomas are:

• Symptomatic hyperprolactinoma (i.e., galactorrhea) and/or its complications (e.g., low sex steroids, infertility, bone loss). 
• A macroadrenoma, particularly if associated with mass effects

How Should Prolactinoma Patients Be Followed?

Microadenoma: The PRL level should be checked periodically (every 1-2 months initially), and the dopamine agonist adjusted to maintain the PRL in a normal range (ideally <10 ng/ml for women). Additional pituitary labs should be checked to ensure resolution of any concomitant low sex steroid levels (hypogonadism). A repeat MRI should be performed, in 6-12 months to ensure that the tumor size decreases with normalization of the PRL levels. For patient with otherwise normal PRL levels, and stable clinic picture, an annual PRL level is sufficient.

Macroadenoma: For patients with large tumors possibly associated with vision loss from optic nerve compression, a formal visual field test should also be performed at the time of diagnosis, and followed periodically.

Do Patients Fail Medical Therapy? What Are Additional Treatment Options?

A small percentage of patients (<10%), either cannot tolerate dopamine agonists, or are inadequately responsive to them. For these patients, surgical resection, via a transsphenoidal resection, is the second-line therapy. Curative rates are approximately: 80% for microadenomas, and <50% for macroadenomas. Radiotherapy is third-line therapy for prolactinomas, but is rarely required. 

What Are Alternative to DA agonists?

Sex steroid replacement, such as estrogen/progesterone (in females) or testosterone (in males), is an option to treat hypogonadism in select patients with the follow conditions:

• No desire for fertility
• Contraindication to dopamine agonists (i.e., on psychiatric meds) 
• Small tumors and without bothersome hyperprolactinemia (i.e., galactorrhea or low sex drive)

For prolactinoma patients seeking fertility that is not restored with a dopamine agonist, consideration can be given to addition medical therapies, such as Clomid or GnRH agonists to assist with fertility.

How Are Pregnant Women with Prolactinoma Followed?

In general, women with prolactinomas, who seek fertility, should be started on bromocriptine (parlodel), because of the significant amount of safety data in 2500 pregnant women, which indicates no increased risk of birth defects. Dopamine agonists are generally discontinued once pregnancy is confirmed, and patients are followed clinically, at least every trimester, for signs and symptoms of pituitary adenoma enlargement. The risk of prolactinoma enlargement is approximately 3-5% for microadenomas, but upwards of 30% for macroadenomas. Clinical features suggestive of significant pituitary enlargement, such as increased headaches, or vision disturbance, warrant evaluation by a visual field exam (and/or a non-contrast pituitary MRI). Bromocriptine can be reinitiated, during pregnancy, for significant tumor enlargement. 

How Long Should a Prolactinoma Patient be Treated?

Most studies recommend a treatment duration of at least 2 years. For select patients who have maintained normal prolactin levels for ~ 2 years, and who have minimal residual tumor, by MRI after treatment, consideration can be given to a drug taper or trial off of medications. Close PRL follow-up is required, however, based on the high risk of recurrent hyperprolactinemia (~50-60%), with most recurrences occurring within the first 1-2 yrs. In cases of dopamine agonist re-initiation, or long-term use, patients should be maintained on the lowest possible dose. 

Are There Any Long-Term Risks Associated with Dopamine Agonist Use?

Recent studies of Parkinson’s patients on high-doses of cabergoline (>3 mg/day for >6 months) reported an increased risk of valvular heart disease. Limited studies in pituitary patients, however, have been reassuring, and have generally not shown an increased risk of valvular heart disease with the standard doses used to treat prolactinomas (<2 mg/week). These risks are not associated with bromocriptine use. 

 

What is a Gonadotrope Tumor? 

Gonadotrope tumors, or non-functioning adenomas, are pituitary tumors not associated with clinical syndromes of hormone excess, and are most commonly derived from the gonadotrope (FSH and LH) cells.

How Common Are Gonadotrope Tumors? How Do They Typically Present?

Gonadotrope, or null cell tumors, account for ~40% of all pituitary tumors. Middle-aged males are more commonly affected (?diagnosed) than females. The majority of these tumors are macroadenomas (>1 cm) at the time of diagnosis, hence patients most commonly present with signs and symptoms of mass effects, including:

• Headaches
• Vision loss or double vision
• Loss of Pituitary Hormone functions-most commonly sex steroid production (hypogonadism) and growth hormone deficiency

What Causes Gonadotrope Tumors?

The etiology of these non-functional pituitary tumors is still not well understood, although a number of candidate genes from among tumor suppressors, tumor activators (oncogenes), and altered signaling pathways have been identified. This is an active area of basic pituitary research, particularly in Dr. Margaret Wierman’s lab, at the University of Colorado.

How are Gonadotrope Tumors Diagnosed? 

The presumptive diagnosis of a Gonadotrope Tumor is based on the radiological finding of a pituitary mass (consistent with an adenoma) in a patient who otherwise does not have clinical or lab testing evidence for a “hypersecretory” tumor of another cell type. Of note: very rarely do these tumors present with symptoms caused by excess FSH/LH secretion, such as hyper-ovarian syndrome (in females) and testicular enlargement (in males). The diagnosis is ultimately established by an expert neuropathologist’s evaluation of the resected tumor.

How are Gonadotrope Tumors Treated?

Transsphenoidal surgery is the preferred treatment for most all patients with a large non-functional pituitary adenoma, particularly if associated with mass effects. For patients with small tumors, without adverse effects, a “watchful waiting” approach with intermittent MRI testing is as acceptable alternative.

How are Gonadotrope Tumor Patients Followed? What is the Risk of Recurrence?

Clinical assessment, laboratory evaluation and radiological imaging are the mainstays for following patients. In general, most patient are followed 3 months after surgery and then annually for evidence of persistent or recurrent disease, and to assess pituitary hormone function. The risk of recurrence, for a patient who has undergone a complete tumor resection (approximately 50-60% of patients) is estimated at 15-20% at 10 years.

What are Additional Treatment Options for Gonadotrope Patients?

For patients with persistent or recurrent tumors, treatment options include: repeat surgical resection (for tumor confined to the sella), or radiation therapy which is excellent at controlling tumor growth. Unfortunately, there are yet no medical therapies to treat these tumors.

What is Acromegaly? 

Acromegaly is a disorder of too much growth hormone (GH) in adults, and is caused by a non-cancerous tumor of the pituitary gland in >95% of cases.

What Signs/Symptoms Commonly Occur in Acromegaly? 

The common signs and symptoms of acromegaly are caused by the growth-promoting effects of GH on bone, soft tissues, cartilage and organs, and include:

• Increased size of hands and feet 
• Boney growth of the brow and lower jaw 
• Headaches
• Increased sweating and oily skin
• Fatigue
• Spacing of teeth
• Soft tissue swelling/enlargement (e.g., tongue, lips, hands and feet)
• Organ enlargement (heart, spleen, thyroid, liver) 
• Muscle weakness 
• Arthritis and joint pain
• Deepening of the voice
• Nerve entrapments (Carpal tunnel syndrome)
• Hormone deficiency (especially low testosterone in men or low estrogen in  women) from tumor compression on the normal pituitary gland
• Vision problems
• Excess body hair (hirsutism) in women

What  Medical Complications Occur with Acromegaly?

Too much growth hormone can affect many organ systems and cause multiple medical problems including:

• High blood pressure 
• Insulin resistance-impaired glucose tolerance and diabetes mellitus
• Heart diseases including: an enlarged heart, heart failure, valvular heart disease and an irregular heart rate (arrhythmia) 
• Elevated lipids, particularly total cholesterol and triglycerides
• Obstructive sleep apnea
• Increased risk for colon polyps and colon cancer
• Osteoporosis and bone fractures

How Common is Acromegaly? 

Acromegaly occurs in 3-4 persons per million population. Males and females are equally affected. 

How is Acromegaly Diagnosed?

Acromegaly is diagnosed by the presence of classical signs and symptoms of GH excess AND a blood test showing an elevated insulin-like growth factor-1 level (IGF-1). IGF-1 is a hormone made by the liver in response to GH, and is the primary mediator of GH excess. An oral glucose tolerance test, which fails to suppress GH levels, is also sometimes used to confirm acromegaly in cases of equivocal IGF-1 levels.

How are GH Tumors Best Visualized?

GH-secreting pituitary adenomas are best visualized with a contrast-enhanced pituitary Magnetic Resonance Image (MRI), with >75% of cases being large (>1 cm) at the time of diagnoses.

How is Acromegaly Treated?

Transsphenoidal surgical resection, by an experienced neurosurgeon, is the first-line therapy for most patients. Surgery is generally curative for small tumors (>80%), but is less likely to be curative for macroadenoma (<50%), or if the tumor is invading the areas next to the pituitary called the cavernous sinus. For patients not cured by surgery, additional medical therapy is often required.

What Are Medical Treatment Options for Acromegaly? 

There are two general classes of medical therapies for acromegaly: Somatostatin analogs and a growth-hormone antagonist. The long-acting somatostatin analogs, sandostatin®LAR and Somatuline®Depot (Lanreotide), are generally first-line medications, and are effective in normalizing IGF-1 levels in upwards of 75% of patients. In general, the likelihood of IGF-1 normalization varies inversely with the extent of the IGF-1 elevation. Somatostatin analogs constrain tumor growth in >90%, and shrink tumors (mild to moderately) in upwards of 50% of patients. For patients whose IGF-1 level is not normalized with a Somatostatin analog, Somavert® (pegvisomant), a growth hormone antagonist, can be added and is effective at normalizing IGF-1 in the majority of patients (>90%), but does not affect tumor growth. Lastly, Cabergoline (a dopamine agonist) can be tried in a subset of patients with small residual tumors, although normalizes IGF-1 in only ~10% of patients.

What are Some Possible Side Effect of the Somatostatin Analogues? 

Sandostatin Analogs  (Sandostatin®LAR and Somatuline®Depot (Lanreotide)

• Stomach cramps, nausea bloating and greasy stools can initially develop in ~30% of patients, although these symptoms usually resolve after the first few months.
• Short-term decreases in insulin secretion that can rarely make diabetes worse.
• Injection site pain: minimized by allowing medication to warm to room temperature before injecting.
• Gallstones or sludge develop in ~ 20–30% of patients, but only 1% patients/year develop symptomatic gallstones.

Growth Hormone Antagonist (Somavert®, Pegvisomant)

• Elevated liver function tests (transaminitis) in 5%, but usually transient.
• Injection site reactions

Are There Significant Difference in the Long-Acting Somatostatin Analogues?

The somatostatin analogs have similar administration schedules (~monthly), efficacies regarding symptomatic improvement and normalization of IGF-1/GH levels, and side-effect profiles. Somatuline ® Depot (Lanreotide) has the advantage of being supplied as a pre-filled syringe that can be administered at home, by the patient or a family member, as a deep subcutaneous shot, rather than an intramuscular shot as with the other long-acting sandostatin formulations. 

What is the Role of Radiation Therapy in the Treatment of Acromegaly?

Radiation therapy is generally third-line therapy, if medical and surgical treatments fail to normalize the IGF-1 level, although it can also be used to decrease the need for life-long medication. Control of tumor growth is rapid after radiation therapy, although normalization of GH hyper-secretion usually takes years. Medical therapy, with either Somatostatin analogs and/or Somavert®, is usually required during this transition period.

What Other Medical Conditions Should be Evaluated in Acromegalic Patients?

Acromegalic patients, at the time of diagnosis, should be evaluated for the potential problems of: an enlarged heart, leaky heart valves, prediabetes or diabetes, high cholesterol or triglyceride levels, obstructive sleep apnea, cardiac disease, osteoporosis and colonic polyps and treated/followed accordingly. 

How is Acromegaly Best Monitored? What Defines Disease Control? 

The assessment of disease activity in acromegaly is based on clinical, biochemical and radiologic evaluations. Disease control is defined as the absence of the clinical signs/symptoms of GH excess (e.g., headaches, sweating, joint pain, fatigue), and the normalization of IGF-1 and GH levels (random levels or after an oral glucose tolerance test). In general, a pituitary MRI is obtained at 3 month post-op and then annually for the first several years. Clinical assessment and hormone testing are initially performed at 3-6 month intervals, particularly during drug titrations and the active disease phases. 

What Sign and Symptoms are Likely to Improve with Successful Treatment?

Surgical resection of macroadenomas usually improves conditions associated with mass effects, such as vision defects, pituitary hormone deficiencies and headaches, although the later may persistent with continued GH/IGF-1 elevations. Marked improvement in fatigue, sweating, soft tissue swelling, headaches and carpal tunnel syndrome occurs with normalization of GH/IGF-1 levels. In addition, improvement in hypertension, insulin resistance, dyslipidemia and sleep apnea are common with successful treatment, in the absence of additional risk factors for these conditions. Lastly, boney overgrowths and advanced arthritic changes do not regress with treatment.

What is Cushing’s Syndrome? Cushing’s Disease?

Cushing’s syndrome is a general term for the disease complex caused by prolonged exposure of the body to high cortisol levels (hypercortisolism) of any cause. Cushing’s disease is a specific term for hypercortisolism due to a pituitary tumor. 

What are the Problems Caused by Hypercortisolism?

Too much cortisol chronically can have multiple adverse affects on the body, including:

• Central weight gain/obesity
• Fatigue
• High blood pressure (hypertension) 
• Insulin resistance/impaired glucose tolerance/diabetes 
• High Cholesterol (hypercholesterolemia and triglycerides) 
• Bone loss (osteopenia/osteoporosis) and bone fractures
  
• Low sex steroids (testosterone and estrogen)
  
• Irregular or loss of periods (amenorrhea)
  
• Infertility
• Depressed mood/anxiety/irritability
• Depressed immune system and risk for infections
• Blood Clots

How Common is Cushing’s Syndrome and Cushing’s Disease?

Cushing’s syndrome is common, and is most often due to chronic oral steroid use for inflammatory diseases (e.g., asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease) or after organ transplantiation. Conversely, Cushing’s disease is rare, with a prevalence of 2-4 per million population, and most commonly affects middle-aged women.

What Signs/Symptoms are Most Suggestive of Cushing’s Disease? 

Cushing’s disease has a varied presentation, including diseases that are common in the general population, such as obesity, diabetes, high blood pressure and hypercholesterolemia. Among the more specific signs and symptoms of Cushing’s disease are:

• Facial fullness (moon facies) and redness
• Spontaneous bruising on the arms and legs
  
• Abnormal fat pad collections on back of neck and above the clavicle
  
• Thin, fragile skin 
  
• Wide (>1 cm), dark purple stretch marks on the abdomen, thighs, and underarms
  
• Muscle weakness (i.e., inability to get out of a chair without using hands)
  
• Spontaneous bone fractures (ribs and spine most commonly)

Are all endogenous (made by the body) forms of hypercortisolism caused by a tumor?

No, and this makes the diagnosis of Cushing’s disease particularly challenging because a number of conditions can stimulate the adrenal gland to secrete excess cortisol. These conditions are called ‘pseudo-Cushing’s disease, and include:  

• Active depression 
  
• Alcoholism 
  
• Uncontrolled diabetes
  
• Sleep apnea
• Marked physical or psychological stressors 

Who and How Should People be Screened for Cushing’s Disease?

Screening for Cushing’s disease is recommended only for those patients with multiple, specific signs and symptoms of hypercortisolism (as detailed above). The three screening tests include: 

• 24 hr urinary cortisol level 
  
• A 1 mg dexamethasone suppression test. 
  
• A midnight salivary cortisol test 

Importantly, a number of medications may interfere with the screening tests (e.g.., estrogens, seizure medication, etc.), hence all your medications should be discussed with your endocrinologist.

What is the Next Step for a Patient with A Positive Screening Test?

Cushing’s disease is supported by positive screening tests, particularly if there are multiple abnormal tests from among the different screening tests. Following positive screening tests, additional tests will be performed to help localize the tumor, and may include:

• Adrenocorticoptropin (ACTH) level. 
  
• High dose dexamethasone suppression test. 
  
• Pituitary MRI-detects the pituitary tumor in ~50% of cases.
  
• Inferior Petrosal Sinus Sampling Test (for a suspected pituitary source, when the MRI does not clearly show a tumor). This is an invasive procedure that must be performed in specialist centers.

What is the Next Step for a Patient with a Negative Screening Test? 

For patients with signs and symptoms of hypercortisolism, but negative screening tests, consideration should be given to repeat screening in 3-6 months, particularly if the symptoms are persistent or progressive.

What Other Conditions Cause an Elevated ACTH and/or Cortisol Levels? 

Elevated cortisol can also occur from ACTH-secreting tumors that are located outside the pituitary gland, which is called Ectopic Cushing’s Syndrome. This occurs in an estimated ~10-15% of Cushing’s cases, and is suggested by the clinical presentation, laboratory testing and imaging studies. These tumors are most commonly located in the chest region (i.e., bronchial carcinoid, thymic carcinoid, lung cancer) or the abdomen, but are often difficult to find because the tumors are so small. Initial anatomical imaging with a chest and abdomen CT scans are first-line tests, in addition to functional studies (i.e., octreotide scan and PET scan). Lastly, benign adrenal tumors may make excess cortisol (but not ACTH), and are best identified by an abdominal CT.

How is Cushing’s Disease Treated?

Cushing’s disease is best treated by transsphenoidal resection of the pituitary tumor. Surgical curative rates are high for microadenomas; estimated at 80-85% over 10 yrs. In the cases of large ACTH tumors, or clinically-silent ACTH-secreting tumors, (which comprise <20% of tumors), however, resection is less likely to be curative (<50%). 

How Are Cushing’s Disease Patient’s managed After Transphenoidal Surgery?

After a successful surgical resection, Cushing’s disease patients require oral glucocorticoids (i.e., prednisone or hydrocortisone) for several months, until the non-tumorous ACTH-secreting cells, in the pituitary gland, resume their normal function. Generally, marked clinical improvement is noted during the first several months-years after transsphenoidal resection, in conjunction with decreased systemic cortisol levels. These improvements may include marked weight loss, blood pressure control, insulin resistance or diabetes, and/or the high cholesterol levels.

What are Options for Cushing’s Patient with Persistent Hypercortisolism?

For patients with evidence of persistent or recurrent hypercortisolism, treatment options include: repeat surgical resection (for tumors located in the sella), medical therapies and radiation therapy. Regarding medical therapies, ketoconazole is generally first-line therapy, although it has a limited ability to normalize the cortisol level, and must be monitored closely for side effects, particularly elevated liver function tests. Additional medical therapies, including etomidate, metyrapone and mitotane are also generally limited by various factors, including: drug availability, route of administration, efficacy, and/or adverse drug effect profile. Lastly, for patients with life-threatening hypercortisolemia that is either not surgically resectable, or responsive to medications, bilateral adrenal gland removal is an option.

What is the role of Radiation Therapy in the Treament of Cushing’s Disease?

Radiation therapy is generally third-line therapy for patient who have failed medical therapies and surgical therapy (or are not good surgical candidates). 

  

What Is a Rathke Cleft Cyst? 

Rathke's pouch is a normal remnant of pituitary gland development. Occasionally, this remnant fills with fluid, and gives rise to a benign cyst called a Rathke cleft cyst (RCC). 

How Common are Rathke Cleft Cysts?

Rathke cleft cysts are common and account for ~1-2% of primary intracranial tumors. There is a female predominance (2:1-♀:♂), and a mean age of diagnosis of 36 years. 

How Do Patients with Rathke Cleft Cyst Typically Present?

The vast majority of Rathke cleft cyst are small (<1 cm) and do not cause symptoms. Large cysts (>1 cm) may cause problems related to mass effects, such as headaches, visual disturbances, or pituitary gland dysfunction. The most common pituitary hormone abnormalities are an elevated prolactin level (hyperprolactinemia) and low sex steroids (hypogonadism) in 30-60%.

Is There a Headache Patterns that Best Distinguish a Rathke Cleft Cyst?

Headaches from RCCs are generally attributed to stretching of the dural membrane that covers the pituitary gland. Studies have shown that RCCs can be associated with all types of headache patterns, although episodic frontal headaches are the most common.

How are Rathke Cleft Cysts Diagnosed?

RCCs can often be diagnosed by MRI, based on their classic imaging location between the anterior and posterior pituitary lobes. The pathologist’s examination of the surgical specimen, and the finding of ciliated epithelium cells establishes the diagnosis of a RCC. 

How are Rathke Cleft Cysts Managed?

Rathke cleft cysts associated with headaches, vision loss, or pituitary hormone deficiencies are best treated with transsphenoidal surgical resection. Conservative decompression is preferred over aggressive cyst wall resection to minimize the risk of pituitary dysfunction. Patients with small, asymptomatic cysts do not require treatment, but can be managed conservatively with periodic MRI imaging. 

What are the Surgical Benefits for Rathke Cleft cyst?

In his series of 82 patients treated at UCH, neurosurgeon-Dr. Kevin Lillehei observed symptomatic improvements in headaches and vision problems in 71% and 83% of patients, respectively. In addition, pre-operative hormone deficiencies normalized in a significant percentage of patients after surgery.

What are the Surgical Risks for Rathke Cleft Cyst?

With an experienced neurosurgeon, transsphenoidal surgery for RCC resection is associated with low complicate rates. Specifically at this institution, the neurosurgical complication rates of: cerebral spinal fluid, symptomatic hyponatremia and permanent diabetes insipidus were observed in 2%, 5% and 0% of patients, respectively. There were no major complications (i.e., vision loss, meningitis, strokes) or deaths.

What is the Follow-up for Recurrence of Rathke Cleft Cysts?

Clinical assessment and imaging are performed 3 months after surgery, and then annually for the first few years.

What is the Risk for Recurrence of Rathke Cleft Cysts?

Recurrence rates for RCC are relatively low with experienced neurosurgeons. At this institution, the recurrence rate is ~10.7% at a median follow-up period of 43 months. The pathology findings of squamous metaplasia or an infected cyst (rare) are associated with higher recurrence rates.

  

What are Craniopharyngiomas?

Craniopharyngiomas are benign (non-cancerous) tumors that are thought to arise from disorders of pituitary gland development.

How Common are Craniopharyngiomas? 

Craniopharyngiomas comprise ~3-5% of all intracranial tumors, and ~10% of all pediatric tumors. They are most common in children between the ages of 5-15 yrs, but also occur in adults (ages 50-75 yrs). Craniopharyngiomas occur equally in males and females.

How Do Craniopharyngiomas Typically Present?

The presentation of craniopharyngiomas varies by age of onset, size, and involvement of adjacent brain structures. These tumors are typically large at the time of diagnosis (2-4 cm). Children and adolescences commonly present with headaches, vision disturbances, growth failure, and delayed puberty. In addition, increased intracranial pressure from cerebral spinal fluid outflow obstruction (obstructive hydrocephalus) may result in nausea, vomiting and altered mental status. Adults commonly present with mass effects (e.g., headaches, vision loss or double vision) and loss of pituitary hormone function (hypopituitarism). Diabetes insipidus, which is characterized by excessive urination and thirst, occurs in 15-20% of cases, and is due to loss of a hormone called vasopressin (or anti-diuretic hormone [AHD]).

How are Craniopharyngiomas Diagnosed? What are The Different Types?

Craniopharyngiomas are ultimately diagnosed by experienced neuropathologists examining the surgically-resected tumor, but can often be suggested by their imaging characteristics (on MRI) in the appropriate clinical context. Craniopharyngiomas extend above the sella region (suprasellar) in the majority of cases (>95%) and are made up of two sub-types; adamantinomatous and papillary. The adamantinomatous variant is more common in young population, typically has a cystic or mixed solid/cystic appearance on MRI, and is generally more invasive than the papillary sub-type. In addition, it frequently contains calcium deposits, which can be seen on CT scans or plain X-rays. Conversely, the papillary variant of craniopharyngiomas is much more common in adults, is typically solid-appearing on MRI, and is rarely associated with calcifications.           

How are Craniopharyngiomas Treated?

Treatment options vary by the patient’s age, tumor size, and compressive symptoms. In general, surgical resection is first-line therapy in most cases. The surgical approach (craniotomy versus transsphenoidal) depends on the size and suprasellar extent of the tumor. Gross-total resection is feasible only for relatively small tumors. Although craniopharyngiomas are benign, they have irregular margins and a tendency to adhere to critical nearby brain structures, particularly the hypothalamus. As such, sub-total resection, followed by radiation therapy is generally preferred over aggressive gross-total resection of large tumors, to minimize the potential complications of damage to the hypothalamus, which include: excessive eating (hyperphagia), severe obesity, cognitive impairment, lethargy, and disorders of thirst, water/electrolyte balance, temperature regulation and sleep.

What is the Role of Pituitary Hormone Replacement in Patients with Craniopharyngiomas?  

Patient with craniopharyngiomas typically have a loss of one of more pituitary hormones, with growth hormone (GH) and gonadotropin deficiencies being the most common.  Thyroid, adrenal and anti-diuretic hormone deficiencies may also occur in patients with large, aggressive tumors, or after treatment. Hormone replacement is readily achieved with oral medications (except GH), and is frequently needed life-long.

How Effective is Radiation Therapy? 

Craniopharyngiomas are radiosensitive and respond to radiation therapies
(i.e., conventional fractionated radiation, stereotactic radiosurgery and fractionated stereotactic radiosurgery). Indications for radiation therapy include persistent or recurrent tumor, that are not amenable to surgical resection.

What are the Risks or Radiation Therapy?

The risks of radiation therapy include a transient enlargement of the cystic components of the craniopharyngiomas (~10%). Radiation therapy also carries a significant risk of hypopituitarism, estimated at 50% at 5-10 years, for conventional therapy. Radiation therapy is associated with secondary brain tumors (e.g., meningiomas and astrocytomas) at an estimated risk of 2.4% at 20 yrs., for conventional radiation. Lastly, the potential long-term effects of radiation therapy on cognition, memory and stroke risks are rare, but not well defined in the adult population.

Are Other Treatments Available for Craniopharyngiomas Following Surgery?

In the case of purely cystic tumors, consideration can be given to surgical decompression, followed by radiation into the cavity (brachytherapy), or less commonly-administering chemotherapy into the cavity (bleomycin). These approaches, however, are less commonly performed in adult patients.

How Should Patients with Craniopharyngiomas be Followed?

The recommended frequency of clinical evaluation, anterior pituitary hormone testing, and imaging depends on the disease severity and status. In general, clinical assessment and hormone testing are performed every 3-6 months, and MRI is recommended every 6-12 months. This interval increases for patients with clinically stable disease, and patients on established pituitary hormone replacement therapies.         

What is the Role of Pituitary Surgery in the Treatment of Pituitary Disorders? 

Surgical resection is generally first-line therapy for most pituitary tumors, except prolactinomas, which are best treated medically.

What are the Major Advantages of Pituitary Surgery?

There are several advantages to surgical resection of a pituitary adenoma, including:

• Immediate tumor decompression and improvement of mass affects, such as headaches and vision disturbances.
• Immediate lowering of any elevated hormone levels caused by the tumor.
• Curative for most pituitary microadenomas and many macroadenomas.
• Normalization of any pre-existing pituitary hormone dysfunction (from compressive effects on the pituitary stalk or the normal pituitary gland).
• In cases of pituitary tumors that cannot be entirely removed, surgical resection decreases the tumor burden, thereby allowing for increased success of medical therapy and/or lowered medical costs.

What Are the Major Surgical Approaches to Pituitary Adenomas?

There are two general surgical approaches to a pituitary tumor.  The vast majority include a transsphenoidal approach (>95%), which takes advantage of the accessibility of the pituitary (sellar region) via the nasal cavity. This approach is usually the procedure of choice because it is less invasive, has fewer complication rates, and is associated with a faster recovery time. The transcranial approach (used much less commonly) involves an incision through a part of the skull and is used for larger tumors, with suprasellar extension that cannot be adequately removed through the transsphenoidal approach.

How Long Have Transphenoidal Pituitary Surgeries Been Performed?

Transsphenoidal surgery was first pioneered by Dr. Harvey Cushing, of Cushing’s disease namesake, in the early 1900’s. The technique has advanced in recent years to include a nasal, instead of a sub-labial (under the lip) approach, as well as intra-operative navigational and endoscopic techniques (used in select cases).

What are the Risks of Pituitary Surgery?

The complication rates, with experienced neurosurgeons, such as at the University of Colorado Hospital is low. Possible minor complications include:

• Diabetes Insipidus (DI) a disorder in which there is an abnormal increase in urine output, fluid intake and thirst, and is caused by a lack of anti-diuretic hormone release from the posterior pituitary gland. This is usually a transient problem, from trauma to the stalk/posterior pituitary gland and can be briefly treated with an anti-diuretic hormone (DDAVP) as either an oral medication or a nasal spray. It is a permanent condition in <1% of cases. 
• Cerebral Spinal Fluid Leak- caused by tumor or surgery-related damage to the thin membrane that covers the pituitary gland. The leak may be repaired intra-operatively (most commonly), or require the placement of a lumbar drain after the surgery, depending on its extent.
• Sinusitis-is usually mild and can be managed conservatively. 
• Epistaxis/Septal perforation
• Hyponatremia-is usually caused by a transient disturbance of the posterior-pituitary hormone-antidiuretic hormone (ADH). This condition is routinely evaluated at the 2 week endocrine visit.
• New Anterior Pituitary Deficiency-is uncommon with an experienced neurosurgeon.
• Very Rare Complications include: loss of vision (damage to optic chiasm), double vision (damage to cranial nerves), major bleeding, meningitis (infection of the dural membrane), stroke (damage to carotid artery), permanent neurological deficits, or death (<0.5%)

What are the Primary Factors that Determine Pituitary Surgery Success?

The experience of the neurosurgeon is the single most important factor in the success of the pituitary surgery. Dr. Kevin Lillehei, head of neurosurgery at the University of Colorado, Denver has performed >1200 transsphenoidal surgeries to date. Additional factors which determine surgical success rates include the pituitary tumor size and the degree of invasiveness.

What Should I Expect Before and Immediately After Surgery?

In general, the surgery last 3 hrs. Patients typically spend a day/night in the neuroICU for close monitoring. They are then transferred to a surgical floor bed for additional monitoring, and are typically discharged 2-3 days after surgery. Common problems during the first few weeks after surgery include: general fatigue, mild headaches and nasal/sinus congestion, although these problems generally resolve within a month.

What Should I Expect Long-term After Surgery?

Generally, headaches attributable to large pituitary tumors improve in the vast majority of patients (>85-90 %). In addition, vision improves in most patients with pituitary tumors complicated by optic nerve compression, but varies by vision loss duration and severity, and may take up to 1 year to fully recover. Lastly, any pre-existing hormone dysfunction, caused by a large tumor compressing the normal pituitary gland or stalk may improve after surgery in upwards of 50% of patients. This is best assessed by blood testing at ~3 months after the pituitary surgery.  

 What General Precautions Will I have to Take After Surgery?

General precautions after pituitary surgery include: the avoidance of actions that increase intracranial pressure such as: blowing your nose, sneezing with your mouth closed, sipping through a straw, heavy lifting or vigorous exercise. These precautions are usually recommended for a period of 1 month after the surgery. Air travel is general restricted until 2 weeks after the surgery.  In addition, most anti-platelet therapies (e.g., aspirin and NSAIDS) and anti-coagulants (i.e., warfarin) are held for a period of time after the surgery.

How Will I Subsequently Be Monitored After Pituitary Surgery?

As a routine part of post-operative care, patients will be seen 2 weeks after surgery, by the neurosurgery and endocrinology teams, to assess progress and to exclude complications (e.g., hyponatremia and sinusitis). A 3 month post-op MRI and pituitary hormone testing are also routinely performed. Subsequent testing and imaging will generally be performed on an annual basis, unless indicated by patients who have persistent tumor and who may require additional medical therapies and closer monitoring.

How Does Radiation Therapy Work?

Radiation therapy uses high energy waves (or particles) to damage tumors and stop them from dividing.

What is the Role of Radiation Therapy in Treating Pituitary Diseases?

External beam radiation therapy has been used in the treatment of pituitary diseases for several decades. In general, radiation therapy is used to control pituitary tumor growth and/or hormone hypersecretion in patients who are not adequately treated by surgery or medical therapies.

What Are the Different Types of Radiation Therapies Used to Treat Pituitary Diseases? 

The different techniques vary primarily in the energy source used to generate the radiation (i.e., photons or protons), and their method of delivery. 

• Conventional External Beam Radiation
• Utilizes a 3-field crossfire technique to focus ionizing irradiation to the pituitary region.
• Requires that a patient wear a mask for immobilization
• Delivers a standard dose (4500-5000 cGy) in small increments, and over a period of ~5-6 weeks.
• Stereotactic Radiation Therapy 
• Represents improved immobilization, radiation-beam focusing and imaging techniques. 
• Stereotactic irradiation can be given as a single-fraction stereotactic radiosurgery (SRS), or delivered as fractionated doses.
• Example include: gamma knife (cobalt energy source) and Novalis brainLAB and Cyberknife (Linear accelerator energy sources). 
• Proton Beam Radiotherapy-requires a cyclotron to generate the high-energy protons, is very costly, and is limited to a few centers in the U.S.

What Forms of Radiation Therapy are Currently Available at University Hospital to Treat Pituitary Tumors?

University Hospital has one of the best Radiation Oncology Departments in the country with expertise in the management of pituitary diseases and state-of-the art radiotherapy technologies, including: conventional external beam radiation therapy and the frameless stereotactic radiosurgery ( Novalis BrainLAB).

What Factors Decides What Type of Radiation Therapy is Used to Treat a Pituitary Tumor?

The main determinants of the type of radiation therapy used are the tumor size and proximity to the optic chiasm. Specifically, stereotactic radiosurgery is generally limited to relatively smaller tumors (<4 cm diameter), and tumors with >5 mm margins from the optic nerve.

How Effective is Radiation Therapy in Controlling Pituitary Tumor Growth? Hormone Secretion?

All forms of radiotherapy are effective in rapidly controlling pituitary adenoma growth, with progression-free survivals of 80-90% at 10 years. The effects of radiation therapy on normalizing hormone hypersecretion, however, are delayed by several months to years. For example, the normalization of GH/IGF-1 levels is ~30-50% in acromegalic patients after ~5-10 yrs of conventional radiation therapy. Normalization of hormone hypersecretion may be shorter with stereotactic radiosurgery, although this may be a function of a smaller initial tumor sizes and hormone levels.

Is there an advantage of one type of radiation therapy over another?

Based on the one-time dose, stereotactic radiosurgery has a convenience advantage over conventional radiation therapy, which is typically administered over ~25 sessions. In addition, with stereotactic radiosurgery, the use of a single high radiation dose, shaped to conform to the tumor shape, has the theoretical advantages, over conventional radiation therapy, of more rapid tumor control and the sparing of normal brain structures from radiation effects. To date, however, no well-designed scientific studies have been performed comparing the efficacy and complication rates of radiosurgery to conventional radiotherapy.

Do Any Pituitary-Specific Medications Need to be Discontinued Prior to Radiosurgery?

Consideration should be given to temporarily discontinuing medications that decrease pituitary tumor growth prior to radiation therapy (i.e., somatostatin analogs and dopamine agonists), in order to maximize the chances for treatment success.

What are the Potential Short-Term Complications of Radiation Therapy?

The most common short-term side effects include: fatigue, nausea, mild headaches, and temporary hair loss at the radiotherapy portals of entry.

What are the Potential Long-Term Complications of Radiation Therapy?

Because cells of the normal pituitary gland can also be damaged and stop dividing in response to by radiation, the loss of normal anterior pituitary hormone function is the most common late complication of radiation therapy. It occurs in an estimated 30-60% of patients 10 years after conventional radiation. The loss of anterior pituitary hormones generally develops in a predictable order: GH~gonadotrophin >ACTH ~ TSH, and can be monitored by regular blood tests.

Regarding important nerves near the pituitary gland, the optic chiasm (which controls vision) is sensitive to radiation therapy, while the cranial nerves (which control eye movement) are generally resistant to adverse effects of radiation therapy. Despite the sensitivity of the optic nerve to radiation, the risk of vision impairment, with modern technology and careful radiation dose planning is rare (<1%).

The development of secondary brain tumors, particularly meningiomas and gliomas, is associated with conventional radiation therapy with an estimated risk of 2.4% at 20 yrs.  Data regarding the potential risk of secondary brain tumors with stereotactic radiosurgery is theoretically less, although this has not yet been proven. In addition, an increased stroke risk has been reported in pituitary patients treated with conventional radiation treatment, although the causal relationship of radiation therapy to stoke remains to be established, as there are other potential risk factors (i.e., aggressive tumor type and/or hypopituitarism). Lastly, the adverse effects of radiation, long-term, on cognition and psychological function, are thought to be uncommon in adults, but are still not well studied.

How Should a Pituitary Patient Who Has Received Radiation Therapy be Followed After Treatment?            

In anticipation of the potential loss of normal pituitary function, biannual blood tests should be performed by your endocrinologist, and hormone replacement therapy started as indicated. In addition, because of the risk of a secondary brain tumor, periodic pituitary MRI imaging, ~ every 5 years, is recommended.