• Development of a novel patient-reported measure for acromegaly: the Acro-TSQ
• A Consensus on the Diagnosis and Treatment of Acromegaly Comorbidities: An Update
• Systemic Complications of Acromegaly and the Impact of the Current Treatment Landscape: an Update
• Safety and tolerability of pasireotide long-acting release in acromegaly-results from the acromegaly, open-label, multicenter, safety monitoring program for treating patients who have a need to receive medical therapy (ACCESS) study

• Mifepristone Increases Thyroid Hormone Requirements in Patients With Central Hypothyroidism: A Multicenter Study

• Hypercoagulability in Cushing’s syndrome, prevalence of thrombotic events; a large single-center retrospective study
• Use of late-night salivary cortisol to monitor response to medical treatment in Cushing’s disease
• Hypercortisolemia Recurrence in Cushing's Disease; a Diagnostic Challenge
• Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing's syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial
• Long-term efficacy and safety of once-monthly pasireotide in Cushing's disease: A Phase III extension study
• Safety and Efficacy of Subcutaneous Pasireotide in Patients With Cushing's Disease: Results From an Open-Label, Multicenter, Single-Arm, Multinational, Expanded-Access Study
• Pituitary-Directed Therapies for Cushing's Disease
• Late-night salivary cortisol may be valuable for assessing treatment response in patients with Cushing's disease: 12-month, Phase III pasireotide study

• Fertility and pregnancy in women with hypopituitarism: a systematic literature review
• Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline

• A tale of pituitary adenomas: to NET or not to NET: Pituitary Society position statement
• Clinical outcomes in male patients with lactotroph adenomas who required pituitary surgery: a retrospective single center study
• Predictors of silent corticotroph adenoma recurrence; a large retrospective single center study and systematic literature review
• Clinical profile of silent growth hormone pituitary adenomas; higher recurrence rate compared to silent gonadotroph pituitary tumors, a large single center experience

• Magnetic resonance imaging in the management of prolactinomas; a review of the evidence
• Dopamine agonist therapy induces significant recovery of HPA axis function in prolactinomas independent of tumor size: a large single center experience

• High prevalence of adrenal insufficiency at diagnosis and headache recovery in surgically resected Rathke's cleft cysts — a large retrospective single center study

Pituitary disease is most often caused by benign tumors (adenomas). Increasing use of brain MRIs has increased the incidental discovery of adenomas.

Adenomas are classified as either:

• Functioning — overproducing one or more hormones
• Nonfunctioning

Other causes of pituitary disorders include infiltrative, immunologic, ischemic, hypothalamic and metastatic disease, as well as trauma.

Symptoms vary widely. Patients may present to several medical specialties with symptoms such as:

• Obstetrics and gynecology: Galactorrhea, menstrual irregularities, infertility, hirsutism
• Urology: Sexual dysfunction, hypogonadism
• Neurology: Headache, proximal muscle weakness, carpal tunnel syndrome
• Ophthalmology: Blurred vision, visual field loss, diplopia
• Dermatology: Dry, oily, diaphoretic skin
• Orthopaedics and rheumatology: Joint pain, joint/bone abnormalities
• Sleep specialists: Sleep apnea or increased snoring
• Family practice and internal medicine: Any of the above; also polyuria, fatigue, depression, hair loss, weight change

Here is a partial list of common symptoms of pituitary deficiency and excess.

Pituitary deficiency

Central adrenal insufficiency:

• Deficiency: Adrenocorticotropic hormone (ACTH)

• Symptoms: Fatigue, low blood pressure, nausea, dizziness with orthostasis, weight loss

Central hypothyroidism:

• Deficiency: Thyroid-stimulating hormone (TSH)
• Symptoms: Constipation, cold intolerance, proximal muscle weakness, dry skin, memory loss, hair loss

Central hypogonadism:

• Deficiency: Luteinizing and follicle stimulating hormones (LH/FSH)
• Symptoms: Sexual dysfunction, hot flashes, menstrual irregularity in women

Adult GH deficiency:

• Deficiency: Growth hormone
• Symptoms: Lack of vigor, decreased exercise tolerance, feelings of social isolation

Diabetes insipidus:

• Deficiency: Vasopressin; also called antidiuretic hormone (ADH)
• Symptoms: Polydipsia, polyuria, nocturia

Pituitary excess

Hyperprolactinemia:

• Excess: Prolactin
• Symptoms: Galactorrhea, sexual dysfunction, menstrual irregularities

Cushing disease:

• Excess: ACTH/cortisol
• Symptoms: Moon facies, truncal obesity, purple striae, hirsutism, hypertension, diabetes mellitus, proximal muscle weakness

Acromegaly:

• Excess: Growth hormone
• Symptoms: Enlarged hands/feet/jaw, carpal tunnel syndrome, oily skin, joint pain, diaphoresis

Three questions

The nonspecific and multifaceted symptomology of pituitary disease can make diagnosis difficult. If your patient shows some of the symptoms listed above, these questions might help you identify potential pituitary disease:

1. Are there signs or symptoms of deficiencies in pituitary hormones? Hormonal deficiencies can occur in isolation or in combination.
2. Are there signs or symptoms of excess in pituitary hormones? Hormonal overproduction can occur in isolation or in combination. It can also occur in the background of other hormonal deficiencies.
3. Are there signs or symptoms of a space-occupying pituitary lesion? Clinical manifestations include headaches, visual problems (especially peripheral vision loss) and occasionally seizures or cranial nerve deficits.

Initial workup

Though a preliminary diagnosis can be challenging, a basic diagnostic workup for pituitary disease is straightforward.

• The OHSU Pituitary Center offers endocrine testing.
• We also offer advice to help referring providers with independent dynamic endocrine testing.

Lab testing

• Prolactin
• 8 a.m. serum cortisol and/or ACTH (cortrosyn stimulation test as needed)
• TSH and free T4
• Basic metabolic panel
• LH/FSH in both sexes, testosterone (men)
• IGF-1 (insulin-like growth factor-1)
• Overnight dexamethasone test, salivary cortisol and or 24-hour urine free cortisol (if clinical suspicion of Cushing’s disease)

MRI (if indicated)

Pituitary MRI (with gadolinium, if no contraindications) if a laboratory evaluation indicates the presence of pituitary disease or a space-occupying lesion is suspected.

If the workup indicates a pituitary tumor or disease, many clinicians seek the help of pituitary disease experts. Treatment typically includes a combination of medical therapy and surgery. Pituitary radiation is rare.

• Most prolactin-secreting tumors can be treated medically.
• Other tumors, if large and inducing compressive symptoms, require surgery. The most common surgical approach is through the sphenoid sinus (transsphenoidal).
• Studies have shown that surgeons who are highly experienced in this procedure obtain the highest cure rates with the lowest rates of recurrence, postoperative complications and pituitary dysfunction.
• Pituitary disease patients should be evaluated before and after surgery by a neuroendocrinologist with experience in managing neuroendocrine diseases.
• Multidisciplinary management of pituitary tumors in a high-volume center such as OHSU produces better short- and long-term clinical outcomes. At OHSU, our team includes:
  • Specialists in neuroendocrinology
  • A dedicated pituitary neurosurgeon
  • Ear, nose and throat specialists
  • Specialists in neuroradiology, neuro-ophthalmology and neuropathology

A previously healthy 50-year-old male presents to your office with several new complaints. About three months earlier, he had been given the diagnosis of Raynaud's phenomenon due to cold intolerance particularly affecting his hands.

Over the past month, he has been fatigued. He also has generalized cramping and achiness. On further questioning, he also thinks he has lost some hair on his hands, and he has had difficulty concentrating and has had some loss of libido. He has no constipation, abdominal discomfort, orthostasis, headaches or visual problems.

He has been told that many of his symptoms are consistent with depression, possibly related to the stress of being diagnosed with Raynaud's phenomenon as well as problems at work. His physical exam is unremarkable (weight is 100 kg). His CBC, metabolic panel and sedimentation rate are all normal, but his free T4 is low at 0.48 (nl 0.8 - 1.8) with a normal TSH of 1.58 (nl 0.38 - 4.70).

What’s your next step?

1. Assure the patient that the normal TSH confirms his thyroid function is adequate and that some normal people have lower than "normal" free T4 levels due to population variance.
2. Start the patient on thyroid hormone replacement and refer him for the next available endocrinology appointment for evaluation of possible central hypothyroidism.
3. Start the patient on thyroid hormone replacement (175 mcg qd based on his weight) and hydrocortisone (20 mg q a.m.). You repeat the TSH and free T4 and order the other labs as described in our Provider’s Guide to Pituitary Disorders, including a head MRI (with and without gadolinium). Refer the patient to a neuroendocrinologist to set up further endocrine testing and management.

C: Start the patient on thyroid hormone replacement (175 mcg qd based on his weight) and hydrocortisone (20 mg q a.m.). You repeat the TSH and free T4 and order the other labs as described in our Provider’s Guide to Pituitary Disorders, including a head MRI (with and without gadolinium). Refer the patient to a neuroendocrinologist to set up further endocrine testing and management.

A 45-year-old man transfers care to you two months after a 1.75-cm pituitary lesion has been discovered as part of a workup for intractable headaches (progressively worsening over the past two years).

He has no signs or symptoms of other pituitary dysfunction or visual field disturbances. Past medical history and review of symptoms is negative. He has been on a low dose of a dopamine agonist for the past two months.

You perform labs that reveal a normal chemistry panel and CBC, and normal pituitary workup as described in our Provider’s Guide to Pituitary Disorders. However, you note that two months ago, the patient's prolactin level was significantly elevated at 75 ng/ml (normal 3-29).

This has now normalized after two months of dopamine agonist treatment. The MRI from two months ago reveals a 1.75-cm noncystic pituitary lesion displacing but not splaying the optic chiasm.

What’s your next step?

1. Stay the course. The clinician that started dopamine agonist therapy had excellent instincts. The fact that the prolactin level returned to normal confirms that this is a tumor sensitive to dopamine agonist therapy. The tumor will substantially shrink in the months ahead.
2. Schedule this patient to see a neurosurgeon because this pituitary lesion is not a prolactinoma and needs to be removed!
3. Be cautious, but don't overreact. Since the prolactin level normalized relatively quickly, it would be prudent to re-image the lesion in six months to confirm that it has decreased in size. Surgery would be indicated only if the lesion continues to grow despite dopamine agonist therapy.

B: Schedule this patient to see a neurosurgeon because this pituitary lesion is not a prolactinoma and needs to be removed!

A 55-year-old man presents to your office one year after transsphenoidal resection of a 2 cm pituitary lesion that had caused significant preoperative pituitary destruction (biochemically proven).

Acromegaly and Cushing disease were adequately ruled out preoperatively. His peripheral vision has now returned to normal, but he continues to "not feel normal" despite pituitary hormone replacement. His main complaints are memory loss, diminished vigor and social isolation. He is noticing mild central obesity. He denies temperature dysregulation, constipation or diarrhea, nausea or abdominal discomfort, orthostasis, decreased libido or decreased sexual function.

His current medications include levothyroxine (150 mcg/day), hydrocortisone (20 mg q a.m.), and testosterone (7.5 g gel per day). You perform laboratory testing, which reveals a normal basic metabolic panel and CBC. His testosterone level is 515 ng/dl (normal 270-1070) and free T4 is 1.2 (normal 0.7-1.8). His one year post-op MRI reveals no residual pituitary tumor.

What’s your next step?

1. Explain to the patient that these symptoms are not related to his history of pituitary problems. Since he has had all his significant pituitary hormones optimally replaced as reflected by his lack of symptoms and normal laboratory testing, discuss with him other non-pituitary causes of his symptoms, such as depression
2. Work to maximize his thyroid, cortisol and testosterone dosing. As you do so, many of these symptoms may resolve.
3. Consider adding growth hormone (GH) replacement in this patient.

C: Consider adding growth hormone (GH) replacement in this patient.