Endo-Pituitary

Question 1

What is the difference between the anterior pituitary and posterior pituitary in relation to hypothalamus?

Answer 1

Anterior: blood supply
Posterior: nerves

The anterior pituitary is made up of glandular tissue that receives its blood supply from the hypothalamus through the hypothalamic-pituitary portal plexus, whereas the posterior pituitary consists of direct extension of neurons from the hypothalamus.

Question 2

ACTH

• Released in response to?
• What does it act on?
• What hormone is produced as a result?

Answer 2

ACTH is released in response to corticotrophin-releasing hormone (CRH) and acts on the adrenal glands to promote the synthesis and secretion of cortisol.

Question 3

TSH

• Released in response to?
• What does it act on?
• What hormone is produced as a result?

Answer 3

TSH is released in response to thyrotropin-releasing hormone (TRH) and acts on the thyroid to stimulate thyroid hormone production.

Question 4

LH and FSH

• Released in response to?
• What does it act on?
• What hormone is produced as a result?

Answer 4

LH and FSH are differentially released from the pituitary gland in response to pulses of gonadotropin-releasing hormone (GnRH). LH and FSH regulate normal male and female reproductive function.

Question 5

What regulates GH?

Answer 5

Prolactin controls lactation and is inhibited by dopamine.

Question 6

What is the posterior pituitary gland responsible for regulating?

Answer 6

The posterior pituitary gland secretes oxytocin, which is necessary for parturition, and antidiuretic hormone (ADH, also called vasopressin), which regulates water balance.

Question 7

What is the most common tumor of the pituitary gland?

Answer 7

Adenoma. It is benign.

Question 8

What is the size cutoff for a micro vs macro adenoma?

Answer 8

A tumor less than 1 cm is defined as a microadenoma, and a tumor 1 cm or larger is termed a macroadenoma

Question 9

What does a seller mass suggest?

Answer 9

It suggests a pituitary adenoma

Question 10

How do you manage an incidental pituitary mass?

Answer 10

DETERMINE:

(1) whether it is causing a mass effect
(2) whether it is secreting excess hormones,
(3) whether it has a propensity to grow and cause problems in the future

If the tumor is not causing mass effect and there is no evidence of hormone excess:
- a pituitary MRI should be repeated in 6 months for a macroadenoma and 12 months for a microadenoma to assess for growth

If no growth occurs… MRIs should be repeated every 1 to 2 years for the next 3 years and then intermittently thereafter.

*In a patient at risk for cancer or with a history of cancer, metastatic disease must be excluded.

Question 11

What is empty sella?

Answer 11

Empty sella is diagnosed when the normal pituitary gland is not visualized or is excessively small on MRI; it is a radiologic finding and not a distinct clinical condition.

Question 12

How is an empty sella managed?

Answer 12

The pituitary sella is said to be “empty” because normal tissue is not seen. The finding may be primarily due to increased cerebrospinal fluid entering and enlarging the sella, or it may be secondary to a tumor, previous pituitary surgery, radiation, or infarction. Empty sella can also occur as a congenital abnormality when the sella is normal size, but the pituitary is small. When empty sella is found incidentally on imaging, an evaluation should be completed to determine if there is a known cause for secondary empty sella and if the patient has signs or symptoms of pituitary hormone deficiency.

***A patient without signs or symptoms should be screened for cortisol deficiency and hypothyroidism with 8 AM cortisol, TSH, and free (or total) T4. A patient with signs of pituitary hormone deficiency should receive a more complete biochemical evaluation of the pituitary axes, based on the signs and symptoms found.

Question 13

Is repeat imaging required for empty sella?

Answer 13

Repeat imaging is not necessary unless indicated as surveillance for the underlying pathology that resulted in the empty sella.

Question 14

Indications for treating a pituitary tumor?

Answer 14

Change in vision due to optic chiasm compression is an indication for treating a pituitary tumor.

Indications for surgery include mass effect, particularly a visual field defect; tumor that abuts the optic chiasm; tumor growth; or an invasive tumor (invading the brain or cavernous sinus). Surgery should also be considered in a patient with a tumor close to the optic chiasm who plans to become pregnant (due to the physiologic enlargement of the pituitary associated with pregnancy).

Question 15

What are some signs/symptoms of a pituitary mass?

Answer 15

Pituitary tumors can also invade surrounding brain tissue leading to seizures and neurologic manifestations. Pituitary tumors can invade the cavernous sinus, causing damage to cranial nerves III, IV, and VI that pass through the sinus causing diplopia and extraocular muscle palsies/paralysis.

• Peripheral vision loss, bitemporal hemianopsia, blindness
• Pan-hypopituitarism

Question 16

How are NONFUNCTIONAL pituitary tumors treated?

Answer 16

Nonfunctioning pituitary tumors that are growing or causing mass effect are treated with neurosurgery.

Nonfunctioning pituitary tumors that are growing or causing mass effect are treated with neurosurgery. The most common surgical approach is transsphenoidal through the nares or the mouth. A very large or invasive tumor may require craniotomy for decompression.

Question 17

What is pituitary apoplexy?

Answer 17

Pituitary apoplexy is acute hemorrhage into the pituitary gland often at the site of a preexisting pituitary adenoma (typically a macroadenoma).

Question 18

Why is pituitary apoplexy an emergency? How is it managed?

Answer 18

Stress-dose glucocorticoid replacement should be initiated emergently in patients with pituitary apoplexy or infarction, as well as emergent neurosurgical intervention; patients with vision loss associated with apoplexy require urgent surgical decompression.

Pituitary apoplexy can cause acute pituitary hormone deficiency or mass effect from rapid expansion of the sellar contents due to bleeding. It is an endocrine and neurosurgical emergency.

Acute ACTH deficiency is common and can be life-threatening. If suspected, stress-dose glucocorticoid replacement should be initiated emergently. Patients with vision changes or loss associated with apoplexy require urgent surgical decompression.

Question 19

What is Sheehan syndrome or postpartum pituitary infection?

Answer 19

Hypopituitarism can occur due to postpartum pituitary infarction (Sheehan syndrome) because of excessive postpartum hemorrhage causing hypotension and hypoperfusion.

Question 20

How should you manage/work up Sheehan Syndrome?

Answer 20

Patients who may have Sheehan syndrome should be

(1) emergently tested and treated for secondary cortisol deficiency
(2) Note: A patient with Sheehan syndrome will not lactate because of prolactin deficiency; no treatment is available to induce lactation.
(3) Other hormone deficiencies can be evaluated 6 weeks after delivery.

Question 21

What are the main ways that cortisol deficiency occurs?

Answer 21

Although secondary cortisol deficiency may result from damage to the pituitary gland or pituitary stalk that impairs ACTH production, it is most commonly iatrogenic due to exogenous glucocorticoid use that suppresses pituitary ACTH secretion.

Patients with secondary cortisol deficiency have only glucocorticoid deficiency. The remainder of the adrenal gland functions normally and the renin-angiotensin system is intact, so these patients do not have mineralocorticoid deficiency

Question 22

How is secondary cortisol deficiency similar/different to primary cortisol deficiency?

Answer 22

Although patients with secondary cortisol deficiency do require stress-dose glucocorticoids, they are at less risk for hypotension, hyponatremia, and adrenal crisis than those with primary cortisol deficiency (failure of the adrenal glands) because the production of mineralocorticoid is retained. Also, unlike patients with primary cortisol deficiency, patients with secondary cortisol deficiency do not develop hyperpigmentation or bronzing of the skin because ACTH and its prohormone responsible for these changes, pro-opiomelanocortin (POMC), are not hypersecreted.

Question 23

With oral glucocorticoids, how do you prevent secondary glucocorticoid insufficiency?

Answer 23

Glucocorticoids prescribed at doses above physiologic replacement for longer than 3 weeks should be tapered when discontinued to allow recovery of the pituitary-adrenal axis; if therapy has lasted less than 3 weeks, no taper is required for pituitary-adrenal axis recovery.

Question 24

What are the symptoms of secondary glucocorticoid insufficiency and how should it be managed?

Answer 24

Symptoms of secondary cortisol deficiency include weight loss, nausea, vomiting, lightheadedness, hypoglycemia, hypotension, and hyponatremia. Secondary cortisol deficiency is also diagnosed using an ACTH stimulation test. Secondary cortisol deficiency can be life threatening and must be treated with glucocorticoid replacement, often with hydrocortisone, although prednisone or dexamethasone may also be used. Hydrocortisone (15-30 mg/d) should be administered in 2 to 3 divided doses, or hydrocortisone should be dosed 10 to 20 mg in the morning and 5 to 10 mg in the early afternoon.

Question 25

For minor or moderate surgery with general anesthesia, as well as, major surgery/trauma/critical illness/childbirth, how should steroids be used?

Answer 25

Patients require stress doses of glucocorticoids when acutely ill, hospitalized, or undergoing the stress of surgery. For moderate physiologic stress (minor or moderate surgery with general anesthesia), hydrocortisone should used (45-75 mg/d orally or intravenously in 3-4 divided doses for 2-3 days). Prednisone (10-20 mg or dexamethasone 2-3 mg/d in 1-2 divided doses) may be used alternatively.

For major physiologic stress (major surgery, trauma, critical illness, or childbirth), hydrocortisone (150-200 mg/d intravenously in 3-4 divided doses; 100 mg/d the next day; taper to baseline in 3-5 days) may be used. An alternative would be dexamethasone (6-8 mg/d intravenously in 2-3 divided doses).

Question 26

For a patient with pituitary apoplexy and urgent/emergent neurosurgery, when should an ACTH test be planned?

Answer 26

If the patient has pituitary apoplexy and urgent/emergent neurosurgery is planned with no time for ACTH-stimulation testing, the patient should empirically be treated with glucocorticoids and then receive an ACTH stimulation test 4 to 8 weeks after surgery.

Question 27

How is secondary or central hypothyroidism diagnosed?

Answer 27

Secondary or central hypothyroidism is diagnosed by demonstrating a simultaneously inappropriately normal or low TSH and low T4 (free or total) level.

Question 28

What is hypogonadotropic hypogonadism caused by? What is the most common cause in women?

Answer 28

Hypogonadotropic hypogonadism may be caused by GnRH deficiency. The most common cause of GnRH deficiency in women is hypothalamic amenorrhea, which is associated with excess exercise, illness, or anorexia. Additional causes of GnRH deficiency include congenital GnRH deficiency and Kallmann syndrome, a condition in which hypothalamic neurons responsible for releasing GnRH fail to migrate into the hypothalamus during embryonic development.

Question 29

Treatment of hypogonadotropic hypogonadism?

Answer 29

Treatment of hypogonadotropic hypogonadism depends on the goals of therapy and whether the patient desires fertility. Fertility treatment requires replacement of the gonadotropins in men and women. Premenopausal women who do not desire fertility may be treated with estrogen- and progesterone-containing oral contraceptives (after assessment of risk of thromboembolic disease). Treatment of premenopausal hypogonadotropic hypogonadism is recommended to avoid loss of estrogen-dependent bone at a young age, which could lead to osteoporosis. Treatment of postmenopausal hypogonadotropic hypogonadism is not indicated. Men who do not desire fertility may be treated with testosterone replacement therapy

Question 30

How is growth hormone deficiency diagnosed? How is it confirmed?

Answer 30

Because GH secretion is pulsatile, testing random levels is not diagnostically useful. Therefore, GH deficiency is diagnosed by measurement of IGF-1.

A GH deficiency is confirmed by measuring the response of serum GH on a stimulatory test, such as the insulin tolerance test.

Question 31

What does central diabetes insidious result from?

Answer 31

Central diabetes insipidus (DI) results from inadequate production of antidiuretic hormone (ADH) by the posterior pituitary gland.

Question 32

How is diabetes insipidus diagnosed?

Answer 32

In the patient with polyuria, DI is diagnosed by clinical symptoms with simultaneous laboratory evidence of inability to concentrate urine with elevated serum sodium (hypernatremia) and high osmolality, and inappropriately low urine osmolality; a water deprivation test can confirm the diagnosis.

Question 33

How is central DI treated?

Answer 33

Treatment of central diabetes insipidus is once or twice daily hormone replacement with desmopressin.

Question 34

How is panhypopituitarysm managed?

Answer 34

Patients with panhypopituitarism require lifelong replacement of T4, cortisol, and ADH because these deficiencies can be life-threatening. GH and sex hormones are replaced dependent on each patient’s preference, coupled with a discussion of the risks and benefits of therapy.

Question 35

What implications are there if a woman with panhypopituitarism is or will become pregnant?

Answer 35

In addition to requiring exogenous gonadotropins to conceive, a reproductive-aged woman with panhypopituitarism will not go into spontaneous labor and will not lactate.

These pregnancies are classified as high risk, and obstetric care should be provided by a maternal-fetal specialist.

Question 36

In emergent situations, what do patients with panhypopituitarism need?

Answer 36

Patients with panhypopituitarism should wear medical alert identification documenting their panhypopituitarism, specifically noting the need for stress-dose glucocorticoid therapy and desmopressin dosing in emergent situations.

Question 37

What is the most common cause of FUNCTIONAL pituitary tumors?

Answer 37

Pituitary tumors are called functional when they secrete excessive amounts of hormone. The most common functional pituitary tumor is a prolactinoma.

Question 38

What is the most common cause of hyperprolactinemia?

Answer 38

The most common cause of hyperprolactinemia is physiologic; prolactin is released during pregnancy and postpartum to cause lactation.

Question 39

What medications cause hyperprolactinemia?

Answer 39

Antipsychotics, risperidone or metoclopramide

Question 40

How can hypothyroidism cause hyperprolactinemia?

Answer 40

Another common cause of hyperprolactinemia is primary hypothyroidism. Hypothyroidism can cause diffuse swelling of the pituitary gland that may resemble enlargement due to a pituitary adenoma on imaging. Therefore, a patient with primary hypothyroidism and hyperprolactinemia should be treated with thyroid hormone replacement with retesting of the prolactin level once the TSH has normalized. Further evaluation is indicated if the hyperprolactinemia does not correct when hypothyroidism is treated. If pituitary imaging has noted pituitary enlargement prior to treatment of hypothyroidism, repeat MRI should be obtained when the TSH is normal.

Question 41

How can a nonfunctional pituitary adenoma and a hyperprolactinoma cause hyperprolactinemia?

Answer 41

Nonfunctioning pituitary adenomas can also cause hyperprolactinemia by compressing the pituitary stalk and decreasing dopamine inhibition of prolactin secretion. It is important to distinguish between prolactinomas and nonfunctioning pituitary adenomas as the cause of hyperprolactinemia because of different treatment approaches.

Question 42

What are the clinical features of hyperprolactinemia?

Answer 42

Galactorrhea

Hypogonadotropic hypogonadism because of negative feedback on GnRH, LH, and FSH by high levels of prolactin. Both men and women present with hypogonadism. Women of reproductive age often present earlier than men because of amenorrhea. They may also have early menopausal symptoms. Symptoms in men are insidious and may go unrecognized for years. Both men and women with hyperprolactinemia are likely to be infertile and are at risk for osteoporosis.

Question 43

How do you work up unexplained hyperprolactinoma?

Answer 43

Diagnostic imaging is indicated in situations in which there is unexplained hyperprolactinemia.

Question 44

How are microprolactinomas managed?

Answer 44

Symptomatic women with microadenomas may be treated with either oral contraceptive pills (if fertility is not desired) or dopamine agonists.

Question 45

How are postmenopausal women with microprolactinomas treated?

Answer 45

Postmenopausal women with microadenomas do not require treatment.

Question 46

How are prolactinomas treated?

Answer 46

Unlike other pituitary tumors, medication rather than surgery is first-line therapy for prolactinomas. Even patients with severe mass effect such as vision loss are treated with medical therapy initially. Rarely, very large tumors or more invasive prolactinomas do not shrink with medical therapy and, also rarely, continue to grow. In these patients, surgery should be considered, followed by radiotherapy if growth recurs or continues. After being debulked, the prolactinoma may respond better to medical therapy.

Question 47

What are the two dopamine agonists approved by the FDA for use against prolactinomas?

Answer 47

The two FDA-approved dopamine agonists are bromocriptine and cabergoline.

Question 48

After starting dopamine therapy for prolactinomas, how is treatment monitored?

Answer 48

Dopamine agonists typically decrease the size and hormone production of prolactinomas rapidly. Response to therapy can be monitored by checking serum prolactin levels 1 month after initiating therapy and then every 3 to 4 months. Decreasing serum prolactin usually correlates with decreasing size of the tumor. MRI should be repeated in 1 year for microprolactinomas if the prolactin level normalizes on dopamine agonists. After tumor shrinkage is confirmed, additional MRIs are not necessary unless the serum prolactin level rises. An MRI should be repeated after 3 months of medical therapy for macroprolactinomas, or if prolactin levels are rising on therapy with good medication adherence. MRI should be repeated every 6 to 12 months until the macroprolactinoma is stable on serial studies and the prolactin level is not rising.

Question 49

What do you do for women who are being treated for prolactinomas and become pregnant?

Answer 49

Hyperprolactinemia is a frequent cause of infertility because of the effect on gonadotropin release. DA therapy lowers prolactin, normalizing gonadotropin regulation and allowing normal ovulation. DA therapy should be discontinued when the pregnancy is diagnosed.

Question 50

How are pregnant women with macroprolactinomas managed?

Answer 50

Women with macroprolactinomas are at risk for clinically significant tumor growth or vision compromise during pregnancy. If the tumor is very large or abuts the optic chiasm, patients should be counseled on risk of tumor growth during pregnancy, as well as the risks and benefits of surgical resection of the tumor before pregnancy. DA therapy is sometimes continued during pregnancy if the patient has a history of visual field defect.

Pregnant women with macroprolactinomas should be assessed clinically at least once per trimester and have visual fields tested every trimester or more frequently for vision change. Changes in visual fields or severe headache are indications to proceed with pituitary MRI. If the macroprolactinoma causes mass effect during pregnancy, bromocriptine may be started. If the bromocriptine does not decrease tumor size and reduce symptoms of mass effect, surgical debulking may be necessary.

Question 51

How is acromegaly diagnosed?

Answer 51

Acromegaly is diagnosed biochemically. Because GH is pulsatile throughout the day, it is not useful for diagnosis, so measurement of serum IGF-1 is used instead. Excess GH is confirmed with an oral glucose tolerance test (see Table 15) because glucose normally suppresses GH levels to less than 1 ng/mL (1 μg/L). GH levels greater than 1 ng/mL (1 μg/L) are diagnostic of GH excess. A pituitary MRI should be obtained once GH excess is confirmed biochemically. Consultation with an endocrinologist is recommended if IGF-1 is elevated.

Question 52

How is acromegaly treated?

Answer 52

Treatment of acromegaly is transsphenoidal tumor resection; surgery is the only treatment that is potentially curative.

Question 53

What is the difference between Cushing’s Disease and Cushing’s syndrome?

Answer 53

Cushing disease is the term used to indicate excess cortisol production due to an ACTH-secreting pituitary adenoma.

Cushing syndrome refers to hypercortisolism from any cause, exogenous or endogenous, ACTH-dependent or not. The most common cause of endogenous Cushing syndrome is Cushing disease. When undiagnosed, Cushing disease is associated with devastating long-term morbidity such as diabetes, morbid obesity, hypertension, infertility, and osteoporosis.

Question 54

How is Cushing’s Disease Diagnosed?

Answer 54

Once ACTH-dependent Cushing syndrome is confirmed biochemically, a pituitary MRI should be obtained. If no pituitary tumor or a tumor less than 6 mm is visualized on MRI, an 8-mg dexamethasone suppression test is used to differentiate Cushing disease from an ectopic source of ACTH. Ectopic ACTH production from a nonpituitary tumor (most often lung, pancreas, or thymus carcinomas) is very uncommon.

Imaging of the chest and abdomen is indicated in patients with a suspected ectopic source of ACTH.

Question 55

How is Cushing’s Disease treated?

Answer 55

Cushing disease is treated by transsphenoidal pituitary tumor resection, which may be curative.

Endogenous ACTH production in the remaining normal pituitary gland will be suppressed after removal of the tumor due to long-standing hypercortisolism, so patients with successful surgical treatment will have acute ACTH deficiency and require glucocorticoid replacement. It may take up to 1 year for endogenous ACTH production to return to normal, and sometimes the hypothalamic-pituitary-adrenal axis does not recover. After successful resection, Cushing disease can recur, and patients must be monitored annually for several years, and then less frequently, or sooner if symptoms of hypercortisolism recur.

Question 56

If Cushing’s Disease is refractory to transsphenoidal surgery, then what?

Answer 56

If surgical cure is not achieved, patients may be offered pituitary radiation or medical therapy. Medical options include inhibitors of adrenal enzyme synthesis of cortisol, ketoconazole, or metyrapone; the dopamine agonist, cabergoline; or the somatostatin analogue, pasireotide. Medical cure of Cushing disease has a relatively low success rate, but hypercortisolism symptom control is an achievable goal in all patients with endogenous Cushing syndrome.

In patients who do not benefit from surgical treatment and who have an inadequate response to medical treatment, bilateral adrenalectomy to remove the target of ACTH stimulation is an option. However, these patients will require lifelong glucocorticoid and mineralocorticoid replacement.