I. Problem/Condition.

Hypopituitarism is a disorder of decreased pituitary hormone secretion. It can occur due to deficiencies of the hypothalamus or pituitary. Its presentation results from the manifestation of insufficient amounts of the anterior pituitary hormones (prolactin, growth hormone, ACTH, TSH, LH, and FSH).

It can manifest at any age and can advance over years, caused by a variety of pathologies in the hypothalamic-pituitary axis or a gene mutation. Evidence of hypopituitarism occurs when approximately 75% of the parenchyma of the anterior pituitary is compromised. Symptoms can be related to the underlying disease itself or the hormonal deficiencies that ensue.

In adults, the most common cause of hypopituitarism is a pituitary adenoma or treatment with pituitary surgery or radiotherapy. Most pituitary lesions are benign, although secondary tumors from metastasis to the pituitary gland from a primary breast, lung, colon, or prostate cancer can occur as well. Macroadenomas (≥1 cm) are frequently associated with deficiencies in anterior pituitary hormones through the compression of portal vessels in the pituitary stalk either from direct tumor expansion or increased intrasellar pressure. The non-functioning pituitary adenomas (<1 cm) are seen more commonly in adults.

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Previous surgical excision or pituitary radiation can cause damage to the nonadenomatous pituitary and cause hypopituitarism. The risk and extent of the hypopituitarism following surgical intervention depends on factors such as tumor size, amount of tumor infiltration, and the experience of the pituitary surgeon. The extent of hypopituitarism after conventional external beam radiotherapy is dose dependent and can occur if the hypothalamic–pituitary axis lies within the radiation fields.

Pituitary apoplexy, ischemic necrosis, traumatic brain injury, aneurysmal subarachnoid hemorrhage and Sheehan syndrome are less common causes. Rathke cleft cysts, empty sella syndrome, craniopharyngiomas, metastases, s as well as infiltrative granulomatous diseases such as arcoidosis, tuberculosis, and histiocytosis X are other causes.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

Endocrine causes:

  • Primary hypothyroidism.
  • Adrenal suppression secondary to corticosteroid therapy.
  • Addison disease.
  • Hypothalamic dysfunction.

Hematologic causes:

  • Cardiogenic shock.
  • Septic shock.
  • Hemochromatosis.

B. Describe a diagnostic approach/method to the patient with this problem.

The diagnosis of hypopituitarism is made primarily by laboratory evaluation. Clinical signs of deficiencies of the target hormones will also be evident. Work-up begins with target-hormone measurement via sensitive and reliable immunoassay techniques. If found to be deficient, the trophic hormones are then investigated to determine if the deficiency is secondary to hypopituitarism. Methods for the measurement of hormones need to be standardized and units of reporting must be consistent.

It is important to evaluate both the target hormones and trophic hormones, as trophic-hormone measurement alone is not sufficient for diagnosis. Imaging is used to evaluate the pituitary and hypothalamus, usually magnetic resonance imaging (MRI), although microadenomas will not be evident in imaging.

1. Historical information important in the diagnosis of this problem.

The patient should be evaluated for the following:

  • Constipation
  • Dry skin
  • Headaches
  • Vision changes
  • Hypoglycemia
  • Incomplete or delayed sexual development (ie, eunuchoidism)
  • Loss of body (axillary and pubic) hair or reduced shaving
  • Amenorrhea
  • Oligomenorrhea
  • Infertility
  • Erectile dysfunction
  • Decreased libido
  • Delayed puberty
  • Failure to thrive
  • Decreased energy, motivation
  • Height loss, low trauma fracture, or low bone mineral density
  • Hot flushes or sweats
  • Poor concentration and memory
  • Sleep disturbance or increased sleepiness
  • Reduced muscle bulk and strength
  • Increased body fat or body-mass index
  • Diminished physical or work performance
  • Short stature
  • Cold intolerance
  • Fatigue
  • Nausea
  • Vomiting
  • Family history of hypopituitarism.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Visual acuity and visual-field exams can determine compression of the optic chiasm if a pituitary adenoma is present. Change in body mass index and Tanner Staging as certain hormonal deficiencies result in weight, height and primary and secondary sexual characteristic changes.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

  • Basic metabolic panel
  • 8:00 am serum cortisol and adrenocorticotropic hormone (ACTH)
  • Plasma free T4 and thyroid-stimulating hormone (TSH)
  • Estradiol, FSH, and LH in females
  • 8:00 am testosterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) in males
  • IGF-1
  • Pituitary MRI
  • Pituitary computed tomography (CT) scan if craniopharyngioma is suspected.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Electrolyte measurement is done to evaluate ACTH deficiency. A low sodium level would be expected in this diagnosis.

In order to investigate basal ACTH secretion, serum cortisol should be measured at 8:00 am. A value less than, or equal to, 3 mcg/dL indicates a deficiency of cortisol. A value greater than, or equal to, 18 mcg/dL implies normal endocrine function of the hypothalamic-pituitary-adrenal axis, and a measurement greater than 3 mcg/dL but less than 18 mcg/dL is indeterminate and requires repeat measurement.

A confirmed value in the indeterminate range then mandates a measurement of ACTH reserve such as the metyrapone test, in which 750 mg of metyrapone are to be given every 4 hours for 24 hours. Hypothalamic or pituitary dysfunction is confirmed if the 11-deoxycortisol concentration is below 10 mcg/dL at 8 am following the 24 hour administration of metyrapone. The ACTH stimulation test, which measures cortisol levels after the administration of 250 mcg of ACTH, can also be used. Plasma cortisol levels are obtained at baseline and 30 and 60 minutes after the injection. A plasma cortisol > 18 mcg/dl (500 nmol/L) at 30 minutes or > 20 mcg/dl (550 nmol/L) at 60 minutes, indicates normal HPA function and rules out AI.

Thyrotropin function should also be investigated. This is done by a plasma free T4 level. If this value is low and the TSH measurement is low or normal, the diagnosis of hypopituitarism is supported.

In many cases, it is possible to diagnose gonadotropin deficiency with the use of a basal hormone test and an evaluation of clinical symptoms. For males, a reduced 8:00 am serum testosterone level < 3 ng/mL with normal or low LH and FSH is seen. In females, normal menses indicates adequate FSH and LH function. Reduced levels of estradiol and normal or reduced levels of LH and FSH, in conjunction with oligomenorrhea or amenorrhea, can indicate secondary hypogonadism. A medroxyprogesterone challenge can also be administered.

When diagnosing GH deficiency in adult patients, the basal GH concentration is not considered to be valuable, however, measurement of insulin-like growth factor 1 (IGF-1) may be of some use, although they are not sufficient themselves. A stimulation test is necessary for a definitive diagnosis. The most widely used and reliable measure is the insulin tolerance test in which GH levels lower than 3 µg/L are considered to indicate a severe deficiency, GH levels between 3.0 and 4.9 µg/L indicate a partial deficiency, and GH levels higher than 5.0 µg/L are considered normal.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Prolactin level testing.

III. Management while the Diagnostic Process is Proceeding

A. Management of hypopituitarism.

Treatment of patients with hypopituitarism is the sum of the treatments of each of the individual pituitary hormonal deficiencies detected. Replacement of the hormones that are deficient is required lifelong.

Patients with hypopituitarism are at risk for progressing to adrenal crisis with hypotension often precipitated by an underlying illness. These patients are in need of immediate intervention, and investigation of an underlying illness is mandated. Patients in adrenal failure are to be given hydrocortisone 100 mg IV q8h. Taper the dose of hydrocortisone gradually. When the total dose of hydrocortisone is below 100 mg/day, fludrocortisone 0.05-0.20 mg/day is added for its mineralocorticoid activity. The hypotension can be corrected with 0.9% saline with 5% dextrose.

For patients not in adrenal crisis, a single dose of dexamethasone 10 mg IV and 0.9% saline with 5% dextrose should be given. Maintenance therapy consists of prednisone 5 mg PO qAM. This maintenance dose can be adjusted to the lowest dose that remains effective, but is to be increased during illness (double the maintenance dose for 3 days), and before surgery (hydrocortisone 50 mg IV before surgery and tapered q8h to maintenance levels by the third post-operative day).

To correct hypothyroidism, levothyroxine is commonly used. Therapy is typically begun with 100 mcg/day, with dose adjustment every 6-8 weeks until normal plasma free T4 levels are achieved.

For patients in whom fertility is desired, endocrinology referral is often utilized. In females who no longer desire fertility, transdermal or oral estrogen along with medroxyprogesterone are used. In men who no longer desire fertility, androgen replacement with testosterone is used. Gonadotropins therapy or pulsatile GnRH is used for women and men who desire fertility.

Growth hormone (GH) replacement is typically only used if symptoms such as fatigue, poor quality of life, truncal obesity, hyperlipidemia, or low bone-mineral density become prominent. Recombinant human GH or somatotropin can be used. GH dosing regimens usually need to be individualized; however, research has not shown its use to be cost-effective, and its risks and benefits are not fully established.

Pituitary macroadenomas will often require transsphenoidal surgical resection.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

  • Patients with adrenal crisis and hypotension require immediate treatment.
  • In patients with coronary artery disease, thyroxine can worsen the patient’s cardiac condition. These patients should begin thyroxine therapy at a dose of only 25-50 mcg/day and be monitored for heart failure, arrhythmia, or angina.
  • Correction of growth-hormone deficiency is unestablished as a mainstay of hypopituitarism therapy.
  • Mortality in hypopituitarism is increased with older age at diagnosis, poorly controlled diabetes mellitus, non-tumor causes, and previous radiotherapy.

What’s the Evidence?

Arafah, B. “Medical management of hypopituitarism in patients with pituitary adenomas”. Pituitary. vol. 5. 2002. pp. 109

Ascoli, P, Cavagnini, F. “Hypopituitarism”. Pituitary. vol. 9. 2006. pp. 335-42.

Biller, B, Samuels, M, Zagar, A. “Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency”. J Clin Endocrinol Metab. vol. 87. 2002. pp. 2067

Chanson, P, Salenave, S. “Diagnosis and treatment of pituitary adenomas”. Minerva Endocrinol. vol. 29. 2004. pp. 241-75.

Dorin, RI. “Diagnosis of adrenal insufficiency”. Ann Intern Med. vol. 139. 2003, Aug 5. pp. 194-204.

Fernandez-Rodriguez, E, Lopez-Ranton, M, Andujar, P. “Epidemiology, mortality rate and survival in a homogenous population of hypopituitary patients”. Clin Endocrinol (Oxf). 2012.

Grossman, A. “Clinical Review: The diagnosis and management of central hypoadrenalism”. J Clin Endocrinol Metab. vol. 95. 2010. pp. 4855

Higham, C, Phil, D, Johannsson, G, Shalet, S. “Hypopituitarism”. The Lancet. 2016.

Toogood, AA, Stewart, PM. “Hypopituitarism: clinical features, diagnosis and management”. Endocrinol Metab North Am.. vol. 37. 2008. pp. 235-61.