Sheehan Syndrome

Etiology

Sheehan syndrome occurs when the anterior pituitary gland is damaged due to significant blood loss. Classically, this happens after delivery, in which the mother loses a significant amount of blood. This blood loss results in the pituitary gland not being able to produce hormones. The diagnosis of Sheehan syndrome is not always apparent immediately after childbirth. Occasionally, the signs and symptoms of Sheehan syndrome may not present until months after childbirth or significant trauma. The first and most common symptom of Sheehan syndrome is the absence of lactation, also known as agalactorrhea. Other symptoms are associated with loss of pituitary gland hormone production and may include amenorrhea or oligomenorrhea, hot flashes, and/or decreased sex drive. Symptoms of hypothyroidism such as fatigue, bradycardia, hypotension, weight gain, and constipation may occur months later, along with the loss of axillary and pubic hair. Adrenal insufficiency can also occur with symptoms of fatigue and weight loss. Laboratory values that may support secondary adrenal insufficiency due to Sheehan syndrome could include hyponatremia, anemia, and hypoglycemia.[2][3]

Epidemiology

Sheehan syndrome is rare in developed countries because of advanced obstetrical practices and more exposure to experienced medical providers and medical facilities. Unfortunately, it can be a complication of childbirth in developing and low-income countries. Some studies have placed the incidence of Sheehan syndrome as high as five patients out of 100,000 births.[1]

Pathophysiology

An increase in pituitary volume and cell count occur in pregnant women in the weeks preceding delivery. This increase is caused principally by hyperplasia of prolactin-producing cells (lactotrophs) and hyperplasia of other cells in the anterior pituitary gland. This hyperplasia leads to increased nutritional and metabolic demand by the anterior pituitary gland as a whole, but the blood supply that feeds the anterior pituitary does not increase. The blood supply that feeds the anterior pituitary gland is a relatively low-pressure system. It is theorized that this is the mechanism that makes the pituitary cells more susceptible to ischemia. Consequently, the cells of the anterior pituitary are more prone to necrosis in pregnancies complicated by significant postpartum hemorrhage. The posterior pituitary gland has its blood supply which functions under higher pressure than the anterior pituitary, so it is not usually affected by shock or hypovolemia.[4]

Sheehan syndrome is the clinical manifestation of anterior pituitary cell necrosis and may present as pan-hypopituitarism or as selective loss of pituitary function. Pan-hypopituitarism is a result when many cells of the pituitary are affected, as opposed to only a few cells. It is far more common than the selective loss of pituitary function. Prolactin and growth hormone are the most common hormones affected by selective pituitary necrosis and hypofunction. The posterior pituitary function is usually not affected, as stated above. However, diabetes insipidus can occur, but it is a rare manifestation of Sheehan syndrome.[5]

History and Physical

Patients may present with an acute or chronic presentation of Sheehan syndrome. The chronic condition of Sheehan syndrome is more common than the acute presentation. Confounding the presentation is that Sheehan syndrome may present months to years after the initial event of hypovolemia and shock.[2]

The acute presenting condition of Sheehan syndrome is usually evident when the mother of the newborn has difficulty with breastfeeding or cannot produce milk at all (agalactorrhea).[6]  However, many women are asymptomatic for months to years after childbirth. Women may report difficulties with menses after childbirth, and some may never have menses until Sheehan syndrome is diagnosed and treated. The acute form of Sheehan syndrome can be quite dangerous if not recognized and treated quickly after childbirth. The persistent hypotension and tachycardia can mimic hypovolemia and shock, but hyponatremia and persistent hypoglycemia can help to clinch the diagnosis of Sheehan syndrome.[1]

Chronic Sheehan syndrome is diagnosed due to symptoms that occur due to hypopituitarism, and again, it can occur months to years after the initial vascular insult to the pituitary gland. Symptoms of hypothyroidism may occur months after childbirth. The patient may complain of fatigue, asthenia or weakness, hair loss, constipation, weight gain, problems with focusing or with their attention span, and cold intolerance. Physicians may note hypotension and bradycardia during the physical exam. Patients may also exhibit a secondary adrenal insufficiency which could have symptoms of fatigue and weight loss.[7] Lab values may reflect hypoglycemia, hyponatremia, and/or anemia.

Evaluation

Evaluation of anterior pituitary function is done by obtaining blood when a high clinical suspicion is evident to diagnose Sheehan syndrome. The hormones that are manufactured in the anterior pituitary gland are the gonadotropins such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH), growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH), and thyroid-stimulating hormone (TSH). They are affected primarily in a certain order when necrosis occurs, GH first, followed by PRL, FSH, LH, ACTH, and then TSH last.[1] Laboratory tests to order would include a complete blood count (CBC) with differential count, basic metabolic profile, thyroid function tests (TSH, FT3, FT4), FSH, LH, prolactin, estrogen, cortisol, and growth hormone.[8] Finding a low basal hormone level along with a history and physical suggestive of Sheehan syndrome would help to make the diagnosis. Other laboratory tests that may occur with Sheehan syndrome include normocytic/normochromic anemia, thrombocytopenia, and/or pancytopenia. Hyponatremia and hypoglycemia may also be present as well. Other less common laboratory tests in the workup for Sheehan syndrome that may be abnormal include multiple thrombophilic genetic mutations, low PT and aPTT tests, anti-pituitary antibodies, and anti-hypothalamus antibodies.[9] These tests may be considered after the primary tests to confirm the diagnosis. Also, a magnetic resonance imaging (MRI) evaluation of the pituitary can be done to confirm the diagnosis. An empty sella is present in about 70% of patients, and a partially empty sella is present in about 30% of patients on a later MRI.[10]  Acute Sheehan syndrome signs on an MRI may demonstrate acute central infarction without hemorrhage in an enlarged pituitary. As the disease progresses, the MRI may show pituitary gland atrophy and eventually a partial or empty sella.[11]

Treatment / Management

The basis for the treatment of Sheehan syndrome is the lifelong replacement of deficient hormones. Hypothyroidism can be treated with levothyroxine or liothyronine replacement. Cortisol deficiency can be treated by replacement with prednisone or hydrocortisone.  Gonadotropin deficiency should be treated with estrogen if the uterus has been removed with a combination of estrogen and progesterone if a uterus is present. Obviously, risks versus benefits must be discussed with that patient in regards to thrombophilia, risks of cancer, myocardial infarction, and others. The growth hormone is probably the most common hormone that needs replacing, and the dosage must be individualized to the patient's need. For patients who develop diabetes insipidus, desmopressin (DDAVP) is the recommended treatment of choice. Referral to an endocrinologist who is familiar with hypopituitarism and the usage of growth hormone is recommended.[12](B3)

Differential Diagnosis

The main differential diagnoses include:

• Addison syndrome
• Lymphocytic hypophysitis
• Pan-hypopituitarism
• Pituitary apoplexy

Prognosis

The prognosis depends on timely diagnosis and hormone supplementation. If not diagnosed in time, the prognosis can be grave.

Complications

• Hypothyroidism
• Addisonian crisis
• Death