Sheehan's syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]

Sheehan’s syndrome is a life-threatening complication of severe postpartum hemorrhage (PPH) that results in mild to severe maternal hypopituitarism. Sheehan’s syndrome is less prevalent in developed countries, but it is still one of the most common causes of hypopituitarism in underdeveloped and developing countries. During pregnancy, enlarged size of the pituitary gland and decreased blood supply due to any cause can result in ischemic necrosis of pituitary gland. Severe PPH, glandular hypertrophy and hyperplasia, smaller sella size, autoimmunity, and disseminated vascular coagulation (DIC) are thought to play an important role in the pathogenesis of Sheehan’s syndrome. The most common causes of Sheehan’s syndrome include massive hemorrhage during parturition, vascular compression, and vascular occlusion. Sheehan’s syndrome needs to be differentiated from diseases causing hypopituitarism and other diseases like lymphocytic hypophysitis, pituitary apoplexy, hypothyroidism, addison’s disease, empty sella syndrome, hypogonadotropic hypogonadism, simmond’s disease, hypoprolactinemia, and menopause. Risk factors for Sheehan’s syndrome include pregnancy, severe/massive PPH, pituitary mass, pre-existing vascular diseases, smaller and rigid sella, traumatic delivery, multiple gestations, placental abnormalities, and type 1 diabetes. If left untreated, Sheehan’s syndrome can lead to panhypopituitarism and empty sella syndrome. Common complications of Sheehan’s syndrome include adrenal crisis, hypotension, hypothyroidism, and hypopituitarism. Prognosis is generally excellent, providing early diagnosis and management may result in complete reversal of symptoms. Diagnosis of Sheehan’s syndrome is made on clinical basis with a recent/remote history of traumatic delivery or delivery complicated by hypotension. The most common presentations include postpartum lactation failure, amenorrhea, loss of sexual hair, fatigue, anorexia, and weight loss. Clinical features depend on the severity of hypopituitarism that results from Sheehan’s syndrome. Almost all the patients have growth hormone (GH), prolactin, and gonadotropin deficiency; and the majority of the patients have ACTH and TSH deficiency. Laboratory evaluation in patients with Sheehan’s syndrome gives a picture of partial or panhypopituitarism. Other laboratory findings include hyponatremia, hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, anemia, pancytopenia, eosinophilia, hypoalbuminemia, low fasting plasma glucose, and decreased levels of anterior pituitary hormones (free thyroxine, estradiol, and cortisol levels). The most sensitive test is inadequate prolactin and gonadotropin response to stimulation. ECG findings associated with Sheehan’s syndrome include QT interval prolongation, type-1 Brugada-like ECG pattern (due to adrenal crisis), findings suggestive of cardiac tamponade (sinus tachycardia, low voltage QRS, and electrical alternans), and dilated cardiomyopathy. CT scan findings in case of acute Sheehan’s syndrome may show non-hemorrhagic pituitary gland enlargement, while chronic presentation may show an empty sella or decreased sella volume. Findings on MRI suggestive of Sheehan’s syndrome include decreased sella volume, empty sella, pituitary remnant tissue or CSF in the sella. The treatment of Sheehan’s syndrome involves appropriate hormone replacement therapy, which must be taken for the rest of the patient’s life, results in significant improvement and reversal of not only the physical symptoms, but also the psychological symptoms.

Sheehan’s syndrome was first discovered by Leon Konrad Gliński about a century ago and it was named after Harold Sheehan (1900-1988).

Sheehan’s syndrome may be classified based on the onset or presentation of symptoms and the degree of glandular damage. Sheehan’s syndrome may be classified into acute and chronic subtypes based on the time period after delivery and also extent of glandular damage. 

It is believed that Sheehan’s syndrome is the result of ischemic necrosis of pituitary gland, due to pituitary gland enlargement during parturition that is precipitated by hypotension due to massive hemorrhage. Apart from pituitary gland enlargement during and before parturition, vasospasm, generalized Schwartzman phenomenon, thrombosis and compression of the hypophyseal arteries, autoimmunity, DIC, and smaller size of sella play a contributing role in pathogenesis of Sheehan’s syndrome. Occlusion and other vascular anomalies of the hypophyseal portal system can also complicate the exchange of hormones between the hypothalamus and the pituitary gland, leading to hypopituitarism. Sheehan’s syndrome may result in mild to severe pituitary dysfunction (partial or panhypopituitarism), which is identified with growth hormone (GH), thyroid hormone, glucocorticoid, gonadotropins, and prolactin hormone deficiencies, and manifests as a wide spectrum of presentation. Usually, GH deficiency is the earliest one to develop.

Common causes of Sheehan’s syndrome include massive hemorrhage, hypotension during pregnancy, vascular compression, and vascular occlusion (thrombosis, DIC). Less common causes are vascular insufficiency due to coronary artery bypass grafting (CABG) in older patients and snake bites (Russell’s viper bites).

Sheehan’s syndrome must be differentiated from lymphocytic hypophysitis, pituitary apoplexy, hypothyroidism, Addison’s disease, panhypopituitarism, empty sella syndrome, hypogonadotropic hypogonadism, Simmond’s disease, hypoprolactinemia, and menopause on the basis of hypo-functioning of the pituitary.

The incidence of Sheehan’s syndrome is difficult to assess. It was found to be the 6th most common cause of growth hormone (GH) deficiency with an incidence of 3.1% of cases. In 2009, the prevalence of Sheehan’s syndrome was estimated to be 5.1 per 100,000 women. Sheehan’s syndrome is less prevalent in developed countries due to better obstetrical care and maternal health awareness. Sheehan’s syndrome is one of the most common causes of hypopituitarism in developing countries.

Common risk factors in the development of Sheehan’s syndrome include pregnancy, severe/massive postpartum hemorrhage (PPH), pituitary mass, pre-existing vascular diseases, autoimmunity, DIC, smaller and rigid sella, and traumatic delivery.

There is insufficient evidence to recommend routine screening for Sheehan’s syndrome.

If left untreated, Sheehan’s syndrome leads to hypopituitarism and empty sella syndrome. Common complications are adrenal crisis, hypotension, hypothyroidism, and hypopituitarism. Prognosis is generally excellent; early diagnosis and management often results in a complete reversal of symptoms.

Diagnosis of Sheehan’s syndrome is made on clinical basis with a recent or remote history of traumatic delivery or delivery complicated by hypotension. Diagnosis is mostly clinical but detailed medical history, measurement of pituitary hormone levels in blood, pituitary hormone stimulation tests and imaging (MRI preferred on CT) studies can help in making the diagnosis.

The most common symptoms of Sheehan’s sydrome are agalactorrhea and failure to resume menstruation after parturition. Common symptoms are hot flashes, decreased pubic or axillary hair, hypotension, hypoglycemia, features of hypothyroidism, hypoadrenalism, and hypogonadism.

Patients with Sheehan’s syndrome usually appear fatigued and lethargic. Physical examination is remarkable for bradycardia, hypotension, pallor, and signs suggestive of respective pituitary hormonal deficiency.

Laboratory findings consistent with the diagnosis of Sheehan’s syndrome include hyponatremia, hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, anemia, pancytopenia, eosinophilia, hypoalbuminemia and low fasting plasma glucose.

Electrocardiogram (ECG) findings associated with Sheehan’s syndrome may include QT interval prolongation, type-1 Brugada-like ECG pattern (due to adrenal crisis), or findings suggestive of cardiac tamponade or dilated cardiomyopathy.

There are no x-ray findings associated with Sheehan’s syndrome.

CT scans in patients with Sheehan’s syndrome shows non-hemorrhagic pituitary gland enlargement in acute cases while chronic cases present as an empty sella or decreased sella volume.

Findings on MRI suggestive of Sheehan’s syndrome are decreased sella volume, empty sella, pituitary remnant tissue, or cerebrospinal fluid (CSF) in sella.

Echocardiography findings associated with Sheehan’s syndrome may include reversible dilated cardiomyopathy and pericardial effusion.

There are no other imaging findings associated with Sheehan’s syndrome.

Surgical intervention may be considered when there is emergency presentation, such as pituitary apoplexy or subarachnoid hemorrhage causing Sheehan’s syndrome to prevent hypopituitarism.

The treatment of Sheehan’s syndrome involves hormone replacement therapy, which generally results in complete recovery and reversal of symptoms.

Surgical intervention is not recommended for the management of Sheehan’s syndrome.

Effective measures for the primary prevention of Sheehan’s syndrome include improved obstetrical care and perinatal monitoring, prevention of pregnancy related complications such as hypotension or hemorrhage, maternal awareness about risk factors of Sheehan’s syndrome, and post-puerperal follow up.

Effective measures for the secondary prevention of sheehan’s syndrome are early diagnosis and treatment to prevent life-threatening complications, such as adrenal crisis and infertility. Other measures of secondary prevention include frequent prenatal visits and prevention of development of hypotension due to any reason.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]

Sheehan’s syndrome was first discovered by Leon Konrad Gliński about a century ago and it was named after Harold Sheehan (1900-1988).

• Sheehan’s syndrome was first discovered by Leon Konrad Gliński about a century ago.
• It was named after Harold Sheehan (1900-1988).^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]

Sheehan’s syndrome may be classified based on the onset or presentation of symptoms and the degree of glandular damage. Sheehan’s syndrome may be classified into acute and chronic subtypes based on the time period after delivery and also extent of glandular damage.

• Sheehan’s syndrome may be classified based on:
  • The onset or presentation of symptoms
  • The degree of glandular damage

• Patient presents within days to weeks after delivery.
• Considerable damage results in acute presentation.

• Patient presents months to years after delivery.
• The damage is little or much less compared to the acute.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]

Common causes of Sheehan’s syndrome are including massive hemorrhage, hypotension during pregnancy, vascular compression, and vascular occlusion (thrombosis or disseminated intravascular coagulation). Less common causes are including vascular insufficiency due to coronary artery bypass grafting (CABG) in older patients and snake bites (Russell’s viper bites).

• Post partum hemorrhage^[1]

Common causes of Sheehan’s syndrome may include:

• Massive hemorrhage during or after pregnancy
• Vascular compression due to enlarged pituitary gland, small and rigid sella or any mass
• Vascular occlusion (thrombosis, DIC)

Less common causes of Sheehan’s syndrome are including:

• Vascular insufficiency due to CABG in older patients^[2]
• Snake bites (Russell’s viper bites)^[3]

• Sheehan’s syndrome is not associated with any genetic mutation

Cardiovascular	Hypotension, Vascular compression, Hemorrhage, post-CABG
Chemical/Poisoning	Snake bites (Russell’s viper bites)
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	Hydrochlorothiazide (HCTZ)
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	No underlying causes
Gastroenterologic	No underlying causes
Genetic	No underlying causes
Hematologic	Thrombosis, DIC
Iatrogenic	No underlying causes
Infectious Disease	No underlying causes
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	PPH, Traumatic birth delivery
Oncologic	No underlying causes
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	Autoimmunity
Sexual	No underlying causes
Trauma	Traumatic delivery
Urologic	No underlying causes
Miscellaneous	No underlying causes

• Autoimmunity
• DIC
• Drugs causing hypotension or hypercoaguability:
  • HCTZ
• Postpartum hemorrhage
• Snake bites
• Small and rigid sella
• Thrombosis
• Traumatic birth delivery

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]

Sheehan’s syndrome must be differentiated from other diseases causing hypopituitarism, such as lymphocytic hypophysitis, pituitary apoplexy, hypothyroidism, Addison’s disease, panhypopituitarism, empty sella syndrome, hypogonadotropic hypogonadism, Simmonds’ disease, hypoprolactinemia, and menopause.

Sheehan’s syndrome should be differentiated from other diseases causing hypopituitarism.^{[1][2][3][4][5][6][7]}

Diseases	Onset	Manifestations					Diagnosis
		History and Symptoms				Physical examination	Laboratory findings	Gold standard	Imaging	Other investigation findings
		Trumatic delivery	Lactation failure	Menstrual irregularities	Other features
Sheehan’s syndrome	Acute	++	++	Oligo/amenorrhea	Symptoms of: Adrenal insufficiency Hypothyroidism	Breast tissue atrophy Decreased axillary and pubic hair growth	Pancytopenia Eosinophilia Hyponatremia Low fasting plasma glucose Decreased levels of anterior pituitary hormones in blood	Clinical diagnosis Most senitive test: Low baseline prolactin levels w/o response to TRH	CT/MRI: Sequential changes of pituitary enlargement followed by: Shrinkage and necrosis leading to decreased sellar volume or empty sella	Pituitary hormone stimulation tests (Metoclopramide and clomiphene citrate stimulation tests)
Lymphocytic hypophysitis	Acute	+/-	+	Oligo/amenorrhea	Associated with autoimmune conditions Generalized headache Retro-orbital or Bitemporal pain Mass lesion effect such as visual field defects	DI Autoimmune thyroiditis	Decreased pituitary hormones(Gonadotropins most common) Hyperprolactinemia(40%) GH excess	Pituitary biopsy: lymphocytic infiltration	CT & MRI: Features of a pituitary mass Diffuse and homogeneous contrast enhancement	Assays for: Anti-TPO Ab Anti-Tg Ab
Pituitary apoplexy	Acute	+/-	++	Oligo/amenorrhea	Severe headache Nausea and vomiting Paralysis of eye muscles (diplopia) Changes in vision	Visual acuity defects CN palsies (nerves III, IV, V , and VI)	Decreased levels of anterior pituitary hormones in blood.	MRI	CT scan without contrast: Hemorrhage on CT presents as a hyperdense lesion MRI: If inconclusive CT	Blood tests may be done to check: PT/INR and aPTT Pituitary hormonal assay
Empty sella syndrome	Chronic	–	+	Oligo/amenorrhea	Erectile dysfunction Headache Low libido	Signs of raised intracranial pressure may be present Nipple discharge	Decreased levels of pituitary hormones in blood.	MRI	Empty sella containing CSF	Pituitary hormone stimulation tests (Metoclopramide and clomiphene citrate stimulation tests)
Simmonds’ disease/Pituitary cachexia	Chronic	+/-	+	Oligo/amenorrhea	Cachexia Premature aging	Progressive emaciation Loss of body hair	Decreased levels of anterior pituitary hormones in blood.	MRI	Done to rule out any pituitary cause	Pituitary hormone stimulation tests (Metoclopramide and clomiphene citrate stimulation tests)
Hypothyroidism	Chronic	+/-	–	Oligomenorrhea/menorrhagia	Cold intolerance Constipation	Dry skin Bradycardia Hair loss Myxedema Delayed relaxation phase of deep tendon reflexes	Low T3,T4 Normal/low TSH Rest of pituitary hormone levels NL	TSH levels	Done to rule out any pituitary cause	Assays for anti-TPO Ab and anti-Tg Ab FNA biopsy
Hypogonadotropic hypogonadism	Chronic	–	–	Oligo/amenorrhea	Hot flushes Energy and mood changes Decreased libido	Breast tissue atrophy Decreased maturation of vaginal mucosa	Low estrogen, testosterone High FSH/LH	FSH LH	Done to rule out any pituitary cause	Genetic tests  (karyotype) Measurement of total and free testosterone and 17-hydroxyprogesterone concentrations
Hypoprolactinemia	Chronic	–	+	–	Infertility Subfertiliy	Puerperal agalactogenesis	No workup is necessary	Decreased prolactin levels	Done to rule out any pituitary cause	Prolactin assay in 3rd trimester LH, FSH Thyrotropin and free thyroxine
Panhypopituitarism	Chronic	–	+	Oligo/amenorrhea	Polyuria Polydipsia Features of hypothyroidism and hypoadrenalism	Growth failure B/L hemianopsia Papilledema	All pituitary hormones decreased	MRI	Done to rule out any pituitary cause	Left hand and wrist radiograph for bone age
Primary adrenal insufficiency/Addison’s disease	Chronic	–	–	–	Hypoglycemia Hypotension	Dehydration Hyperpigmentation loss of pubic and axillary hair	Hyponatremia with/without hyperkalemia Plasma renin activity to aldosterone ratio	Abdominal CT	Abdominal CT	Serum cortisol testing Serum ACTH testing Anti-adrenal Ab testing
Menopause	Chronic	–	+/-	Oligo/amenorrhea	Hot flashes Insomnia Weight gain and bloating Mood changes	Vaginal atrophy Loss of pelvic muscle tone	↑ FSH ↓ Estradiol and inhibin	FSH > LH	Normal	Endometrial biopsy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]

The incidence of Sheehan’s syndrome is difficult to assess. It was found to be the 6th most common cause of growth hormone (GH) deficiency with an incidence of 3.1% of cases. In 2009, the prevalence of Sheehan’s syndrome was estimated to be 5.1 per 100,000 women. It is less prevalent in developed countries due to better obstetrical care and maternal health awareness. It is still one of the most common causes of hypopituitarism in developing countries.

• The incidence of Sheehan’s syndrome is difficult to assess.^[1]
• It was found to be the 6th most common cause of GH deficiency with an incidence of 3,100 per 100,000 persons.^[2]
• Nowadays, Sheehan’s syndrome is not a common consequence of puerperal hemorrhage due to improved obstetrical care.^[3]

• In 2009, the prevalence of Sheehan’s syndrome was estimated to be 5.1 per 100,000 women in Iceland.^[4]

• Sheehan’s syndrome is usually diagnosed in women of childbearing age only.

• There is no racial predilection for Sheehan’s syndrome but it usually affects females of Asian or Hispanic ethnicity.

• Sheehan’s syndrome affects only females.

• The majority of Sheehan’s syndrome cases are reported in developing countries.

• It is less prevalent in developed countries due to better obstetrical care and maternal health awareness.^[3][5]

• It is still one of the most common causes of hypopituitarism in developing countries.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]

Common risk factors in the development of Sheehan’s syndrome include pregnancy, severe/massive postpartum hemorrhage (PPH), pituitary mass, pre-existing vascular diseases, autoimmunity, DIC, smaller and rigid sella, and traumatic delivery.

• Common risk factors in the development of Sheehan’s syndrome are including:^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]}
  • Pregnancy
  • Severe/massive post partum hemorrhage
  • Pituitary mass
  • Pre-existing vascular diseases
  • Autoimmunity
  • Disseminated intravascular coagulation
  • Smaller and rigid sella
  • Traumatic delivery

Less Common Risk Factors

• Multiple gestations
• Placental abnormalities
• Type 1 Diabetes mellitus

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]

There is insufficient evidence to recommend routine screening for Sheehan’s syndrome.

There is insufficient evidence to recommend routine screening for Sheehan’s syndrome.

​ Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Iqra Qamar M.D.[2]

Sheehan’s syndrome leads to hypopituitarism and empty sella syndrome, if left untreated. Common complications are including adrenal crisis, hypotension, hypothyroidism, and hypopituitarism. Prognosis is generally excellent provided early diagnosis and management resulting in complete reversal of symptoms.

• Sheehan’s syndrome usually results in anterior pituitary shrinkage within 20 days, followed by disappearance of pituitary tissue in 6-8 week; resulting in hypopituitarism and empty sella syndrome.
• The symptoms of Sheehan’s syndrome can develop during immediate post-puerperal period to years after delivery.
• It may result in sparing or reversal of gonadotropic dysfunction as few cases of successful pregnancies have been reported following Sheehan’s syndrome.^[1][2]
• If left untreated, lead to mitral regurgitation, pericardial effusion, and diminished left ventricular motion, adrenal crisis, hypopituitarism, and empty sella syndrome.^[3]

• Common complications of Sheehan’s syndrome are including:
  • Adrenal crisis
  • Hypotension
  • Hypothyroidism
  • Menstrual irregularities
  • Empty sella syndrome

• Prognosis is generally good, and results in reversal of symptoms once respective hormones are being replaced.

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