Sheehan's syndrome pathophysiology

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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]

Overview

It is thought that Sheehan's syndrome is the result of ischemic necrosis of pituitary gland, due to pituitary gland enlargement during parturition; 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 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; manifests as a wide spectrum of presentation. Usually, GH deficiency is the earliest one to develop.

Pathophysiology

Anterior pituitary (Adenohypophysis)

• Anterior pituitary does not have a direct blood supply and is supplied by the hypophyseal portal system.
• The hypophyseal portal system is a fenestrated set of capillaries that allows rapid exchange of hormones between the hypothalamus and anterior pituitary.
• Occlusion of the blood supply and other vascular abnormalities of the hypophyseal portal system may also cause complications with the exchange of hormones between the hypothalamus and the pituitary gland leading to hypopituitarism.

Posterior pituitary (Neurohypophysis)

• Posterior pituitary has its own blood supply via inferior hypophyseal artery and is less commonly affected as compared to anterior pituitary.
• If posterior pituitary is affected, it can result in neurohypophseal dysfunction and ischemic necrosis of thirst center leading to increased osmotic threshold for thirst onset.

Hypothalamic and pituitary hormones with their action on the target glands

	Hypothalamic hormone	Mode of action	Pituitary hormone or target organ	Action
Anterior pituitary hormones	Thyrotropin-releasing hormone	Stimulatory	Thyrotropin	Stimulates triiodothyronine and thyroxine production
	Corticotropin-releasing hormone	Stimulatory	Corticotropin	Stimulates production of cortisol and adrenal androgens
		Stimulatory	Prolactin	Stimulates milk production from breasts in females
	Gonadotropin-releasing hormone	Stimulatory	Follicle stimulating hormone Leutinizing hormone	Males: stimulates testosterone production and spermatogenesis Female: stimulates estradiol and progesterone production, ovulation and folliculogenesis
	Dopamine	Inhibitory	Prolactin	_
	Growth hormone-releasing hormone	Stimulatory	Growth hormone	Stimulates insulin-like growth factor 1 production
	Somatostatin	Inhibitory	Growth hormone	_
Posterior pituitary hormones	Vasopressin	Stimulatory		Stimulates free water reabsorption in the collecting ducts
	Oxytocin	Stimulatory	Breast, uterus	Stimulates milk ejection and uterine contraction

Pathogenesis

DIC‡

Severe PPH†

Glandular hypertrophy and hyperplasia

Small sella size

Autoimmunity

Hypotension/Shock

Pituitary enlargement

Pituitary compression

Blood supply compression

Ischemic necrosis

Hypopituitarism

Amenorrhea

Agalactorrhea

Secondary adrenal insufficiency

Hypothyroidism

‡Disseminated intravascular coagulation (DIC) due to Amniotic fluid embolism or HELLP Syndrome.
†Postpartum hemorrhage (PPH) i.e., >500 ml after vaginal delivery or 1000 ml after C-section.

• Pituitary gland is amongst the most vascularized tissues in the body that normally weighs about 0.5 g but gets doubled in size during pregnancy.
• Pituitary gland enlargement due to hypertrophy and hyperplasia of lactotrophic cells in anterior pituitary result in superior hypophyseal artery compression which is complicated by decreased portal pressure and vasospasm during delivery, playing an important role in the pathogenesis of Sheehan's syndrome.
• 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 are understood to play a role in the pathogenesis of Sheehan's syndrome.
• It is believed that tissue necrosis results in release of sequestered antigens, precipitating autoimmunity of the pituitary gland and hypopituitarism in Sheehan's syndrome.
• Type 1 diabetes, pre-existing vascular diseases and any pituitary masses are associated with increased risk of developing Sheehan's syndrome in pregnancy.

Anterior pituitary

• Anterior pituitary does not have a direct blood supply and is supplied by hypophyseal portal system.
• The hypophyseal portal system is a fenestrated set of capillaries and allows rapid exchange of hormones between hypothalamus and anterior pituitary.
• Occlusion and other vascular abnormalities of the hypophyseal portal system can also cause complications in the exchange of hormones between the hypothalamus and the pituitary gland leading to hypopituitarism.

Posterior pituitary

• Posterior pituitary has its own blood supply via inferior hypophyseal artery and is less commonly affected as compared to anterior pituitary.
• If posterior pituitary is affected, it can result in neurohypophseal dysfunction and ischemic necrosis of thirst center leading to increased osmotic threshold for thirst onset.
• Severe PPH (loss of >500ml of blood during the first 24hr) leading to hypotension and ischemic necrosis of pituitary gland is the most common cause of Sheehan's syndrome.
• Sheehan's syndrome results in mild to severe pituitary dysfunction resulting in partial or panhypopituitarism such as GH, thyroid hormone, glucocorticoid, gonadotropins (LH, FSH), and prolactin hormone deficiencies that manifest as a wide spectrum of presentation.
• Usually, GH levels decrease first before others.

Genetics

There is no genetic association found to be associated with Sheehan's syndrome.

Associated Conditions

Sheehan's syndrome is associated with:

• Pregnancy
• PPH
• Type 1 diabetes
• Pre-existing vascular diseases such as thrombosis and DIC
• Hypotension

Gross Pathology

• On gross pathology, pituitary gland sequentialy changes from an enlarged pituitary gland to a small shrunken or atrophic gland which is later replaced by remnants of pituitary or CSF.

Microscopic Pathology

On microscopy, the following findings may be observed:

• Ischemic necrosis leading to scarring of neurohypophysis
• Scarring of paraventricular and supraoptic nuclei

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