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Sheehan's syndrome, also known as postpartum pituitary gland necrosis, occurs when the
pituitary gland The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the human brain, brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus contr ...
is damaged due to significant
blood loss Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, v ...
and
hypovolemic shock Hypovolemic shock is a form of Shock (circulatory), shock caused by severe hypovolemia (insufficient blood volume or extracellular fluid in the body). It can be caused by severe dehydration or blood loss. Hypovolemic shock is a medical emergency ...
(ischemic
necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...
) or stroke, originally described during or after
childbirth Childbirth, also known as labour, parturition and delivery, is the completion of pregnancy, where one or more Fetus, fetuses exits the Womb, internal environment of the mother via vaginal delivery or caesarean section and becomes a newborn to ...
leading to decreased functioning of the pituitary gland ( hypopituitarism). Classically, in the milder partial form, the mother is unable to breastfeed her baby, due to failure of the pituitary to secrete the hormone prolactin, and also has no more periods, because FSH (Follicle Stimulating Hormone) and LH (Luteinising Hormone) are not secreted. Although postmenopausal, the mother with this milder form of Sheehan's syndrome does not experience hot flushes, because the pituitary fails to secrete FSH (high levels of FSH, secreted by the pituitary in healthy postmenopausal women is an attempt to trigger ovulation, and these high levels of FSH cause hot the flushes). The failure to breastfeed and
amenorrhea Amenorrhea or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age. Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding). In humans, it is wher ...
no more periods, were seen as the syndrome (a collection of symptoms), but we now view Sheehan's as the pituitary failing to secrete 1-5 of the 9 hormones that it normally produces (the anterior (front) lobe of the pituitary produces FSH, LH, prolactin, ACTH (Adreno-cortico-trophic hormone),TSH (Thyroid Stimulating Hormone) and GH (Growth Hormone); the posterior (the lobe at the back) pituitary produces ADH (Anti-Diuretic Hormone) and Oxytocin, i.e. the pituitary is involved in the regulation of many hormones. It is very important to recognise Sheehan' stroke as, the ACTH deficiency Sheehan's in the presence of the stress of a bacterial infection, such as a urine infection, will result in death of the mother from Addisonian crisis. This gland is located on the under-surface of the brain, the shape of a cherry and the size of a chickpea and sits in a pit or depression of the sphenoid bone known as the
sella turcica The sella turcica (Latin for 'Turkish saddle') is a saddle-shaped depression in the body of the sphenoid bone of the human skull and of the skulls of other hominids including chimpanzees, gorillas and orangutans. It serves as a cephalometric la ...
(the Turk's saddle). The pituitary gland works in conjunction with the
hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
, and other endocrine organs to modulate numerous bodily functions including growth, metabolism,
menstruation Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and Mucous membrane, mucosal tissue from the endometrium, inner lining of the uterus through the vagina. The menstrual cycle is characterized ...
,
lactation Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The process ...
, and even the "
fight-or-flight The fight-or-flight or the fight-flight-freeze-or-fawn (also called hyperarousal or the acute stress response) is a physiological reaction that occurs in response to a perceived harmful event, attack, or threat to survival. It was first describ ...
" response. These endocrine organs, (like the thyroid gland in the neck, or adrenals on the upper pole of the kidneys), release hormones in very specific pathways, known as hormonal axes. For example, the release of a hormone in the hypothalamus will target the pituitary to trigger the release thyroid stimulating hormone (TSH), and the pituitary's released hormone (TSH) will target the next organ in the pathway i.e. the thyroid to release thyroxin. Hence, damage to the pituitary gland can have downstream effects on any of the aforementioned bodily functions.


Signs and symptoms

The various signs and symptoms in Sheehan's syndrome are caused by damage to the pituitary, thereby causing a decrease in one or more of the hormones it normally secretes. Since the pituitary controls many glands in the
endocrine system The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant Organ (biology), organs. In vertebrat ...
, partial or complete loss of a variety of functions may result. Many of the signs and symptoms of Sheehan's are considered "nonspecific" in the medical community; in other words these signs and symptoms are seen in a number of different disease processes, and are not specific to a singular disease or syndrome. In some cases, a woman with Sheehan syndrome may be relatively asymptomatic initially; therefore, the diagnosis would not be made until years later when features of hypopituitarism become evident. In rare instances this syndrome can present acutely with unstable vital signs, dangerously low blood glucose levels, heart failure, or even psychosis. Hypopituitarism can lead to an interruption in any of the following hormone pathways: thyroid disorder (secondary
hypothyroidism Hypothyroidism is an endocrine disease in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as cold intolerance, poor ability to tolerate cold, fatigue, extreme fatigue, muscle aches, co ...
), adrenal gland (adrenal insufficiency due to glucocorticoid deficiency), sex hormone (gonadotropin deficiency), prolactin (a hormone responsible for lactation), growth hormone, or rarely anti-diuretic hormone deficiency (central
diabetes insipidus Diabetes insipidus (DI) is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced can be nearly 20 liters per day. Reduction of fluid has little effect on the concentration of the urine. ...
). Since damage to the pituitary can cause a deficiency in more than one of these hormone pathways simultaneously, it is possible to have a mix of any of the signs or symptoms listed below. Sheehan's syndrome's most common initial symptoms are difficulties with or total absence of lactation ( agalactorrhea). Another common sign is infrequent menstrual cycles (
oligomenorrhea Oligomenorrhea is characterised by infrequent menstrual periods. Generally, the menstrual periods occur at intervals of greater than 35 days, with fewer than 9 periods in a year, where previously there had been a regularly established pattern. Th ...
) or absent menstrual cycles (
amenorrhea Amenorrhea or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age. Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding). In humans, it is wher ...
) following delivery. In addition to menstrual irregularities other signs of sex hormone deficiency are hot flashes, decreased libido, and breast involution. Symptoms and signs of thyroid disorder are tiredness, intolerance to cold,
constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...
,
weight gain Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition. Description Weight gain occurs ...
,
hair loss Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarring ...
, slowed thinking, as well as a slowed heart rate and low blood pressure. Adrenal gland malfunction can present acutely or chronically. In a more chronic case, it is similar to
Addison's disease Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adr ...
with symptoms including
fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...
,
weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...
,
hypoglycemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...
(low blood sugar levels), low hemoglobin levels (anemia) and
hyponatremia Hyponatremia or hyponatraemia is a low concentration of sodium in the Serum (blood), blood. It is generally defined as a sodium concentration of less than 135 mmol/L (135 mEq/L), with severe hyponatremia being below 120 mEq/L. Symp ...
(low sodium levels) that develop over several months or years. Acute adrenal insufficiency is referred to as an adrenal crisis, which can be life-threatening, and occurs very shortly after the inciting event i.e. significant blood loss post-partum in the context of Sheehan's syndrome. Adrenal crisis signs and symptoms include hypoglycemia, hypotension, weakness, fatigue, and seizures from severe hyponatremia. Growth hormone deficiency is one of the most common hormone deficiencies of hypopituitarism seen in Sheehan's syndrome. Low levels of growth hormone may present with low energy, body aches, or subtle wrinkling of the skin around the eyes or mouth. The symptoms of anti-diuretic hormone deficiency are increased thirst, excessive urination, headache, and fatigue. Hematological changes might be seen as well such as anemia or low platelets (thrombocytopenia). Hyponatremia is seen in many cases of Sheehan's syndrome because it can result from multiple etiologies. Drops in thyroid hormones and glucocorticoid/adrenal hormones can indirectly lead to hyponatremia through water retention, while blood loss can trigger hyponatremia through ADH secretion. The development of Syndrome of Inappropriate Anti-Diuretic Hormone in patients with Sheehan's syndrome has been documented in the literature, although the mechanism is not well understood.


Causes

As stated, Sheehan's syndrome is caused by damage to the pituitary, thereby causing a decrease in one or more of the hormones it normally secretes. Sheehan's syndrome typically occurs because of excessive blood loss after delivery (post-partum hemorrhage), although there are several risk factors that may contribute to its development. This syndrome does not appear to be exclusively linked to childbirth, as Sheehan's syndrome has been reported in pregnant patients that experienced massive hemorrhage from non-obstetrical causes. The pituitary gland grows and has a higher metabolic demand during pregnancy because the pituitary needs to rev up the production of certain hormones associated with pregnancy. This higher metabolic demand, in turn, leads to higher demand for blood flow. Thus, if the body enters a state of shock from excessive blood loss in post-partum delivery, the pituitary gland is more susceptible to injury. Although the vast majority of cases of Sheehan's syndrome occur in the setting of massive blood loss, cases have been documented of acute Sheehan's syndrome occurring with blood loss volumes that are not considered "massive". Some possible predisposing factors to Sheehan's syndrome may include: disseminated blood coagulation (DIC), hypotension, small sella turcica size, and blood clots from a pre-existing hypercoagulable disorder.
Atony This glossary of medical terms is a list of definitions about medicine, its sub-disciplines, and related fields. A *Aarskog–Scott syndrome – (AAS) A rare, inherited (X-linked) disease characterized by short stature, facial abnormalities, s ...
of the uterus is a leading cause of post-partum hemorrhage, therefore uterine atony could induce Sheehan's syndrome.


Pathophysiology

This syndrome seems to arise when certain factors compound each other to cause pituitary injury. The physiologic enlargement of the pituitary gland in conjunction with an interference in its blood supply, such as
episiotomy Episiotomy, also known as perineotomy, is a surgical incision of the perineum and the posterior vaginal wall generally done by an obstetrician. This is usually performed during the second stage of labor to quickly enlarge the aperture, allowing ...
progressing to anal tearing, ultimately result in pituitary ischemia and necrosis. One cause of pituitary growth associated with the risk of Sheehan's syndrome is the hyperplasia of lactotrophs which produce prolactin, the hormone responsible for milk production. Other hormone-secreting cells of the pituitary undergo rapid growth in pregnant women as well, which contribute to the gland's enlargement. The anterior pituitary is supplied by a low pressure
portal venous system In the circulatory system of vertebrates, a portal venous system occurs when a capillary bed pools into another capillary bed through veins, without first going through the heart. Both capillary beds and the blood vessels that connect them ar ...
. The anterior pituitary is more commonly affected in Sheehan's syndrome because of the structure of the portal venous system. Posterior pituitary involvement leading to central diabetes insipidus is much rarer, and typically reflects more extensive damage to the organ and more severe disease. It has been suggested that the arrangement of the pituitary's blood supply contribute to its susceptibility for injury. "The highly vascularized pituitary tissue involves one of the most rapid blood flow in the human body and probably, therefore, has a tendency to infarction because even small degrees of change in the pituitary intravascular pressure cause an arrest of blood flow".
Ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
may occur as a result of
vasospasm Vasospasm refers to a condition in which an arterial spasm leads to vasoconstriction. This can lead to tissue ischemia (insufficient blood flow) and tissue death (necrosis). Along with physical resistance, vasospasm is a main cause of ischemi ...
from shock, hypotension,
thrombosis Thrombosis () is the formation of a Thrombus, blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thrombocytes) and fib ...
, or direct vascular compression of the hypophyseal artery from the enlarged pituitary gland itself. The presence of
disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking Microvessel, small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems ...
(i.e., in
amniotic fluid embolism An amniotic fluid embolism (AFE) is a life-threatening childbirth ( obstetric) emergency in which amniotic fluid enters the blood stream of the mother, triggering a serious reaction which results in cardiorespiratory (heart and lung) collapse a ...
or HELLP syndrome) also appears to be a factor in its development.


Diagnosis

Typically an important clue that leads to a diagnosis of Sheehan's syndrome is identifying a deficiency in one or more of the hormones produced directly, or indirectly, by the pituitary gland. The extent of hormone deficiency, and which hormones are affected depends on the extent of the damage to the pituitary. Hormonal assays measure the levels of these hormones which include but are not limited to T4, TSH,
estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
,
gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. They are central to the complex endocrine system that regulates normal growth, sexual development, and reproductive function. T ...
,
cortisol Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone. Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...
, and
ACTH Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...
. It might be difficult to detect damage to these hormone pathways if hormone levels are at the borderline of the abnormal range. In this case, stimulation tests will be done to determine if the pituitary is responsive to hypothalamic hormones.
MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
is useful in diagnosing Sheehan's syndrome since it examines the structure of the pituitary and may identify any anatomical damage. MRI findings will vary based on how early or late in the disease process the test is being conducted. If an MRI is conducted early enough in the disease process the pituitary may appear larger than normal, and show changes that are consistent with damage from lack of blood supply. Later in the disease process of this syndrome the damage imposed on the pituitary gland will cause it to shrink, and leave a partially empty or totally empty sella turcica on MRI.


Treatment

The mainstay of treatment is hormone replacement therapy for the hormones that are missing. Treatment plans and dosages should be individualized by an
endocrinologist Endocrinology (from ''endocrine'' + '' -ology'') is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions known as hormones. It is also concerned with the integration of developmental events ...
. Glucocorticoids may be administered to address or prevent an adrenal crisis, a potential serious complication of Sheehan's syndrome. Hormone replacement is vital in reducing the morbidity and mortality of this syndrome.


Epidemiology

The exact prevalence of this syndrome is difficult to define because the incidence varies so much from country to country. Sheehan syndrome is more prevalent in developing countries than developed countries. In a study from the United Kingdom in 2001 only 1.4% of patients with hypopituitarism were diagnosed with Sheehan's syndrome. Just a few years earlier in 1996 the World Health Organization estimated that 3 million women were effected by Sheehan's syndrome. In a study of 1,034 symptomatic adults, Sheehan's syndrome was found to be the sixth-most frequent etiology of growth hormone deficiency, being responsible for 3.1% of cases (versus 53.9% due to a pituitary tumor). Additionally, it was found that the majority of women who experienced Sheehan syndrome gave birth at home rather than in a hospital.


History

The specific association with postpartum shock or hemorrhage was described in 1937 by the British pathologist Harold Leeming Sheehan (1900–1988). The initial distinction was made in the research article "Post-Partum Necrosis of the Anterior Pituitary". In his research, Dr. Sheehan reviewed (through
autopsy An autopsy (also referred to as post-mortem examination, obduction, necropsy, or autopsia cadaverum) is a surgical procedure that consists of a thorough examination of a corpse by dissection to determine the cause, mode, and manner of deat ...
) the effects of pituitary necrosis on 12 cases of patients that experienced postpartum necrosis. He observed cases where lesions and death occurred during or after pregnancy, as well as cases where death occurred in the late stage of necrosis (years later). This started the initial distinction of Sheehan's syndrome from Simmonds' disease (also known as hypopituitarism). Sheehan noted that significant feature of these patients' cases was hemorrhaging, which in his experience was most commonly caused by either:
placenta Previa Placenta praevia or placenta previa is when the placenta attaches inside the uterus but in a position near or over the cervical opening. Symptoms include antepartum bleeding, vaginal bleeding in the second half of pregnancy. The bleeding is bright ...
(low placenta), uterine rupture, cervical or uterine tears, post-partum
atony This glossary of medical terms is a list of definitions about medicine, its sub-disciplines, and related fields. A *Aarskog–Scott syndrome – (AAS) A rare, inherited (X-linked) disease characterized by short stature, facial abnormalities, s ...
, or retained placenta.
Simmonds' disease Sheehan's syndrome, also known as postpartum pituitary gland necrosis, occurs when the pituitary gland is damaged due to significant blood loss and hypovolemic shock (ischemic necrosis) or stroke, originally described during or after childbirth le ...
, however, occurs in either sex due to causes unrelated to pregnancy. However, in his 1939 publication, "Simmonds' Disease due to Post-partum Necrosis of the Anterior Pituitary", Sheehan displays post-partum necrosis as a cause of Simmonds' disease, thus establishing the relationship between the two conditions. According to Sheehan in 1939 approximately 41% of survivors of severe
postpartum hemorrhage Postpartum bleeding or postpartum hemorrhage (PPH) is often defined as the loss of more than 500 ml or 1,000 ml of blood following childbirth. Some have added the requirement that there also be signs or symptoms of low blood volume fo ...
(PPH) and/or
hypovolemic shock Hypovolemic shock is a form of Shock (circulatory), shock caused by severe hypovolemia (insufficient blood volume or extracellular fluid in the body). It can be caused by severe dehydration or blood loss. Hypovolemic shock is a medical emergency ...
experienced severe or partial hypopituitarism.


Society and culture

In the developed world Sheehan's Syndrome is a rare complication of
pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...
; although this syndrome is more prevalent in developing countries it continues to effect women around the world. A retrospective study in Turkey found that the prevalence of Sheehan's syndrome was directly proportional to the amount of at-home deliveries each decade. This may be due to previously limited obstetric techniques present in a home environment. Blood loss associated with episiotomy and forceps exacerbating blood loss when the placenta separates from the wall of the uterus, particularly in mothers with low blood pressure, even in obstetric setting, namely hospital, caused a more subtle Sheehan's syndrome of Growth Hormone, Anti-Duretic Hormone, ACTH deficiency, which may be life threatening if missed; PubMed.gov Sheehan's in modern times:a nationwide retrospective study Iceland 2011, where every mother gives birth in hospital, with full obstetric care available.


Research

At present, the part that autoimmunity plays in the development of Sheehan's syndrome is uncertain. Several case reports have identified anti-pituitary antibodies in patients diagnosed with Sheehan's. Some patients also tested positive for anti-hypothalamus antibodies. Given that many patients that have developed Sheehan's syndrome do not have detectable levels of these antibodies, it is unclear whether these antibodies cause this syndrome or result from it.


References


External links

{{Authority control Pituitary disorders Obstetrics Syndromes