PRIMER

Sheehan syndrome
Züleyha Karaca1, Bashir A. Laway2, Hatice S. Dokmetas3, Hulusi Atmaca4
and Fahrettin Kelestimur1
Abstract | Sheehan syndrome or postpartum hypopituitarism is a condition characterized by
hypopituitarism due to necrosis of the pituitary gland. The initial insult is caused by massive
postpartum haemorrhage (PPH), leading to impaired blood supply to the pituitary gland, which has
become enlarged during pregnancy. Small sella turcica size, vasospasms (caused by PPH) and/or
thrombosis (associated with pregnancy or coagulation disorders) are predisposing factors;
autoimmunity might be involved in the progressive worsening of pituitary functions. Symptoms are
caused by a decrease or absence of one or more of the pituitary hormones, and vary, among others,
from failure to lactate and nonspecific symptoms (such as fatigue) to severe adrenal crisis.
In accordance with the location of hormone-secreting cells relative to the vasculature, the secretion of
growth hormone and prolactin is most commonly affected, followed by follicle-stimulating hormone
and luteinizing hormone; severe necrosis of the pituitary gland also affects the secretion of thyroid-
stimulating hormone and adrenocorticotropic hormone. Symptoms usually become evident years
after delivery, but can, in rare cases, develop acutely. The incidence of Sheehan syndrome depends, to
a large extent, on the occurrence and management of PPH. Sheehan syndrome is an important cause
of hypopituitarism in developing countries, but has become rare in developed countries. Diagnosis is
based on clinical manifestations combined with a history of severe PPH; hormone levels and/or
stimulation tests can confirm clinical suspicion. Hormone replacement therapy is the only available
management option so far.

Sheehan syndrome refers to postpartum hypopitu­
itarism or a decrease or absence of one or more of
the hormones secreted by the pituitary gland (further
referred to as hypopituitarism) (TABLE 1). The disorder
is caused by necrosis of the pituitary gland (FIG. 1a) as a
consequence of severe hypotension or shock owing to
­massive uterine bleeding during or soon after child­
birth. The disorder was first described by Harold
Leeming Sheehan in 1937 (REF. 1), although he used the
terms postpartum pituitary necrosis and hypopituitar­
ism2. Sheehan syndrome is characterized by variable
degrees of anterior and sometimes posterior pituitary
gland dysfunction. Deficiencies of the hormones that
are secreted by the anterior pituitary gland can result
in secondary hypothyroidism, adrenal failure, hypo­
gonadism, lactation failure and growth hormone (GH)
Correspondence to F.K. deficiency. Although rare, the posterior pituitary gland
Department of Endocrinology, might also be affected, which can result in central dia­
Erciyes University Medical betes insipidus (a lack of arginine vasopressin (AVP)
School, 38039, Kayseri,
that causes polyuria). The incidence of Sheehan syn­
Turkey.
fktimur@erciyes.edu.tr drome has declined in the past few decades in the devel­
oped world as a result of modernized obstetrical care,
Article number: 16092
doi:10.1038/nrdp.2016.92 although the numbers might be underestimated owing
Published online 22 Dec 2016 to less recognition of the syndrome among medical
professionals3,4. The syndrome has been increasingly
recognized as one of the leading causes of hypopitu­
itarism in developing countries5,6 and thus represents a
considerable public health concern worldwide. Sheehan
syndrome is associated with increased morbidity con­
sidering its nonspecific signs and symptoms and most
patients remain undiagnosed and untreated for a long
time. In  this Primer, we provide a comprehensive
­overview of Sheehan syndrome.
Epidemiology
Studies conducted so far, although limited in number,
show that hypopituitarism is a relatively rare condi­
tion in the developed world (TABLE 2). One population
study in Spain reported a prevalence of hypopitu­
itarism of 45.5 per 1,000,000 and an incidence of 4.2
new cases per 1,000,000 per person per year in 2001
(REF. 7). Pituitary tumours and their treatments are the
most common causes of hypopituitarism (~60%) and
~30% of hypopituitarism cases have a non-tumour
origin. Sheehan syndrome explains 6% of all causes of
hypopituitarism. A more recent study in the same area
published in 2013, comprising 405,218 adults followed
for a period of 10 years, showed a prevalence and an

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Author addresses Mechanisms/pathophysiology

1
Department of Endocrinology, Erciyes University Medical
School, 38039, Kayseri, Turkey.
2
Department of Endocrinology, Sher‑I‑Kashmir Institute
of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir,
India.
3
Department of Endocrinology, Istanbul Medipol
University Medical School, Istanbul, Turkey.
4
Department of Endocrinology, Ondokuz Mayıs University
Medical School, Samsun, Turkey.
incidence of hypopituitarism of 37.5 cases per 100,000
inhabitants and 2.07 cases per 100,000 inhabitants per
year, respectively 8. No cases of Sheehan syndrome were
identified, which might be explained by an improve­
ment in ­obstetrical care during the 12 years between
these two studies.
Indeed, severe postpartum haemorrhage (PPH) is an
important risk factor for the development of Sheehan
syndrome. As early as in 1939, Sheehan estimated that
41% of women who survived severe PPH and/or hypo­
volemic shock had either partial or severe hypopitu­
itarism compared with 15% of women with moderate
PPH9. Improvements in obstetrical care and methods
of preventing hypovolemic shock despite severe blood
loss (such as early blood trans­fusion and/or administra­
tion of intravenous fluids) have considerably decreased
the incidence of Sheehan syndrome in developed
­countries10,11. However, owing to the continuing practice
of home deliveries12 and poor health care structure in
some primary-care hospitals, Sheehan syndrome con­
tinues to be a cause of prevent­able h­ ypopituitarism in
women in developed countries (TABLE 2).
The prevalence of Sheehan syndrome is higher in
developing countries than in developed countries
(TABLE 2). For example, in Kashmir, India, the preva­
lence of Sheehan syndrome was estimated to be ~3.1%
of parous women ≥20 years of age; ~63% of the women
with Sheehan syndrome in this study had given birth
at home. The high prevalence of Sheehan syndrome
has been suggested to be representative not only of
the whole of India but also of some other developing
­c ountries with similar obstetrical care available to
the general population6. A retrospective study from a
tertiary-care hospital in the Philippines showed that
pituitary adenomas were the most common cause of
hypopituitarism (40% of 143 patients with hypopitu­
itarism), whereas Sheehan syndrome was the third-
most common aetiology (8% of all patients with
hypopituitarism)13. Sheehan syndrome was even the
most common cause of hypopituitarism in women
in Turkey 14. The disorder is more common in older
women than in young women (<40 years of age), with
a mean age of diagnosis of 52.8 years (standard devi­
ation (SD) ± 12.3 years)14. Another retrospective study
conducted in Turkey showed that the number of new
patients with Sheehan syndrome diagnosed each ­decade
was directly proportional to the number of home-­
conducted deliveries, although five new cases were seen
in patients who had delivered in the hospital5.
Vascularization of the pituitary gland
The pituitary gland receives its arterial blood supply
from the superior and inferior hypophyseal arteries
(FIG. 1b). The infundibulum, the median eminence (a part
of the hypothalamus from which regulatory hormones
are released) and the pars tuberalis are supplied by the
superior hypophyseal artery (a branch of the internal
carotid artery) and the posterior lobe by the inferior
hypophyseal artery (arising from the meningohypo­
physeal trunk, which is a branch of the internal carotid
artery). By contrast, the pars distalis receives very little to
no arterial blood supply by the internal carotid artery 15,16.
Instead, the pars distalis is mainly supplied by the venous
system; one route of blood supply is through the long
portal veins that descend via the infundibulum and
connect the capillary beds in the pars distalis with those
of the portal capillary system in the median eminence.
In addition, the pars distalis receives venous blood from
the posterior pituitary gland through the short portal
vessels; this route accounts for 30% of the total blood
supply to the anterior pituitary gland17,18. Its unique
circulation allows the pars distalis to receive hormones
from the hypothalamus and the posterior pituitary
gland, besides substances from peripheral circulation.
However, this circulation type makes the pituitary
vulner­able to ischaemia due to hypovolemia and hypo­
tension during the postpartum period, as pregnancy
leads to physiological growth of the pituitary gland and
compression of the vasculature19. Venous drainage of
the anterior pituitary gland is by the hypophyseal veins
and the posterior pituitary gland via the short portal and
hypophyseal veins to the cavernous sinus.
Pituitary hormones
Anterior pituitary hormones are controlled by the releas­
ing and inhibiting factors secreted from the hypothala­
mus20 (TABLE 1). Anterior pituitary hormones stimulate
the secretion of their target hormones, which mediate
most of the outcome, except for prolactin (PRL) and par­
tially GH, which both also have direct effects. Pituitary
hormone secretion is regulated by a feedback mech­
anism. Anterior pituitary hormones regulate the secre­
tion of hypothalamic factors by a feedback mechanism.
The regulation of the hypothalamic–pituitary–adrenal
(HPA) axis as a representative of hormonal axes is shown
in FIG. 2 (REF. 21).
The posterior pituitary gland releases AVP and
oxytocin, both of which are mainly synthesized in the
hypothalamus. Oxytocin is one of the few hormones to
create a positive-feedback loop. Indeed, uterine contrac­
tions stimulate the release of oxytocin, which, in turn,
increases uterine contractions. This positive-feedback
loop continues throughout labour 22.
Pituitary gland enlargement in pregnancy
Pregnancy is a physiological state that puts strains on
the pituitary gland owing to changing demands of
the mother and fetus and the release of hormones by the
­placenta (such as adrenocorticotropic hormone (ACTH),
human chorionic gonadotropin (hCG), estradiol and

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Table 1 | Hormones released by the pituitary gland

Pituitary hormone Secretory Hypothalamic Target hormone Target Disease caused Characteristic
pituitary cell regulatory by deficiency symptoms
hormone of the pituitary
hormone
Anterior lobe
Growth hormone Somatotropic GH-releasing Insulin-like growth Direct effect on GH deficiency Weight gain, impaired
(GH) cells hormone (GHRH) factor 1 (IGF‑1) many organs, quality of life and
and GH-release- mainly the liver decreased lean
inhibiting body mass
hormone
(somatostatin)
Prolactin (PRL) Lactotroph Dopamine Not known Direct effect on the PRL deficiency Failure to lactate
cells mammary gland
Follicle-stimulating Gonadotropic Gonadotropin- Inhibin, estradiol and Release of sex Secondary Amenorrhoea,
hormone (FSH) cells releasing testosterone steroids and inhibin hypogonadism infertility and hair loss
hormone (GnRH) by the gonads
Luteinizing Gonadotropic GnRH Estradiol (in women) Release of sex
hormone (LH) cells and testosterone steroids by the
(in men) gonads
Thyroid-stimulating Thyrotropic Thyrotropin- Tetraiodothyronine Release of thyroid Secondary Weight gain,
hormone (TSH) cells releasing (T4) and hormones by the hypothyroidism constipation and cold
hormone (TRH) tri-iodothyronine (T3) thyroid gland intolerance
Adrenocorticotropic Corticotropic Corticotropin- Cortisol and adrenal Release of Secondary Hypocortisolaemia-
hormone (ACTH) cells releasing androgens glucocorticoids by adrenal related symptoms
hormone (CRH) the adrenal gland insufficiency (for example, weakness,
and AVP fatigue, weight loss,
hypotension and
hypoglycaemia) and
impaired well-being
Posterior lobe
Arginine Produced in the None None Water reabsorption Polyuria Diabetes insipidus
vasopressin (AVP) hypothalamus in the kidney
Oxytocin (OXT) Produced in the None None; Uterine contraction No Absence of uterine
hypothalamus positive-feedback during labour and recognizable contraction during
loop milk flow clinical picture delivery

progesterone, among others). Enlargement of the pitu­
itary gland during pregnancy is well established19; the
gland increases by 45% during the first trimester, reach­
ing up to 120–136% of its original size near term and its
highest volume during the first few weeks of the post­
partum period23,24. The height of the pituitary gland on a
coronal section of an MRI is a good indicator of pituitary
size. The height of the normal pituitary gland is 4–8 mm
in women25, but may increase up to 10 mm during gesta­
tion and up to 12 mm during the immediate postpartum
period. The pituitary gland was shown to regain its nor­
mal size, shape and volume within 6 months following
delivery 26,27 (FIG. 3).
Enlargement of the pituitary gland during preg­
nancy is explained by hyperplasia of the PRL-secreting
(lacto­troph) cells in the anterior pituitary gland28. The
levels of maternal PRL, which is responsible for prepar­
ation of breast tissue for lactation, increase up to ten­
fold parallel to the increased levels of oestrogen during
pregnancy. By 6 weeks after delivery, estradiol secretion
decreases and the basal serum PRL concentration is
usually normal, even when the mother is breastfeed­
ing 29. In contrast to hyperplasia of lactotroph cells, the
numbers of gonado­tropic cells (which secrete luteinizing
hormone (LH) and follicle-stimulating hormone (FSH))
and somatotropic cells (which secrete GH) were shown
to be decreased, whereas the numbers of thyrotropic
cells (which secrete thyroid-stimulating hormone
(TSH)) and corticotropic cells (which secrete ACTH)
remained unchanged during pregnancy 28.
Overall, the pituitary gland becomes vulnerable to
changes in blood flow during and shortly after preg­
nancy owing to the increased size of the gland, leading to
both increased demand and compression of the vascu­
lature of the gland. This explains why haemorrhage and
resulting hypovolemia during delivery causes Sheehan
syndrome, whereas this is not the case if hypovolemia
occurs owing to any other cause.
Mechanisms of Sheehan syndrome
The pathogenesis of Sheehan syndrome remains
­uncertain. Not every patient has a history of massive
PPH nor does every massive PPH lead to Sheehan syn­
drome. Extensive necrosis of the pituitary gland results
in a permanent lack or insufficiency of pituitary hor­
mones; the mechanisms underlying the progression
of the disease in untreated patients have not yet been
fully elucidated. Importantly, the pituitary gland cannot

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a b
Hypothalamic
Hypothalamus
vessels

Optic
chiasma Infundibulum
Posterior lobe
(neurohypophysis)
Primary plexus of
the hypophyseal
portal system
Superior
hypophyseal Long hypophyseal
artery portal veins
*
Anterior
lobe Artery of Short hypophyseal
(adenohypophysis) trabecula portal veins
Pars *
tuberalis Efferent
Pars hypophyseal vein to Capillary plexus of
distalis the cavernous sinus* * the infundibulum
Sphenoid sinus Secondary plexus *
of the hypophyseal
Sella turcica portal system Inferior hypophyseal artery

Figure 1 | Anatomy and vascularization of the pituitary gland. a | The pituitary gland isNaturelocated in the sphenoid
Reviews | Disease bone
Primers
(sella turcica) and is composed of the anterior lobe (adenohypophysis) and the posterior lobe (neurohypophysis).
The anterior lobe is composed of three parts: the pars distalis, which is the main component of adenohypophysis that
secretes anterior pituitary hormones; the pars intermedia, which is suppressed in humans; and the pars tuberalis, which
surrounds the infundibulum144. The optic chiasma (where the optic nerves cross) is located on top of the superior part of
the pituitary gland. b | The infundibulum, median eminence, pars tuberalis and posterior lobe are supplied by the internal
carotid artery, whereas the pars distalis receives most of its blood supply from venous drainage from the infundibulum
and the posterior lobe of the pituitary gland. The venous blood supply makes the anterior pituitary gland vulnerable
to disturbances in blood supply. Part b courtesy of M. E. Aykurt, Erciyes University, Kayseri, Turkey.

regenerate2 and Sheehan syndrome is thus a permanent
secretion disorder 30. There are numerous confounding
factors that affect the initiation and progression of
the disease, which require further investigation: the
severity and spread of necrosis; the age of the patient;
a history of previous births associated with PPH; and
the number of births. Sheehan syndrome is believed
to have an autoimmune component in its pathology,
and a genetic ­predisposition is likely but requires
further investigation.
Predisposing factors. The pathogenesis of postpartum
pituitary necrosis is not well understood. The highly
vascularized pituitary tissue is susceptible to ischae­
mia even with relatively small changes in blood flow 31.
Restricted pituitary blood supply following untreated
severe hypotension associated with PPH is the most
common cause for the development of Sheehan syn­
drome32. Pituitary gland enlargement, small sella tur­
cica (the depression in the skull that houses the pituitary
gland) size, vaso­spasm, thrombosis and coagulation
abnormalities (either acquired, such as disseminated
intravascular coagulation (DIC, which is an acquired
syndrome characterized by disordered blood coagula­
tion) or inherited) are among the proposed predisposing
factors for restricted pituitary blood supply 32 (FIG. 4).
The major contributing factor in the aetiopatho­
genesis of Sheehan syndrome is PPH. Typical obstetrical
history of women with Sheehan syndrome includes a
massive uterine bleeding during or following delivery.
In fact, massive PPH may be predictive for developing
Sheehan syndrome33. PPH results from atony (a loss
of muscle tone) of the uterus, which allows the flow of
blood to the placenta to continue even after d ­ elivery.
Many factors during both pregnancy and deliv­
ery predispose to PPH34 (such as anaemia, obesity and
advanced maternal age), but PPH may occur despite
the absence of these risk factors. PPH is traditionally
defined as blood loss of 500 ml after a vaginal delivery
or 750–1,000 ml after a caesarian s­ ection; massive PPH
is defined as the loss of ≥2,000 ml of blood32,35. Most
pregnant women tolerate a loss of 1,000 ml of blood
with maintenance of heart rate and blood pressure;
blood pressure starts to drop when the loss exceeds
1,500 ml (REF.  36). Untreated PPH, which is defined
as >500–1,000 ml of fluid loss in the 24 hours follow­
ing delivery, might also cause Sheehan syndrome30,33.
In addition to restricted blood supply owing to fluid
loss, blood flow to the pituitary gland might be compro­
mised owing to arterial vasospasm following untreated
severe hypotension. Arterial compression as a conse­
quence of pituitary gland enlargement during preg­
nancy in the setting of a small sella turcica size might
also restrict blood flow. However, Sheehan syndrome
only very rarely develops without any obvious post­
partum blood loss37. Importantly, Sheehan syndrome
may also develop despite the rapid correction of
­hypovolemic shock and DIC38.

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A smaller than normal sella turcica size is a predis­
posing factor for Sheehan syndrome as it may lead to
the compression of the hypophyseal arteries against the
wall of the sella turcica and diaphragm sellae30. The vol­
ume of the sella turcica has been shown to be smaller,
with some exceptions, in women with Sheehan syn­
drome than in those without Sheehan syndrome5,39,40.
The mean sella turcica volume of the patients with
Sheehan syndrome (mean ± SD = 340.5 ± 214 mm³) was
found to be significantly less than that of healthy women
(mean ± SD = 602.5 ± 192 mm³), and, interestingly, the
minimum sella turcica size in ~50% of the patients with
Sheehan syndrome was <308 mm³, which was the lowest
sella turcica size found in healthy women5.
In the absence of PPH, DIC can also contribute to
postpartum pituitary necrosis33,41. The coagulation sys­
tem is continuously activated by exposure to the decidua
(the term for the endometrium during pregnancy) or the
endothelium in patients with DIC42. In addition, patients
with DIC have an increased risk of developing o ­ bstetrical
disorders, including massive PPH43.
The association of haematological abnormalities
with Sheehan syndrome might provide insight into its
aetiology 44,45. The frequency of genetic mutations of
coagulation factor V (F5), coagulation factor II (F2),
methylenetetrahydrofolate reductase (MTHFR*C677T
and MTHFR*A1298C) and plasminogen activator
inhibitor type  1 (PAI1; also known as SERPINE1),
which are well-established risk factors for thrombosis46,
is increased in patients with Sheehan syndrome com­
pared with the general population47, suggesting that
genetic factors involved in the coagulation cascade might
be a predisposing factor. Other recent reports also show
coagulation abnormalities in patients with Sheehan
syndrome48,49 and with pregnancy 50. In genetically pre­
disposed women, pregnancy increases susceptibility
either to thrombophilia or thrombosis.
Disease initiation. The initial insult in Sheehan syn­
drome involves necrosis of the anterior lobe of the pitu­
itary gland owing to infarction or an arrest of blood
flow. Although rare, the posterior pituitary gland can
also be affected51. Tissue infarction can be caused by
vasospasm due to hypotension or shock, thrombosis or
arterial compression. The potential role of vasospasm
is difficult to assess, but the involvement of thrombo­
sis (caused by platelet aggregation or sequestration
along previously damaged endothelial cells) is highly
likely 2. Depending on the size and site of necrosis,
this acute insult can lead to hypofunction of the pitu­
itary gland: it can result in deficiency of hormones2,33.
If ~50% of the normal pituitary gland remains intact,

Table 2 | Epidemiological studies assessing the prevalence of Sheehan syndrome

Study Study period Study type Findings
(study population)
Incidence or prevalence of Sheehan syndrome in the general population
Ramiandrasoa et al.4 1980–2011 (France) Retrospective study 40 patients were diagnosed with Sheehan syndrome
in the southeast of France between 1980 and 2011
Kristjansdottir et al.145 2009 (Iceland) Population-based study Sheehan syndrome was diagnosed in 5.1 individuals
per 100,000 population
Famuyiwa et al.146 1992* (Nigeria) Observational study Two new cases of Sheehan syndrome in a year
Zargar et al.6 2005* (Indian Kashmir) Population-based study Sheehan syndrome was diagnosed in 3.1% of parous
women ≥20 years of age
Diri et al.5 1960–2000 (Turkey) Large cohort of patients diagnosed with 114 patients; the prevalence of Sheehan syndrome
hypopituitarism decreased with hospital deliveries in recent times
Laway et al.95 2010* (Indian Kashmir) Observational study Incidence of one new case a month
Prevalence of Sheehan syndrome in populations with PPH
Sheehan et al.9 1938* (England) Retrospective study in women who 41% of patients with Sheehan syndrome had a
showed symptoms of hypopituitarism history of severe postpartum shock, whereas 15%
had moderate postpartum shock
Asaoka et al.10 1961–1970 (Japan) Retrospective study using questionnaires None among 392 women who responded had
of 1,010 women with a history of PPH Sheehan syndrome‡
Feinberg et al.11 1998–2002 (Chicago) Retrospective study using questionnaires None among 55 women with previous PPH who
of 109 women with previous PPH responded had Sheehan syndrome‡
Prevalence of Sheehan syndrome in a population with GH deficiency or hypopituitarism
Abs et al.3 1999* (Europe) Large multinational cohort of adult GH 3.1% of patients with adult GH deficiency had
deficiency (n = 1,034) Sheehan syndrome
Regal et al.7 1992–1999 (Spain) Population-based study involving 146,000 6% of patients with hypopituitarism had
individuals Sheehan syndrome
Elumir-Mamba et al.13 2010* (Philippines) Retrospective data 8% of patients with hypopituitarism had
Sheehan syndrome
GH, growth hormone; PPH, postpartum haemorrhage. *Publication date instead of study period. ‡Studies limited by questionnaire-based methodology and poor
response rate.

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function is usually not impaired2. However, if >70% gland53 and hypothalamus54 in patients with Sheehan
of the anterior pituitary gland is affected, partial or syndrome may appear many years after the onset of
panhypopituitarism (the absence of anterior pituitary hypopituitarism; however, their presence cannot be
hormones) occurs52. excluded immedi­ately after the initial insult. Whether
these antibodies are a cause or a consequence of
Disease progression. Sheehan syndrome is commonly Sheehan syndrome remains to be answered. However,
characterized by slow progression of pituitary dysfunc­ the exposure of normally sequestered antigens due to
tion, even several years after the initial insult 5 (FIG. 4). tissue necrosis could trigger autoimmunity and may
This finding suggests that there are other contrib­ cause delayed hypopituitarism55. In accordance with
uting factors in the pathogenesis of the disease that these findings, some subsets of peripheral lymphocyte
lead to anterior lobe cell loss in addition to the initial cells were found to be at different levels in patients with
insult. An autoimmune process might be involved in Sheehan syndrome compared with healthy controls,
the worsening of pituitary dysfunction. Some studies which is suggestive of an altered immune regulation56.
have reported that autoantibodies against the pituitary In addition, the percentage of cells that express both
CD3 and DR1, which correlates with the duration of
illness in patients with Sheehan syndrome, is sug­
Hippocampus Amygdala
gestive of an ongoing inflammation accompany­
ing the slow p­ rogression of pituitary dysfunction in
Sheehan syndrome56.
Hypothalamus
Paraventricular Characteristics of pituitary necrosis. In the first
nucleus
reports, acute ischaemic infarction led to extensive
acute necrosis of the pituitary gland, which involved
~90% of the anterior lobe. In the necrotized tissue,
CRH adeno­hypophysis cells were replaced by necrotic debris,
coagulated blood, inflammatory cells and ghost cells.
Immunohistochemical staining showed some cells con­
taining adenophyseal hormones on the edge of the
necrotic areas, but hormones were completely absent
in the centre of the necrotic area1,4. In the chronic phase
Pituitary of the syndrome, a fibrous scar is formed. In addition,
gland the fibrous scar leads to a time-dependent atrophic
change of the pituitary gland and results in an empty
sella ­turcica, which can be radiologically detected33.
Lactotroph and somatotropic cells in the pituitary
gland are usually completely lost, whereas gonadotropic
ACTH and corticotropic cell functions can be preserved57.
This pattern of cell loss is explained by the location
of the cells in the pituitary gland: corticotropic and
Adrenal thyrotropic cells are located in the median wedge
gland and gonado­tropic cells are scattered throughout the
pituitary, whereas somatotropic and lactotroph cells are
located in the lateral wings, which receive blood supply
Glucocorticoids only from the portal circulation32,57.

Regulation of brain and peripheral function Diagnosis, screening and prevention

(stress response)
Figure 2 | Regulation of the
Naturehypothalamic–pituitary–
Reviews | Disease Primers
adrenal axis. Glucocorticoid secretion is regulated by
adrenocorticotropic hormone (ACTH) secretion from
the pituitary gland, which is stimulated by corticotropin-­
releasing hormone (CRH) secretion from the
hypothalamus. CRH is suggested to be regulated from
the upper centres of the brain. Glucocorticoids have
negative-feedback effects on the upper centres of the
brain, the hypothalamus and the pituitary gland. ACTH not
only stimulates glucocorticoids but also stimulates adrenal
androgens and mineralocorticoids. However, given that
aldosterone secretion is primarily regulated by the renin–
angiotensin system, ACTH deficiency does not result in
mineralocorticoid deficiency, but leads to glucocorticoid
deficiency and adrenal androgen deficiency in women.
Clinical manifestations
Sheehan syndrome can be diagnosed by clinical symp­
toms of hypopituitarism32 (BOX 1). According to the
severity of damage to the pituitary gland, patients can
present at the hospital with symptoms ranging from
isolated hypopituitarism to panhypopituitarism5,52,58–64
(TABLE 3). GH and PRL are the most commonly affected
hormones. PRL deficiency leads to postpartum failure
of lactation, and gonadotropin (FSH and LH) deficiency
leads to amenorrhoea. Profound pituitary gland necro­
sis can also lead to TSH and, less frequently, ACTH
deficiencies, which might result in symptoms such as
weight gain, constipation, cold intolerance followed
by hypocortisolaemia-­related symptoms (for exam­
ple, weakness, fatigue, weight loss, hypotension and

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a b Physical examination of patients with chronic

Figure 3 | Enlargement of the pituitary gland during pregnancy.
Nature Reviews | Disease
Coronal Primers
MRI scan
showing the pituitary gland (arrows) of a pregnant women in the third trimester (part a)
and 6 months after delivery (part b).
hypoglycaemia). Although rare, the posterior lobe can
also be affected, which can lead to diabetes insipidus2,65.
Sheehan syndrome can also result in severe clinical
outcomes (such as adrenal crisis, circulatory collapse,
myxoedema coma and hyponatraemia) and can lead to
death if not properly treated. Mortality rate is increased
by 1.2–2.7 times in these patients with Sheehan
­syndrome compared with the general population66.
Some patients are diagnosed with symptoms of
acute hypopituitarism immediately after giving birth67.
Sheehan syndrome can result in death if it is not diag­
nosed and treated in the acute stage. Clinical presen­
tation of acute Sheehan syndrome includes headache,
visual disturbances, loss of consciousness, failure of
lactation and features of acute adrenal insufficiency,
such as hypotension, hypoglycaemia, extreme fatigue,
nausea, vomiting and hyponatraemia37. The syndrome
should be investigated in patients who present with
postpartum hypotension and hypoglycaemia60,67.
However, most patients present with nonspecific
symptoms years after delivery 5,58,64. This delay between
submission for diagnosis and preceding pituitary insult
is common and variably reported to be 7–19 years4–6,68.
Symptoms can emerge late because of incomplete
hypophyseal damage immediately after giving birth
with a slow progression of damage over time64. In addi­
tion, other stress factors trigger the presentation of
Sheehan syndrome. For example, latent ACTH defi­
ciency might become obvious during an infection or
surgery. Nonspecific clinical findings are more evident
in patients who are diagnosed in the chronic stage. In a
study that included 114 patients with chronic Sheehan
syndrome, nonspecific symptoms were seen in >50% of
patients5. The high prevalence of nonspecific symptoms
is considered to be one of the possible reasons for late
diagnosis. History of failure of lactation and absence of
resumption of normal menstrual cycles after delivery
(especially when delivery was associated with PPH),
symptoms of secondary hypothyroidism and adrenal
insufficiency, involution of secondary sexual character­
istics due to secondary hypogonadism and subtle
features of GH deficiency are seen and should raise
suspicion for Sheehan syndrome57. Absence of these
symptoms does not exclude Sheehan syndrome and
10% of cases may be asymptomatic in the long term32,60.
Sheehan syndrome frequently shows sparse axillary and
pubic hair, breast atrophy, increased wrinkling around
the mouth and eyes, hypopigmentation, dry skin,
slowing of reflexes, bradycardia or sometimes coma59.
Patients might present with adrenal crisis due to cortisol
deficiency or myxoedema coma, a state of decompen­
sated hypothyroidism triggered by infection, surgery or
trauma32. Hyponatraemia (an electrolyte disorder that
can lead to malaise, nausea, vomiting, cognitive changes
and even death69) is the most commonly observed
electro­lyte abnormality in patients with Sheehan syn­
drome, and the rate of hyponatraemia has been reported
to be between 21% and 59%60,63. Sheehan syndrome
should be kept in mind in patients who are presented
to the emergency department with hypo­natraemia63,70.
Clinical symptoms related to hypoglycaemia can also be
seen in Sheehan syndrome, especially patients who are
in a coma52. Sheehan syndrome was the second-most
frequent factor of hypoglycaemia-­associated coma, after
diabetes mellitus71. Although polyuria and polydipsia
(excessive thirst) due to diabetes insipidus are rare clin­
ical symptoms (4.5–5%) of Sheehan syndrome5,72, the
osmotic threshold that is required to perceive thirst was
high in patients with Sheehan syndrome and partial dia­
betes insipidus; partial diabetes insipidus without poly­
uria was observed in one-third of patients with Sheehan
syndrome51. In addition, Sheehan syndrome increases
the risk of osteoporosis and osteopenia. The Z score
(a measure of bone density) was ≤2 in 40% of the
patients (a Z score of >–2.0 is considered normal)73–75.
The aetiology is not yet elucidated, but multiple pitu­
itary hormone deficiencies, particularly secondary
hypo­gonadism, and delayed diagnosis are claimed to
have a role74,76.
Laboratory findings
Endocrine abnormalities. Pituitary hormone insuf­
ficiencies vary depending on the hypophyseal cells
affected and on the studies 5,52,58,60,61,63,64,77 (TABLE  4) .
A probable reason for the discrepancy between studies
is the different time elapsed from the initial insult to
the diagnosis. In Sheehan syndrome, stimulation tests
are necessary to determine if there is a hormone defi­
ciency, especially when hormone levels are borderline.
This is particularly true when evaluating cortisol or
GH deficiencies.
In most patients with Sheehan syndrome, baseline
(measured in the morning at basal conditions) FSH and
LH levels are not increased to postmenopausal levels
(representative for physiological ovarian failure) and
LH levels do not increase following stimulation with
gonadotropin-releasing hormone, thus can be used as
a diagnostic test in rare situations58,78,79. To show corti­
sol and GH deficiencies, an insulin tolerance test and
a glucagon stimulation test can be used80,81. Correct
release of cortisol can also be assessed with an ACTH
stimulation test. However, when this test is carried out
soon after the initial insult, adequate response might
be observed because the adrenal glands might not yet
have atrophied.

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Patients with central hypothyroidism can have Electrolyte abnormalities. Patients also often exhibit
normal, decreased or slightly increased levels of TSH, abnormalities in blood electrolyte levels. Hyponatraemia
whereas tetraiodothyronine (T4) levels are decreased. is the most common, but hypokalaemia, hypomagne­
Enhanced sialylation of TSH might explain the increased saemia, hypocalcaemia and hypophosphataemia were
levels as this reduces metabolic clearance but also also observed in patients with Sheehan syndrome63.
decreases biological activity. Administration of thyro­ The aetiology of hyponatraemia is not known, but
tropin-releasing hormone fails to increase the levels of might involve increased antidiuretic hormone (ADH)
TSH or PRL in patients with Sheehan syndrome82. The release as a consequence of reduced blood pressure and
circadian rhythm of TSH was shown to be disrupted and cardiac output owing to glucocorticoid deficiency 85.
there is an increase in total TSH release in patients with In addition, cortisol deficiency causes an increase in
Sheehan syndrome83,84. the levels of corticotropin-releasing hormone (CRH),
which in turn stimulates ADH secretion86. It was shown
that cortisol and thyroid hormone deficiencies lead to
Pregnancy decreased free water clearance independent from ADH.
In addition, it has been demonstrated that GH, PRL and
thyroid hormone deficiencies were related with hypona­
traemia63. Hyponatraemia associated with diabetes
insipidus can rarely be seen72.
Small sella
turcica size Haematological abnormalities. Many patients with
Normal pituitary
gland Pituitary gland enlargement Sheehan syndrome also show anaemia (45–87%),
thrombocytopenia (63–105%), pancytopenia (15%)
and coagulation disorders 44,58,87. Coagulation dis­
Compression of the vascular
structure of the pituitary gland
orders were presented as a case report in literature88.
Genetic factors
Although anaemia generally occurs as normochro­
mic normocytic, it can be hypochromic microcytic
Ischaemia or rarely macrocytic58,87. Cortisol and thyroid hor­
mone deficiencies are suggested to be involved in the
Coagulation abnormalities Sequestered develop­ment of anaemia by decreasing the synthesis of
(congenital and/or acquired) antigens erythro­poietin or by decreasing the biological effects
(autoimmunity)
of endogen­ous erythropoietin89. Bone marrow hypo­
Severe postpartum
haemorrhage plasia and pancyto­penia can occur; both are reversed
after the replacement of deficient hormones 90,91.
Coagulation disorders can be diagnosed by measuring
adaptive factor VIII and von Willebrand factor defi­
Anti-pituitary ciencies, decreased prothrombin time and activated
GH deficiency Postpartum necrosis
of the pituitary gland
antibodies pro­t hrombin time, and an increase in the levels of
­fibrinogen and d‑dimer 48,88.
Muscle, bone
and adipose
tissue FSH and LH Radiological findings
PRL deficiency deficiency Pituitary MRI is the preferred radiological imag­
ACTH
ing procedure used for differential diagnosis, but CT
TSH deficiency
deficiency Ovary may also be helpful in the diagnosis of Sheehan syn­
drome32,92. MRI findings vary with the stage of the
disease. Although evidence is limited, some studies
describe the acute structural changes as an enlarged
non-­haemorrhagic pituitary gland with central infarc­
Mammary gland Thyroid gland Adrenal gland tion30,38,67,93,94 (FIG. 5a,b). Within several weeks, the gland
shrinks to the confines of the sella turcica, followed
Hypopituitarism Worsening of hypopituitarism by further progressive atrophy over several months
or years with a final image of an empty sella turcica,
Figure 4 | Pathogenesis of Sheehan syndrome. The pituitary gland is physiologically
Nature Reviews | Disease Primers which represents complete atrophy of the pituitary
enlarged during pregnancy as a result of massive hyperplasia of the lactotroph cells, gland3,4 (FIG. 5c,d). At diagnosis, patients with Sheehan
which are stimulated by oestrogens produced by the placenta. The vascular structure of syndrome can have partially (25–30%) or completely
the pituitary gland might become compressed because of pituitary gland enlargement (70–75%) empty sella turcica on imaging studies4,5,59,61,95.
and/or small sella turcica size. Vasospasm (caused by massive postpartum
Only a few patients have been reported to have struc­
haemorrhage) and/or thrombosis (associated with pregnancy, genetic predisposition
or disorders of blood coagulation) might result in ischaemia. Autoimmunity might turally normal pituitary gland4,59,61. Thus, an empty
worsen hypopituitarism over the years. Solid arrows indicate the well-known sella turcica can be considered as a characteristic for
mechanisms; dashed arrows indicated mechanisms that have not yet been proven. Sheehan syndrome diagnosis30. The remnant pituitary
ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth tissues may be necrotic and thus non-functioning or
hormone; LH, luteinizing hormone; PRL, prolactin; TSH, thyroid-stimulating hormone. intact and thus functioning 96. Because of this, there is

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Box 1 | Diagnostic criteria for Sheehan syndrome
Criteria proposed by Kelestimur et al.*
• Typical obstetrical history of severe postpartum
haemorrhage
• Severe hypotension or shock, for which blood
transfusion or fluid replacement is necessary
• Failure of postpartum lactation
• Failure to resume regular menses after delivery
• Varying degree of anterior pituitary insufficiency that
ranges from partial to complete hypopituitarism
• A partially or completely empty sella turcica on a CT
or MRI scan
Criteria proposed by Diri et al.‡
Essential criteria for the diagnosis:
• Typical history of severe postpartum uterine bleeding,
particularly at last delivery
• At least one pituitary hormone deficiency
• A partially or completely empty sella turcica on a CT
or MRI scan in the chronic phase
Criteria that are not essential, but, if present, are strongly
suggestive of the diagnosis:
• Severe hypotension or shock at index delivery
• Postpartum amenorrhoea
• Failure of postpartum lactation
*See REF. 32. ‡See REF. 5.
can resemble Sheehan syndrome; sudden onset of a
severe headache, loss of vision and unconsciousness
may be present in both93 and MRI scans can be simi­
lar. However, enlargement of the sella turcica and ero­
sion of the sellar floor, lateral deviation of the pituitary
stalk, contrast enhancement of periphery (because of
the presence of healthy pituitary tissue) and the per­
sistent presence of a mass near the pituitary gland on
repeated imaging several months apart, point towards
apoplexy associated with pituitary adenoma rather than
Sheehan syndrome. These features, coupled to a history
of antecedent delivery complicated by PPH and hypo­
volemic shock in the case of Sheehan syndrome, help
in the differential diagnosis93.
Lymphocytic hypophysitis may be present in the
immediate postpartum period with hypopituitarism
and pituitary enlargement 97,98. Although most auto­
immune diseases go into remission during pregnancy,
lymphocytic hypophysitis manifests at this time owing
to the release of pituitary antigens and relatively more
vascular supply to the pituitary gland from systemic
rather than portal circulation32. Differentiating lym­
phocytic hypophysitis from Sheehan syndrome can be
difficult as both present with a headache, hypopituitar­
ism and pituitary mass in the immediate postpartum
period and an empty sella turcica later on99–101. Despite
these similarities, some features distinguish the two
conditions30,102 (TABLE 5).

no correlation between the degree of postpartum pitu­ Prevention

itary necrosis and the severity of clinical expression and
between the severity of h­ ypopituitarism and the degree
of empty sella turcica5,92.
Differential diagnosis
Acute presentation of Sheehan syndrome immedi­
ately after an eventful delivery, although not that
common, makes the diagnosis of Sheehan syndrome
more straightforward. Diagnosis of Sheehan syndrome
years after the initial insult is more challenging and
conditions such as pituitary tumours and lympho­
cytic hypophysitis (an autoimmune disorder affecting
the pituitary gland) need to be considered. Pituitary
tumours are the most common cause of hypopitui­
tarism. Clinical presentation of an apoplexy (acute
bleeding inside the pituitary tumour) associated with
a pituitary adenoma around the peripartum period
To prevent Sheehan syndrome, minimizing the risk and
aggressive management of PPH is paramount. PPH is
the leading cause of maternal mortality, e­ specially
in low-­income countries. A multi-country survey of
low-income countries that included 275,000 deliveries
showed that 1.2% were associated with PPH. Of the
women who had PPH, 18% had adverse maternal out­
comes and 3% died103. Although in western countries
mortality due to PPH is decreasing, the actual inci­
dence of PPH is increasing possibly because of more
interventions (such as the induction of labour and
caesarian section)104.
Three broad strategies improve the outcome in
PPH: prevention, treatment and effective management
of PPH. The WHO has published guidelines and key
interventions for the prevention of PPH, which include
a combination of interventions, such as cord clamping

Table 3 | Clinical characteristics of patients with Sheehan syndrome

Study n Postpartum Nonspecific Amenorrhoea Failure to Loss of Hypoglycaemia Cognitive Diabetes
haemorrhage symptoms (%) lactate pubic and (%) changes insipidus
(%) (%) (%) axillary hair (%) (%)
(%)
Diri et al.5 114 NR 52 85 48 10 8 NR 4
Du et al. 59
97 99 NR 82 74 86 26 8 1
Lim et al.63 78 100 NR 100 94 NR 4 21 0
Gei-Guardia et al.60 60 82 88 73 67 93 15 17 0
Dokmetas et al. 58
20 100 80 80 70 100 5 20 0
NR, not reported.

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Table 4 | Anterior pituitary hormone deficiency in Sheehan syndrome

Study n GH deficiency PRL deficiency FSH and LH TSH deficiency ACTH
(%) (%) deficiency (%) (%) deficiency (%)
Dokmetas et al.58 20 100 100 100 90 55
Diri et al.
5
114 100 71 100 90 71
Kelestimur et al.62 91 100* NR 80 86 87
Lim et al.63 78 100 95 9 90 91
Sert et al. 64
28 100 100 100 100 100
Ozbey et al.52 40 93 100 43 76 93
Gokalp et al. 61
124 100 79 100 73 76‡
Hormone levels at the time of diagnosis. ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth
hormone; LH, luteinizing hormone; NR, not reported; PRL, prolactin; TSH, thyroid-stimulating hormone. *Only patients with GH
deficiency were taken into that study. ‡According to basal cortisol levels.

and cutting (within 1–3 minutes); controlled cord trac­ Glucocorticoid replacement

tion (measures to reduce the risk of retained placenta);
and the use of an uterotonic agent (such as oxytocin,
which causes rhythmic contractions of the uterus)34.
All obstetrical care hospitals must have institutional
protocols for the management of women who develop
PPH of >1,000 ml. These protocols should combine
the most recent recommendations, also taking note
of experiences of the other countries. Staff should be
adequately trained and simulated PPH drills should
be included in the training curriculum105. However, in
developing countries, there is a shortage of medical staff.
Whereas these ­countries account for 25% of the global
burden of disease, they have only 1.3% of the world’s
skilled care providers, including doctors, nurses and
midwives106. Anaemia during pregnancy, which is again
more ­common in the developing world, is an important
preventable risk factor and timely administration of oral
or parental iron can help in a long way in the prevention
of PPH35. Moreover, uterotonic agents have an important
role in the prevention of PPH. Oxytocin is recommended
but its sensitivity to heat, the need for refrigeration and
the requirement for a trained person for its administra­
tion limit its use in resource-poor nations. Availability
of aerosol or topical preparations will in the future
overcome these limitations107. Finally, more studies are
needed for widespread use of miso­prostol as an utero­
tonic agent, especially in developing countries where
PPH is common. As opposed to oxytocin, misoprostol
does not need a skilled person to administer and can be
given by the patient herself and is a preferred drug in
resource-poor settings. Once PPH has occurred, a close
follow-up is necessary for the detection and ­treatment
of Sheehan syndrome.
Management
General principles in the treatment of hypopituitar­
ism are valid in the treatment of patients with Sheehan
syndrome. Deficient hormones should be replaced
appropriately. Hormone replacement therapy does not
improve pituitary function and does not prevent the pro­
gression of pituitary necrosis. Pituitary functions need
to be assessed at regular intervals as hypopituitarism can
be progressive5.
In acute-onset patients with high clinical suspicion of
adrenal insufficiency, glucocorticoid treatment should be
started immediately after taking a serum sample for the
measurement of cortisol and ACTH levels78,108. As adre­
nal insufficiency in Sheehan syndrome is due to ACTH
deficiency, mineralocorticoid replacement is not required.
The dose of glucocorticoid agent should be titrated
according to the clinical findings of the patient instead
of laboratory results. Lifelong glucocorticoid treatment is
necessary in the case of secondary adrenal insufficiency.
Adverse effects of glucocorticoids, such as osteopor­
osis, hyperglycaemia and weight gain, should be moni­
tored5. Although some experts favour hydrocortisone and
cortisone acetate for replacement therapy in hypocor­
tisolism, outcome data to support the use of one gluco­
corticoid over another do not exist. In addition, even three
daily doses of hydrocortisone, which are often suggested
for glucocorticoid replacement, cannot approximate the
circadian rhythm of endogenous cortisol production109.
To avoid adverse effects, more physiological replacement
policies are preferred. Nowadays, dual-release hydrocor­
tisone (a tablet with an immediate-release coating sur­
rounding an extended-­release core) given once daily 110
or a continuous subcutaneous hydrocortisone infusion
may be used111. These modalities have a better physiolog­
ical diurnal rhythm associated with weight loss, decrease
in blood pressure, improved glucose metabolism and
enhanced health-­related quality of life (QOL) compared
with the classic 2–3 daily glucocorticoid administration112.
Patients should be informed about the risk of adrenal
crisis if they do not increase their daily dose in some situ­
ations that increase the need for cortisol, such as infec­
tion, surgery and trauma112. When hypothyroidism and
hypoadrenalism occur together, thyroid hormone therapy
should follow glucocorticoid replacement to avoid adrenal
crisis112. Hydrocortisone dose may need to be increased
after GH treatment in patients with GH deficiency 113.
Thyroid hormone replacement
Regarding thyroid hormone replacement, titration of
levothyroxine dose depends on free T4 and free tri-­
iodothyronine (T3) levels rather than on TSH levels, which
may be normal, decreased or increased114. In elderly

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patients and those with coronary artery disease, levo­ tumours. GH replacement therapy should be started in
thyroxine should be given at low doses and dose titra­ low doses, which should be increased gradually accord­
tions should be carried out slowly. Transformation of T4 ing to the evaluation of clinic response and IGF‑1 levels
to T3 increases in patients who are administered GH and that are assessed once every 4–8 weeks120. A prospective
these conditions can convert the masked hypothyroid­ study showed that 18 months of GH replacement ther­
ism into an overt state or increase levothyroxine require­ apy decreased the levels of total cholesterol and LDL-
ment in those who are already on replacement therapy 115. cholesterol and increased the levels of HDL-cholesterol,
Different levothyroxine preparations exist, such as ­tablets, while waist circumference and waist-to-hip ratio were
oral soft gel capsules and liquid formulations. decreased significantly 121. GH replacement therapy for
6 months improved cognitive function (assessed by P300
Oestrogen and progesterone replacement auditory potentials) in patients with Sheehan syndrome
Although oestrogen and progesterone replacement with severe GH deficiency 49,122. GH replacement ther­
therapy in hypogonadal postmenopausal women with apy for 1 year improved QOL, body composition and
Sheehan syndrome is controversial, replacement ther­ the lipid profile in a study that included 91 patients
apy is usually recommended in premenopausal women from 19 countries62, whereas another study showed
with Sheehan syndrome, unless there is a contra­ that 6 months of GH replacement therapy improves
indication (such as deep vein thrombosis, pulmonary the sebum content on the forehead, which is signifi­
embolism, severe cirrhosis, active viral hepatitis and cantly decreased in GH-deficient patients with Sheehan
­uncontrolled severe hypertension). In young women, syndrome123. In addition, GH replacement therapy
a high dose of estrogen is preferred, whereas lower doses in severely GH-deficient patients, most of whom had
are used when menopause has started; treatment is dis­ Sheehan syndrome, improves sympathetic tone without
continued in women ≥50 years of age116. Oral estrogen an obvious arrhythmogenic effect 49. Conversely, some
suppresses hepatic insulin-like growth factor 1 (IGF‑1) parameters were not improved upon GH replacement
release in response to GH117, which can be prevented by therapy. In that study, Tanriverdi et al.49 showed that
using transdermal estrogens118. 6 and 12 months of GH replacement therapy increased
sympathetic activity and normalized sympathovagal
GH replacement balance. GH replacement therapy for 6 months failed
Opinions about efficacy and the routine use of GH to improve the abnormal sleep patterns in patients with
treatment in patients with Sheehan syndrome are Sheehan syndrome, who show more non-rapid eye
divided because of the risk–benefit ratio and cost-­ movement (NREM) sleep, less REM sleep and sleep effi­
effectiveness119. GH deficiency is more severe in patients ciency than healthy controls124. No data are available for
with Sheehan syndrome than in patients with pituitary longer duration of GH replacement therapy on abnor­
mal sleep parameters124. GH replacement therapy did not
have any effects on bone mineral density 121.
a b
AVP replacement
Diabetes insipidus can develop as a consequence of
damage to the posterior gland, leading to impaired AVP
secretion. In addition, diabetes insipidus can develop
in patients with Sheehan syndrome who are treated
with glucocorticoids, which increase water diuresis51.
Symptoms of diabetes insipidus may be masked by
concomitant ACTH deficiency. Glucocorticoid therapy
has been shown to suppress AVP secretion in patients
with ACTH deficiency 125. Polyuria and polydipsia
c d should be assessed following glucocorticoid treatment
in patients with Sheehan syndrome. Desmopressin,
which is a modi­fied form of AVP, can be administered
orally, nasally and parenterally to treat diabetes insipi­
dus, ­usually around bedtime. If needed, morning and
afternoon doses can be added. Antidiuretic effects
of desmopressin commence between 6 and 12 hours
when administered via the nasal route. If switching to
oral from intranasal, oral desmopressin should start at
least 12 hours after the last intranasal dose. However,
Figure 5 | Radiological characteristics of Sheehan syndrome. a,b | Acute phase.
Nature Reviews | Disease Primers the duration of effect is less when administered by the
Post-contrast MRI scans of the pituitary gland in a patient 2 months after postpartum
haemorrhage showing gland atrophy and non-haemorrhagic central infarction oral route. Care should be taken when treating uncon­
characterized by central hypointensity on T1‑weighted images (part a) and scious patients. Serum sodium level and fluid volume
hyperintensity on T2‑weighted images (part b). c,d | Chronic phase. Coronal (part c) and should be evaluated and the desmopressin dose should
sagittal (part d) T1‑weighted MRI scans showing an empty sella turcica. Sella turcica size be adjusted accordingly. In addition, as the risk of
is normal in all images. Arrows indicate the pituitary gland. severe hypernatraemia is high in patients with diabetes

NATURE RE VIE WS | DISEASE PRIMERS VOLUME 2 | 2016 | 11

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Table 5 | Differentiating features between lymphocytic hypophysitis and Sheehan syndrome

Feature Sheehan syndrome Lymphocytic hypophysitis
Epidemiology Common in developing countries Common in developed countries
Patients Women only Men, women and children
Association with other No Yes
autoimmune disorders
Parity Follows pregnancy Can also occur without pregnancy
Postpartum haemorrhage Common Not required
Common tropic hormone Lactotroph, thyrotropic and somatotropic Corticotropic and thyrotropic hormones
deficiencies hormones
Common hormones Corticotropic and gonadotropic hormones Somatotropic and gonadotropic hormones
preserved
Hyperprolactinaemia No Yes
Diabetes insipidus Very rare Yes
Pituitary MRI Empty sella turcica Pituitary mass with contrast enhancement;
later, an empty sella turcica

insipidus, who are adipsic (the absence of thirst), daily
fluid intake, regular desmo­pressin use, body weight and
serum sodium levels should be monitored116.
Pregnancy and lactation
Ovulation induction can be used in women who want
to become pregnant, although some patients can have
spontaneous pregnancies126. When pregnant, regular
follow‑up to adjust glucocorticoid doses is needed.
Physiological gestation is associated with increased
maternal HPA axis activity despite the fact that cortico­
tropic cell numbers remain the same. Both total and free
cortisol levels have been shown to increase by 11 weeks
of gestation; however, this does not cause feedback
inhibition as the set point for ACTH secretion is also
altered127,128. Besides maternal HPA axis overactivity,
the placenta also contributes to the production of both
ACTH and CRH129.
Levothyroxine doses also need adjustment. The bio­
chemical similarity of TSH and hCG results in increased
thyroid hormone synthesis, which in turn inhibits
maternal TSH secretion from the pituitary gland dur­
ing the first trimester of normal pregnancy 130. In addi­
tion, there is an increased requirement for T4 during
pregnancy not only due to increased serum thyroxine-­
binding globulin but also due to the placental degrad­
ation of T4, the transfer of T4 from mother to fetus
and increased maternal clearance of T4 (REF. 131). The
requirement for l‑thyroxine increases by about 30%
during gestation132.
Maternal GH secretion is decreased during normal
gestation. Instead, the placenta starts to produce placen­
tal variant GH, which is detectable in the circulation
by 5 weeks of pregnancy, and the levels progressively
increase throughout gestation and peak at 35–37 weeks.
Placental variant GH is secreted continuously; placen­
tal variant GH binds to the hepatic GH receptor with
similar affinity to pituitary GH, inhibiting its secretion
by stimulating IGF‑1 production133,134. GH treatment is
usually discontinued after confirmation of pregnancy as
its use is not licenced during gestation; however, in some
patients, treatment is continued until placental variant
GH that is secreted from the placenta from 12 weeks of
pregnancy is synthetized, whereafter treatment is gradu­
ally discontinued by administering decreased doses
until 20 weeks of pregnancy 116. Generally, placental
variant GH can comprise enough IGF‑1 after 20 weeks
of pregnancy 135. It is not yet clear which patients with
Sheehan syndrome should use GH replacement during
pregnancy, but GH replacement seems to have no major
adverse effects and no negative influences on maternal
and fetal outcome.
Ovulation induction is necessary in patients with
Sheehan syndrome with gonadotropin deficiency, so
oestrogen replacement is discontinued. When preg­
nancy occurs, sex steroids are secreted from the placenta,
which eliminates the need for exogenous replacement.
In normal pregnancy, the levels of maternal serum
gonado­tropins decrease during the early weeks and
become undetectable in the second trimester owing to
increased levels of sex steroids (such as 17 β‑estradiol
and progesterone) and regulatory peptides (such as
inhibin)136. There are no data about the replacement of
PRL during gestation and the postpartum period for
­lactation in PRL-deficient patients.
Quality of life
Most patients with Sheehan syndrome have nonspecific
symptoms, such as weakness, cold intolerance, anae­
mia and feeling unwell, which affect QOL, especially
because of long diagnostic delay 32. These patients can
remain undiagnosed or misdiagnosed for a long time
and receive inappropriate treatments. Furthermore,
hormone deficiencies progress and worsen over the
years, which suggests a progressive deterioration of this
chronic condition5. Although there are no prospective
studies specifically investigating morbidity and mortality
in Sheehan syndrome, undiagnosed Sheehan syndrome
results in increased mortality and morbidity. Increased
awareness of this condition will result in earlier diag­
nosis and hence better QOL, and lower morbidity
and mortality.

12 | 2016 | VOLUME 2 www.nature.com/nrdp

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 PRIMER

Treatment improves QOL in patients with Sheehan
syndrome. The effects of GH replacement therapy in
adults with hypopituitarism with non‑Sheehan syn­
drome has been well documented and include improve­
ment in QOL, well-being, change of body composition
and cognitive function137, which have also been shown in
patients with Sheehan syndrome121,122. Although supra­
physiological glucocorticoid exposure is deleterious on
QOL, increasing glucocorticoid doses in patients who
complain of impaired QOL, which may or may not be
related to adrenal axis deficiency, are common prac­
tice138,139. Thus, physicians need to consider and evaluate
the causes of impaired QOL during patient follow-up,
such as insufficient glucocorticoid and thyroid hormone
replacement and GH deficiency.
Outlook
Because of its scarcity in the western society, Sheehan syn­
drome has become a neglected disorder and is not suffi­
ciently included in medical education. Owing to recent
increases in migration to developed countries, physicians
need to suspect the disease in women who have delivered
in their countries of origin, especially if those are devel­
oping countries. Although the underlying mechanisms
responsible for the development of post­partum pituitary
necrosis have not been completely defined, recent studies
have provided new insight into the pathogenesis, such as
pituitary autoimmunity and coagulation abnormalities.
Insight into the pathophysio­logy of postpartum pituitary
necrosis may provide new options in the treatment of
permanent pituitary failure associated with other causes,
such as treatment with pituitary stem cell140 and target
cell transplantation (such as lactotroph and gonado­
tropic cells, among others) therapy 141. In a transgenic
mouse model, it was shown that the pituitary gland is
competent to repair tissue after cell loss by diphtheria
toxin-induced injury and that somato­tropic cells were
considerably regenerated during the months after injury,
suggesting recovery of somatotropic cells from stem or
progenitor cells142. It seems that the regener­ative cap­
acity of the pituitary gland relies on stem cell-associated
pathway activaton140. Pituitary stem cell transplantation
has experimentally been investigated in other causes
of pituitary insufficiency; however, it may also have a
potential use in Sheehan syndrome. Human embryonic
stem cell-derived pituitary tissues provide a platform
for therapeutic application and disease model­ling 141.
After transplantation into hypopituitary mice (hypo­
physectomized severe combined immunodeficient mice),
in vitro-­generated corticotropic cells can secrete ACTH
in response to CRH141. Sheehan and Davis143 published a
very comprehensive book dedicated to Sheehan syndrome
in 1982, in which they suggested that this condition
serves as an excellent model for the study of pure insuf­
ficiency of the anterior lobe. In fact, Sheehan syndrome
is an exceptional pituitary disorder that is character­ized
by a long-term severe hypopituitarism and, hence, it is a
perfect model to see the effects of replacement treatment
on morbidity, mortality and QOL in women. An animal
model that mimics Sheehan syndrome, which does not
currently exist, would be beneficial not only to under­
stand the underlying mechanisms of Sheehan syndrome
but may also be useful to understand the pathophysiology
of the other types of hypopituitarism.

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Acknowledgements
The authors express their profound gratitude to their medical
illustrator, M. E. Aykurt, for his original artwork of Figure 1b
and the help of Dr A. Sehgal, Dr S. Malik and Dr H. Ashraf,
who are senior residents in the Department of Endocrinology
at Sher-I-Kashmir Institute of Medical Sciences (SKIMS),
for their help in preparation of the manuscript.
Author contributions
Introduction (F.K.); Epidemiology (B.A.L.); Mechanisms/patho‑
physiology (Z.K., H.A. and F.K.); Diagnosis, screening and
prevention (B.A.L., H.S.D. and H.A.); Management (B.A.L.,
H.S.D. and F.K.); Quality of life (H.A. and B.A.L.); Outlook
(All); Overview of Primer (F.K.).
Competing interests
The authors declare no competing interests.

NATURE RE VIE WS | DISEASE PRIMERS VOLUME 2 | 2016 | 15

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