EPONYM

Eponym

Sheehan syndrome

Kalman Kovacs

Sheehan syndrome
Sheehan syndrome is the name given to postpartum
hypopituitarism.1 The syndrome is caused by an
infarction in the adenohypophysis, usually precipitated
by massive uterine haemorrhage. Necrotised areas of the
adenohypophysis undergo organisation and form a
fibrous scar (figure 1). Extensive destruction of cells
results in varying degrees of hypopituitarism. Acute loss
of adenohypophysis function can be fatal without
glucocorticoid and thyroid hormone replacement
therapy, and survivors will require lifelong treatment.
Protracted hypopituitarism can result in premature
atherosclerosis and increased cardiovascular mortality.2
Patients with apparent hypopituitarism, mainly
caused by pituitary necrosis, were reported in the 19th
century. However, understanding of pituitary gland
pathology was in its infancy at that time, and
interpretation of the significance of those early cases is
difficult. In 1914, Morris Simmonds (18551925), a
diagnostic pathologist with an interest in pituitary gland
morphology and the pathogenesis of pituitary diseases,
described autopsy findings in a 46-year-old woman.3 11
years earlier, she had had severe puerperal sepsis after
the delivery of her fifth child. She recovered, but
remained weak, emaciated, and amenorrhoeic. 2 days
before her death she lapsed into coma and died,
probably from chronic hypopituitarism. At autopsy, her
pituitary gland was severely atrophied, weighing 03 g.
The anterior lobe was markedly shrunken and almost all
its cells had been replaced by a fibrous scar. Simmonds

Figure 1: Necrotic area replaced by hypocellular connective

tissue in the late phase of the syndrome
Haematoxylin-phloxin-saffron stain, original magnification 250.
Slide taken by K Kovacs.

Lancet 2003; 361: 52022

Division of Pathology, Department of Laboratory Medicine and
Pathobiology, St Michaels Hospital, University of Toronto, Toronto,
Ontario M5B 1W8, Canada (Prof K Kovacs MD)
(e-mail: kovacsk@smh.toronto.on.ca)

520

Case studies
Case 1
A 29-year-old woman had had an uneventful first pregnancy,
apart from her blood pressure being moderately raised during
the last trimester. At delivery she had a massive uterine
haemorrhage, resulting in hypotension and loss of
consciousness. She died 4 days later from multiorgan failure.
The pituitary gland was enlarged at autopsy, weighing 11 g
(normal weight 06 g). On the cut surface, the
adenohypophysis seemed soft with a grayish-red colour.
Histological analysis showed extensive acute necrosis,
affecting around 90% of the anterior lobe. In the necrotic area,
adenohypophysis cells could not be recognised, and had been
replaced by ghost cells, necrotic debris, coagulated blood, and
inflammatory cells. Immunohistochemical analysis showed
absence of adenohypophyseal hormones in the necrotic areas.
Adenohypophysis cells with hormone content shown by
immunohistochemical analysis were evident in the surviving
rim. The diagnosis was of acute ischaemic infarction of the
pituitary gland. Hypoxic changes were apparent in several
organs including liver, kidneys, and adrenal glands and there
was acute disseminated bronchopneumonia in both lungs.
Case 2
A 55-year-old woman had had a difficult labour 30 years earlier
and had gone into coma followed by extensive uterine bleeding
and hypotension. She had gradually recovered but had been
unable to lactate and her periods had not returned. She lost
her pubic and axillary hair. Her skin became dry and wrinkled,
she developed cold sensitivity, and her mental status
deteriorated. She had memory loss and was lethargic. The
diagnosis of panhypopituitarism was made, and she was
treated with thyroid, glucocorticoid, and sex hormone
replacement therapy. At age 52 years, she had the first of
three acute myocardial infarctions and died 3 years later of
congestive heart failure. At autopsy, the pituitary gland was
very small, weighing only 02 g. Shrinkage was marked in the
anterior lobe. The gland was brown, and on the cut surface the
anterior lobe was gray. Histological assessment showed loss
of around 90% of adenohypophysis cells. The cells had been
replaced by hypocellular connective tissue rich in collagen
fibres, which immunohistochemical analysis showed to lack
adenohypophysis hormones. Some 10% of the
adenohypophysis cells seemed to be normal and were
immunoreactive against various adenohypophysis hormones.
The diagnosis was massive fibrosis with loss of
adenohypophyseal cells secondary to postpartum pituitary
necrosis. The heart was significantly enlarged, weighing 540 g.
Large areas of the myocardium had been replaced by fibrosis,
and there was extensive atherosclerosis affecting the coronary
arteries and aorta. There was congestive hepatomegaly and
splenomegaly and the lungs showed patchy acute
bronchopneumonia. The thyroid, adrenals, and ovaries were
atrophic.
Both case studies are from Sheehans collection.

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EPONYM

Incidence
Hypopituitarism is an endocrine disorder with diverse
causes. Today, the most common causes of decreased
adenohypohyseal and endocrine function are neoplasms,
which either damage the hormone-producing cells of the
adenohypophysis or interfere with their hypothalamic
control; other causes such as autoimmune inflammation
of the pituitary, infection, trauma, and granuloma are
much rarer. The incidence of pituitary gland tumours
ranges from 02 to 28 per 100 000 population per year.14
The prevalence of hypopituitarism is 29455 per
100 000: 61% result from pituitary tumour and only a
few from Sheehan syndrome.15 Small foci of pituitary
necrosis can be seen in around 5% of unselected adult
autopsies, but in most cases the necrotic or fibrotic areas

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are
small,
occupying
only
510%
of
the
adenohypophysis parenchyma and unlikely to have
affected pituitary function.12,13
Pituitary necrosis unrelated to postpartum ischaemic
infarction occurs in raised intracranial pressure, damage
to the pituitary stalk, acute pituitary apoplexy,
accidental trauma, massive stroke, and subarachnoid
haemorrhage. Increased incidence of pituitary necrosis
has also been reported in diabetes mellitus, acute
haemorrhagic fever, after cardiac surgery, and in
patients who were ventilated before death.12,13

Rights were not granted to include this

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to the printed journal.
By courtesy of the University of Liverpool Library

diagnosed pituitary infarction resulting from mycotic

bacterial emboli. He went on to study the histology of
pituitary glands obtained from patients who had had
septicaemia, and noted that acute focal necrosis from
bacterial emboli was common; in patients who survived
the acute illness, this necrosis could transform to fibrous
atrophy, causing pituitary hypofunction.
However, it is doubtful whether Simmonds was the
first to make such a diagnosis, since Glinski, a Polish
pathologist, had reported two patients with extensive
pituitary gland necrosis only 1 year earlier, in 1913.4
The first was a 37-year-old woman who had an
extensive uterine haemorrhage during delivery and died
9 days later from puerperal sepsis. The second was a 33year-old woman who died from congestive heart failure
after a miscarriage in the 6th month of pregnancy.
Extensive necrosis was identified in the pituitary glands
of both women. Glinski attributed the necrosis to
thrombosis in the hypophyseal arteries, and concluded
that if the process were extensive, it could affect
pituitary function. These cases were published in a
Polish medical journal in 1913,4 but a report of the
findings also appeared in a leading German medical
journal in the same year.5
Simmonds later emphasised that cachexia is a
prominent symptom in patients with pituitary
involution.6 He called the disease hypophyseal cachexia,
which was the term used to describe hypopituitarism for
several years. The importance of cachexia was noted by
Zondek, an authority in endocrinology; a photograph of
one of his cachectic patients was reproduced in several
textbooks. Ironically, it seems that when this patient
died, autopsy showed that the pituitary gland was
normal; the patient had had anorexia nervosa.
Sheehan recorded many cases of acute postpartum
pituitary necrosis and described in great detail the
early and late histological changes in the anterior
and posterior lobes of the pituitary and the
hypothalamus.1,711 He established the sequence of
events of the disease, and emphasised that many
patients did not have cachexia. Sheehan concluded that
pituitary necrosis is an infarction caused by arrest of
blood flow to the adenohypophysis, and clarified that
ischaemia, rather than puerperal sepsis or mycotic
bacterial emboli, caused the necrotic process. He
correlated clinical and morphological findings and
assessed the incidence of the disease. Despite the earlier
findings of Glinski and Simmonds, it is entirely
appropriate that postpartum pituitary necrosis should
be known as Sheehan syndrome. The history, incidence,
pathomorphology, pathogenesis, consequences of
pituitary necrosis, and Sheehans work have been
reviewed in detail.12,13

Figure 2: Prof Harold Leeming Sheehan (190086)

Pathogenesis
The pathogenesis of Sheehan syndrome is not totally
certain, although there is no doubt that the basic process
is infarction secondary to arrest of blood flow to the
anterior lobe of the pituitary gland. Whether this process
results from vasospasm, thrombosis, or vascular
compression is unclear. The pituitary gland is significantly
enlarged towards the end of pregnancymainly from
hyperplasia of prolactin-secreting cells. The enlargement
could compress the blood vessels that supply oxygen and
other nutrients to the gland, or adenohypophysis cells in
pregnant women could be more susceptible than normal
to ischaemia, or both. However, primary thrombosis is a
strong possibility, whether caused by platelet aggregation
or sequestration along previously damaged endothelial
cells. The presence or absence of vasospasm cannot be
assessed by microscopic investigation.
The pituitary gland cannot regenerate; new cells do not
form to replace the necrotised cells that have been
replaced by scar tissue. Normal gland function can be
supported by about 50% of the gland, but part and total
hypopituitarism accompanies loss of 75% and 90%,
respectively, of the adenohypophysis cells.
Cases of autoimmune lymphocytic hypophysitis have
been described, often associated with pregnancy.16 If left

521

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EPONYM

untreated, this disorder can lead to hypopituitarism from

massive destruction of the pituitary gland and its
replacement by fibrous tissue. Once organisation has
taken place, histological signs can be similar to those in
Sheehan syndrome, although the pathogenesis is very
different. Sheehan syndrome results from ischaemia,
whereas chronic lymphocytic hypophysitis is due to
autoimmune destruction of adenohypophyis cells.

Clinical presentation and treatment

Hypopituitarism can be mild, moderate, or severe, and
part or total. Decreased endocrine function can be
restricted to one hormone or can affect all hormones
secreted by adenohypophysis cells. Clinical presentation
varies and is dependent on the age of the patient,
rapidity of onset, nature and causes of the pathological
process, and the proportion of affected adenohypophysis
cells. Mild hypopituitarism can remain undetected for
years. Complete loss of adenohypophysis function is life
threatening and requires immediate treatment.
Deficient adenohypophysis endocrine activity can lead
to secondary hypocortism, hypothyroidism, hypogonadism, and loss of growth hormone and prolactin
production. Indeed, Sheehan syndrome is one of the few
conditions in which hypoprolactinaemia can occur.
Symptoms of patients with Sheehan syndrome include
weakness, decreased muscular strength, dryness and
wrinkling of the skin, premature ageing, hypotension,
cold intolerance, constipation, pallor, anaemia,
bradycardia, hypoglycaemia, insulin hypersensitivity,
loss of pubic and axillary hair, amenorrhoea, infertility,
absence of lactation, breast atrophy, decreased vaginal
secretion, mental slowing, apathy, and psychiatric
disturbances. Treatment aims to replace the missing
hormones and restore endocrine homoeostasis.

The man behind the syndrome

Harold Leeming Sheehan was the son of a general
practitioner, and was born in 1900, in Carlisle, close to
the Scottish border in the UK (figure 2). He graduated
in medicine from the University of Manchester in 1921,
but was already fascinated by pathology. After
graduation, he returned to Carlisle and practised
medicine. He returned to Manchester in 1927, and
taught pathology until 1934. He then went to the USA
as a Rockefeller fellow and spent 1 year at the Johns
Hopkins University. In 1935, he became scientific
director at the Royal Maternity Hospital in Glasgow,
and remained there until appointed Professor of
Pathology and Chairman of the Pathology Department
at the University of Liverpool in 1946. As chairman, he
was extensively involved in teaching, research, and
diagnostic pathology. For many years after his
retirement in 1965, he continued to study, write papers,
publish chapters and books, and give lectures at
international congresses. He died in 1986.

522

Sheehan was a dedicated pathologist with an

outstanding intelligence, knowledge, and curiosity, which
made him a stimulating and entertaining lecturer. He was
an original thinker, and a hard-working and committed
professional. If a patient with pituitary necrosis or
postpartum hypopituitarism died during the night, he
would do the autopsy immediately, whatever the time.
Like many great achievers, he was also modest. If
somebody mentioned Sheehan syndrome, he insisted it be
referred to as postpartum pituitary necrosis or
hypopituitarism. He was, however, interested in many
aspects of gynaecological and obstetrical pathology, and
established an endocrine unit at Liverpools Radium
Institute. His other works contributed substantially to the
understanding of renal ischaemia, renal infarcts, and renal
cortical necrosis. Sheehan was involved in the study of
fatty liver in pregnancy and the pathogenesis and
pathological features of eclampsia. His publications
include the discovery of the subventricular nucleus of the
hypothalamus, and the intriguing finding that the size of
nerve cells can vary in different diseases.
Acknowledgments
It was a great privilege for me to work with Prof Sheehan. This paper was
supported by the Jarislowsky Foundation, the Lloyd Carr Harris
Foundation, and the St Michaels Hospital Research Centre.

References
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4 Glinski LK. Z kazuistyki zmian anatomo-patologicnych w przysadce
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11 Sheehan HL, Stanfield JP. The pathogenesis of post-partum necrosis
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479510.
12 Kovacs K. Necrosis of anterior pituitary in humans (part I ).
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13 Kovacs K. Necrosis of anterior pituitary in humans (part II).
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15 Regal M, Paramo C, Sierra SM, Garcia-Mayor RV. Prevalence and
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16 Thodou E, Asa SL, Kontogeorgos G, Kovacs K, Horvath E, Ezzat S.
Clinical case seminar: lymphocytic hypophysitis: clinicopathological
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