Seminar

Hypopituitarism
Claire E Higham, Gudmundur Johannsson, Stephen M Shalet

Hypopituitarism refers to deficiency of one or more hormones produced by the anterior pituitary or released from the Lancet 2016; 388: 2403–15
posterior pituitary. Hypopituitarism is associated with excess mortality, a key risk factor being cortisol deficiency due to Published Online
adrenocorticotropic hormone (ACTH) deficiency. Onset can be acute or insidious, and the most common cause in March 31, 2016
http://dx.doi.org/10.1016/
adulthood is a pituitary adenoma, or treatment with pituitary surgery or radiotherapy. Hypopituitarism is diagnosed
S0140-6736(16)30053-8
based on baseline blood sampling for thyroid stimulating hormone, gonadotropin, and prolactin deficiencies, whereas
Department of Endocrinology,
for ACTH, growth hormone, and antidiuretic hormone deficiency dynamic stimulation tests are usually needed. Christie Hospital NHS
Repeated pituitary function assessment at regular intervals is needed for diagnosis of the predictable but slowly Foundation Trust, Manchester,
evolving forms of hypopituitarism. Replacement treatment exists in the form of thyroxine, hydrocortisone, sex steroids, UK (C E Higham DPhil,
Prof S M Shalet MD); Centre for
growth hormone, and desmopressin. If onset is acute, cortisol deficiency should be replaced first. Modifications in
Endocrinology and Diabetes,
replacement treatment are needed during the transition from paediatric to adult endocrine care, and during pregnancy. Institute of Human
Development, Faculty of
Introduction adenomas is low in childhood and peaks at age Medical and Human Sciences,
University of Manchester,
Hypopituitarism is deficiency of one or more pituitary 60–65 years.3,4 The combined results from these studies
Manchester Academic Health
hormones. The pituitary gland has two lobes. Within the suggest an increase in the prevalence of hypopituitarism, Science Centre, Manchester, UK
anterior lobe, six hormones are produced: growth which might be a result of increased use of high- (C E Higham, Prof S M Shalet);
hormone, the gonadotropins follicle stimulating resolution imaging. Department of Internal
Medicine and Clinical
hormone (FSH) and luteinising hormone, adreno-
Nutrition, Sahlgrenska
corticotropic hormone (ACTH), thyroid stimulating Mortality Academy, University
hormone (TSH), and prolactin. The posterior pituitary Findings from several studies have shown excess of Gothenburg,
lobe contains two hormones, oxytocin and antidiuretic mortality in patients with hypopituitarism,5 with higher Gothenburg, Sweden
(Prof G Johannsson MD); and
hormone (ADH), which are produced in the supraoptic mortality in women than in men.6 This excess mortality Department of Endocrinology,
and paraventricular nuclei of the hypothalamus and was mainly attributable to cardiovascular and respiratory Sahlgrenska University
transported axonally via the pituitary stalk to be stored diseases. This reported increased mortality was most Hospital, Gothenburg, Sweden
and released from the posterior lobe. likely multifactorial and related to young age at diagnosis, (Prof G Johannsson)

In this Seminar, we describe the range of mechanisms
underlying hypopituitarism, geographic variations both
in terms of causation and treatments, and future
therapeutic options.
Epidemiology
The incidence and prevalence of anterior pituitary
hormone deficiency, including growth hormone
deficiency (GHD), has only been reported in one study,1
which comprised a mean population sample of
146 000 adult inhabitants in South Galicia, Spain, and
showed an increase in the prevalence of hypopituitarism
from 29·0 per 100 000 people to 45·5 per 100 000 people
between 1992 and 1999, with a mean annual incidence of
4·21 cases per 100 000 population, which remained stable
during this period. In other studies, the epidemiology of
the underlying causes of hypopituitarism has been
reported, such as pituitary adenomas, a common cause
of hypopituitarism in adults. In Sweden, the national
incidence of non-functioning pituitary adenomas
increased from 0·6 cases per 100 000 people to 1·1 cases
per 100 000 people between 1975 and 1991.2 Between
2002 and 2011, the annual incidence was 2·03 cases
per 100 000 people, suggesting a further increase.3
In a regional Finnish study,4 the annual incidence
of non-functioning pituitary adenomas was 1·0 per
100 000 people between 1992 and 2007, with occurrences
of incidentally discovered masses tripling during this
time period. The incidence of non-functioning pituitary
the underlying cause of the hypopituitarism (eg, cranio- Correspondence to:
Prof Stephen M Shalet, Endocrine
pharyngioma), tumour treatment using transcranial
Department, Christie Hospital
surgery or radiotherapy, and presence of diabetes NHS Foundation Trust,
insipidus.6–8 In other studies, increased mortality in Manchester M20 4BX, UK
patients with cortisol deficiency has been reported.9 In a stephen.m.shalet@manchester.
ac.uk
nationwide study of patients with non-functioning
pituitary adenoma,3 excess mortality was noted in women
with hypopituitarism, but not in men, suggesting the
importance of sex on outcome in patients with
hypothalamic–pituitary disorders.
Findings from prospective studies in patients with
hypopituitarism who were receiving growth hormone
have shown an excess mortality of 13–42%7–9 or no excess
mortality.10 Excess cardiovascular mortality was not
found, although increased mortality from stroke was
reported among women and those who received
radiotherapy.8 The varying pattern of mortality might be a
result of improved care of patients, but could also be due
to heterogeneity of patient selection.
Search strategy and selection criteria
We searched PubMed, Embase, and Cochrane Databases (last
search done Sept 29, 2015) using the search terms “hypopit*”
AND “epidemiology” OR “presentation” OR “signs and
symptoms” OR “investigations” OR “management”. Relevant
articles written in English were reviewed for inclusion, with
the emphasis on those published in the past 5 years.

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 Seminar
Causes
In adults, the most common cause of hypopituitarism is
a pituitary adenoma or treatment with pituitary surgery
or radiotherapy.11 The profile of pituitary hormone
deficiencies varies depending on the site within the
hypothalamic–pituitary axis and the nature of the
underlying pathological process. For example, diabetes
insipidus can occur in patients with lesions affecting the
pituitary stalk, but not with lesions confined to the
pituitary fossa.
Pituitary and hypothalamic mass lesions
Benign pituitary tumours account for most pituitary
mass lesions, although secondary tumours do occur,
with metastasis to the pituitary gland reported from
carcinomas of the breast, lung, colon, and prostate. At
presentation, macroadenomas (≥1 cm) are commonly
associated with deficiencies in anterior pituitary
hormones.12,13 Evidence suggests that the causative
mechanism is compression of the portal vessels in the
pituitary stalk, either secondary to direct expansion of the
tumour mass or due to raised intrasellar pressure.14 Non-
functioning pituitary microadenomas (<1 cm) are more
common than macroadenomas, being found in between
1·5% and 27% of autopsies in the general population;
these tumours are rarely associated with hypopituitarism.
Craniopharyngiomas are the third most common
intracranial tumour and account for most parasellar
tumours; 35% occur in patients younger than 18 years.15
Other mass lesions in the parapituitary area capable
of causing hypopituitarism include chondromas,
chordomas, germinomas, suprasellar meningiomas,
astrocytomas of the optic nerve, and other primary
tumours of the third ventricle.
Pituitary surgery
Hypopituitarism is a common consequence of pituitary
surgery. The risk and extent of hypopituitarism depends
on several factors, including the original tumour size and
amount of tumour infiltration. The experience and
volume load of the pituitary surgeon also has a substantial
effect on the chance of a surgical cure for the pituitary
adenoma and the mortality and morbidity associated
with surgery.16,17 Prompt postoperative assessment of
pituitary function is mandatory; however, a decrease in
pituitary function is not universal. Paradoxically, surgery
for non-functioning pituitary adenomas is sometimes
associated with substantial recovery of pituitary
function.12,18
Radiotherapy
Hypopituitarism can occur after treatment with
conventional external beam radiotherapy if the
hypothalamic–pituitary axis lies within the radiation
fields.19 The extent of hypopituitarism and the speed of
onset are dose dependent. Radiation-induced hypo-
pituitarism occurs in patients who receive radiotherapy
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for pituitary tumours, nasopharyngeal carcinoma, retino-
blastoma, and other tumours in the hypothalamic–
pituitary area and in those who receive whole head
irradiation for brain tumours. Additionally, children who
receive prophylactic cranial irradiation for acute
lymphatic leukaemia or total body irradiation for various
malignant diseases are at risk of hypopituitarism, and, in
particular, GHD, many years later.19
Newer methods of delivery of radiation to pituitary
tumours have been introduced, such as proton beam
therapy, and radiosurgery involving stereotactic irradiation
with the Leksell gamma knife or a stereotactic linear
accelerator. The principal advantage of these methods is
the consistent dose delivery to the tumour, which is
associated with less irradiation outside the targeted
volume. Findings from reports20–22 suggest that hypo-
pituitarism occurs even after these newer methods of
irradiation, but the prevalence of this complication might
be reduced;23 however, lengthy follow-up is needed before
this finding can be proved conclusively, in view of the
known relation between radiation dose and speed of onset
of hypopituitarism.24
Trauma and vascular injury
Traumatic brain injury (TBI) is a long-recognised cause
of hypopituitarism.25–27 The extent of hypopituitarism
ranges from isolated deficiency to panhypopituitarism,
and the prevalence of reported hypopituitarism after TBI
varies widely (15–90%).25–27 A possible relation between
the severity of TBI and the prevalence of hypopituitarism
has not been shown, and is complicated by reports of
hypopituitarism after low-intensity repeated trauma25 in
participants of some sports (eg, kickboxing) and
uncertainty regarding the ideal diagnostic strategy and
the optimum timing after TBI for detection of permanent
hypopituitarism.25–27
Pituitary apoplexy is the abrupt destruction of pituitary
tissue, resulting from infarction or haemorrhage into the
pituitary, usually into an underlying pituitary adenoma.
Severe headache accompanies a variable amount of
visual loss or cranial nerve palsies, or both. Pituitary
hormone deficiencies can develop rapidly.28,29
In Sheehan’s syndrome, pituitary infarction occurs
secondary to severe post-partum haemorrhage and
ensuing circulatory failure.30,31 In a normal pregnancy, the
pituitary gland can double or treble in volume; a small
fall in blood pressure can precipitate pituitary infarction.
Aneurysmal subarachnoid haemorrhage can cause
hypopituitarism, but there is no agreement on the
precise incidence, clinical course, and effect on overall
quality of life in long-term survivors.32–34
Infiltrative
Granulomatous diseases including sarcoidosis, tuber-
culosis, and histiocytosis X can involve the hypothalamic–
pituitary axis, and, in particular, the pituitary stalk,
causing hypopituitarism. Diabetes insipidus is a
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 Seminar

common complication of neurosarcoidosis (25–33%) Genetic

and histiocytosis X.35
Iron overload states, which occur in patients with
haemochromatosis36 and in those who need several blood
transfusions for disorders such as β thalassaemia, can
cause hypopituitarism. Gonadotropin secretion seems to
be especially affected, but other pituitary hormone
deficiencies can occur.
Immunological
Lymphocytic hypophysitis is caused by an immune-
mediated diffuse infiltration of the anterior pituitary with
lymphocytes and plasma cells. It occurs predominantly
in women and is often first evident in pregnancy or after
delivery.37 Classic presentation is hypopituitarism in the
peripartum, often with a pituitary mass, visual failure,
and headaches.
Increasing use of immunologically based treatments in
patients with cancer has resulted in a growing number of
reports of hypophysitis.38,39 Ipilimumab is a humanised
monoclonal antibody that blocks cytotoxic T-lymphocyte
antigen 4 and enhances T-cell activation. In a large series
of patients with metastatic melanoma treated with
ipilimumab, more than 10% developed hypophysitis,
particular risk factors being male sex and older age.38
Hypopituitarism only involved anterior pituitary
function, was persistent in most patients, and was
associated with pituitary enlargement that often resolved
rapidly.38,39
The development of the pituitary gland depends on the
sequential temporal and spatial expression of tran-
scription factors and signalling molecules; these include
the transcription factors HESX1, PROP1, POUF1, LHX3,
LHX4, PITX1, OTX2, SOX2, and SOX3. Genetic
mutations in any of these factors can lead to congenital
hypopituitarism in association with a wide spectrum of
craniofacial and midline defects (table).40 Congenital
hypopituitarism can present with non-specific symptoms
in neonates, but in some instances the full expression of
the hypopituitarism evolves over time, with the last
deficiency presenting in adolescence or young adult-
hood.41,42 Isolated pituitary hormone deficiency can be
caused by a mutation in genes involved in the
development and functional activity of that specific
pituitary cell line.41
International variation
In most countries, the main cause of hypopituitarism
that presents in adult life is a benign pituitary tumour or
its treatment by surgery or radiotherapy, or both. The
prevalence of some of the less common causes is greater
in countries situated in the tropics than in developed
countries,43 and not just because of very rare causes, such
as acute pituitary infarction caused by snakebite.44 In
countries situated within the tropics, hypopituitarism
due to infective causes, such as pituitary abscess, HIV
infection, and tuberculosis, is more common than in

Inheritance Types Endocrinopathies Phenotypes

GLI2 Haploinsufficiency Missense or frameshift CPHD (GH, TSH, LH, FSH, or ACTH) Holoprosencephaly, craniofacial abnormalities, polydactyly, HH, and
partial agenesis of the corpus callosum
FGF8 AR and AD Missense or chromosome deletion LH, FSH, or diabetes insipidus HH, anosmia, holoprosencephaly, Moebius syndrome, and SOD
LHX3 AR Missense, non-sense, frameshift, or CPHD (GH, TSH, LH, FSH, prolactin, or Limited neck rotation, short cervical spine, and sensorineural
splicing ACTH) deafness
LHX4 AD Missense or frameshift CPHD (GH, TSH, and ACTH) or Cerebellar abnormalities
variable gonadotropin deficiency
HESX1 AR and AD Missense or frameshift IGHD or CPHD SOD
SOX2 AD Missense, non-sense, or frameshift LH, FSH, or variable GHD Anophthalmia or microphthalmia, oesophageal atresia, genital tract
abnormalities, hypothalamic hamartoma, sensorineural hearing loss,
or diplegia
SOX3 X linked Variations in polyalanine tract IGHD or CPHD Mental retardation, infundibular hypoplasia, EPP, or midline
length, or chromosome duplication abnormalities
OTX2 AD Missense, non-sense, or IGHD or CPHD Anophthalmia or microphthalmia, coloboma, or developmental
microdeletion delay
PROP1 AR Missense, non-sense, frameshift, or CPHD (GH, TSH, LH, FSH, or prolactin) Transient anterior pituitary hyperplasia
splicing or evolving ACTH deficiency
POU1F1 AR or AD Missense, non-sense, frameshift, or CPHD (GH, TSH, or prolactin) Variable anterior pituitary hypoplasia
splicing
TBX19 AR Missense, non-sense, frameshift, or ACTH Neonatal hypoglycaemia or neonatal cholestatic jaundice
splicing

ACTH=adenocorticotropic hormone. AD=autosomal dominant. AR=autosomal recessive. CPHD=combined pituitary hormone deficit. EPP=ectopic posterior pituitary. FSH=follicle stimulating hormone.
GH=growth hormone. GHD=growth hormone deficiency. HH=hypogonadotropic hypogonadism. IGHD=isolated growth hormone deficiency. LH=luteinising hormone. SOD=septo-optic dysplasia. TSH=thyroid
stimulating hormone. Reproduced from McCabe and Dattani,40 by permission of Elsevier.

Table: Mutational characteristics of transcription factors mediating pituitary development

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 Seminar
developed countries.43 Sheehan’s syndrome is more
common in countries situated in the tropics43 and in
Turkey31 than in other developed countries because of
less well developed obstetric care.
Clinical presentation and diagnosis
The clinical presentation of hypopituitarism is varied and
depends on the nature and acuity of the damage to the
hypothalamic–pituitary region and the resultant order
and amount of hormonal loss.
Acute
Pituitary apoplexy, acute pituitary inflammation, and
Sheehan’s syndrome can all cause acute hypopituitarism,
which, if untreated, have a high risk of mortality, usually
secondary to loss of ACTH and subsequent hypo-
adrenalism. This presentation is rare but crucial to
recognise.
Sudden onset of acute severe headache, usually retro-
orbital in nature, should alert clinicians to the possibility
of acute pituitary damage. Increased intrasellar pressure
in the pituitary as a result of haemorrhage, infarct, or
inflammation generates pain, and is also associated with
neuro-ophthalmic signs in up to 70% of patients45 These
symptoms and signs can constitute a surgical
emergency.45,46 Clinicians should also recognise these
symptoms as suggestive of a possible association with
acute hypopituitarism, and many patients will have
coincident nausea, vomiting, hypotension, and hypo-
natraemia caused by an acute loss of ACTH and
subsequent hypocortisolism.
Diabetes insipidus can also be a presenting feature of
acute pituitary damage and should be suspected if
polyuria and polydipsia are present. Hypocortisolism
can mask diabetes insipidus, and therefore the
symptoms of diabetes insipidus might not manifest
until cortisol is replaced.
In acute hypopituitarism, rapid replacement with
hydrocortisone is crucial. Before urgent administration
of hydrocortisone, measurements of cortisol and ACTH
concentrations are needed to confirm the diagnosis. In
an acute setting, serum cortisol concentrations of less
than 500 nmol/L would be regarded as subnormal for
this setting. A short Synacthen test in this setting can be
falsely reassuring because adrenal atrophy would
probably be absent and therefore the adrenal glands
would respond appropriately to ACTH.45,46
Other pituitary hormone defects occur with acute
hypopituitarism but rarely result in acute symptoms.
Measurement of insulin-like growth factor 1 (IGF-1),
luteinising hormone and FSH, testosterone or oestradiol,
TSH, and thyroxine and prolactin are also useful for the
diagnosis of hypopituitarism.
Chronic
The onset of hypopituitarism is usually insidious, and
the clinical presentation non-specific. The pattern of
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symptoms and signs depends on the order and extent of
hormonal loss. The typical symptoms and signs
associated with each hormonal deficiency are described
in the following sections that relate to hormone
measurements and dynamic testing.
Hormone measurements and dynamic testing
Methods for hormonal measurement need to be
harmonised, international standards need to be used,
and units of reporting need to be consistent to eliminate
the need for conversion factors.47 Binding globulins can
be affected by many disorders and drugs, most
commonly oral forms of oestrogen, leading to variability
in total hormone concentrations. Measurement of
concentrations of free hormone using salivary methods
and mass spectrometry has been advocated to avoid
these issues.48,49 Knowledge of local laboratory methods
and potential interferences is vital in the assessment of
pituitary function. Robust normative data are also
needed to provide meaningful reference ranges.50
Ideally, reference ranges and cutoffs for stimulation
tests should be derived locally, and the suggested values
provided in this Seminar need to be interpreted with
this in mind.51
GHD in childhood
In childhood, the most prominent feature of GHD is
reduced growth. The Growth Hormone Research Society
suggest a combination of convincing auxology, bio-
chemical assessment of the growth hormone–IGF-1 axis,
and pituitary imaging is needed for a diagnosis of GHD
in children.52 Growth hormone is secreted in a pulsatile
fashion and therefore a random growth hormone
estimation is rarely helpful in excluding GHD unless the
sample coincides with a growth hormone secretory peak.
Stimulation of growth hormone using, for example,
insulin-induced hypoglycaemia, arginine, or glucagon, is
the usual method of diagnosis, and diagnosis is more
likely in the presence of several hormone deficiencies,
low serum IGF-1 concentration, and a structural lesion.
In the case of isolated GHD, two dynamic tests should be
done to confirm a diagnosis.
GHD in adulthood
Adults with GHD have increased fat mass and reduced
muscle mass, low energy, and reduced quality of life,
which is ideally assessed clinically and by a validated
questionnaire. Although GHD exists as a continuum of
deficiency, strict diagnostic criteria exist for severe
GHD in adults, which determines replacement
strategies in many countries. Guidance from inter-
national and national societies is largely followed.53 In
the presence of a known structural pituitary lesion and
several other pituitary hormone deficiencies, severe
GHD is probable. In this situation, the presence of
three other pituitary hormone deficiencies and a low
serum IGF-1 concentration is conclusive of diagnosis
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and justifies no further testing.54 In less clear-cut
situations, dynamic pituitary function tests are
necessary. The insulin tolerance test is the gold
standard55 for diagnosis in adults, although the growth
hormone releasing hormone (GHRH)–arginine
stimulation test has similar sensitivity and specificity.56
Thought must be given to the choice of stimulation in
patients with a probable hypothalamic contribution to
pituitary failure (eg, after irradiation), because direct
pituitary stimulation with drugs such as GHRH can
give a false negative diagnosis.57 Other pituitary
hormones must be replaced adequately before under-
taking growth hormone stimulation tests. The insulin
tolerance test has many contraindications, and GHRH
is no longer available in some countries, making other
stimulation tests necessary. Recommendations are for a
glucagon stimulation test in this situation.55
The growth hormone cutoff values for diagnosis of
severe GHD are arbitrary. In the UK, the cutoff value for
growth hormone during an insulin tolerance test to
diagnose severe GHD and allow growth hormone
treatment under National Institute for Health and
Clinical Excellence approval is less than 3 μg/L; this
concentration has been translated across all dynamic
tests in most UK centres. However, the accuracy of this
threshold is questionable and some recommend a cutoff
of less than 5 μg/L for the insulin tolerance test.55
Cutoffs for GHRH–arginine testing should be
dependent on body-mass index (BMI; 11·5 μg/L for
patients with a BMI <25 kg/m²; 8·0 μg/L if
BMI is ≥25 kg/m² and <30 kg/m²; and 4·2 μg/L if BMI
is ≥30 kg/m²), and evidence suggests that the cutoff
should be reduced to 1 μg/L in a glucagon stimulation
test for those with an increased BMI above 25 kg/m² to
avoid overdiagnosis.58
Gonadotropin deficiency
Gonadotropin deficiency in premenopausal women
can present with menstrual irregularities, ameno-
rrhoea, or difficulty with conception. A low serum
oestradiol concentration with coincidentally low
luteinising hormone and FSH is the diagnostic key,
but must be interpreted in the context of the menstrual
cycle phase.
In men, hypogonadotropic hypogonadism can
present with testosterone deficiency or infertility, or
both (panel). The presence of low (<10·4 nmol/L)
morning serum total testosterone concentrations with
non-raised gonadotropin concentrations on two
occasions is needed for diagnosis.51 Total testosterone
measurements represent testosterone bound to sex
hormone binding globulin and therefore if results
are borderline, sex hormone binding globulin
concentrations and measurement of free or bioavailable
testosterone should be considered.51 In adolescents,
failure to progress through puberty is usually the
presenting symptom.
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Seminar
ACTH deficiency
Chronic ACTH deficiency causes lethargy, tiredness, and
weight loss. However, it can be asymptomatic when only
partial, such as when there is sufficient ACTH to
maintain cortisol concentrations for day-to-day activity
but not at times of intermittent stress or illness. Patients
with a low cortisol concentration (<80 nmol/L) at 0900 h
can be diagnosed with complete ACTH deficiency, but a
stimulation test is needed to elucidate the cortisol reserve
in those with intermediate cortisol results (>80 and
<400 nmol/L) at 0900 h.59 The gold standard for testing
pituitary ACTH deficiency is the insulin tolerance
test. Stimulated concentrations of cortisol less than
500 nmol/L suggest an inability to respond adequately to
stress, and hydrocortisone replacement should be
considered. Insulin tolerance tests are contraindicated in
patients with ischaemic heart disease and those with
epilepsy.60,61
A short Synacthen test (250 μg ACTH[1–24]) is a less
labour intensive alternative to the insulin tolerance test;
it has been validated for the detection of ACTH deficiency,
using the peak cortisol concentration.60,61 However, the
short Synacthen test can be less sensitive in some
situations and can provide a false negative result,
including when the pituitary damage occurred less than
6 weeks before the test. Caution must be taken when
using the short Synacthen test in patients with a history
of asthma and anaphylaxis.62 Controversy exists regarding
whether to use a 30 min or 60 min cutoff for diagnosis
and the usefulness of the low dose, 1 μg short Synacthen
test.61 Other tests to detect ACTH status include the
Panel: Symptoms and signs suggestive of androgen deficiency in men
More specific signs and symptoms
• Incomplete or delayed sexual development (ie, eunuchoidism)
• Reduced sexual desire (ie, libido) and activity
• Decreased spontaneous erections
• Breast discomfort or gynaecomastia
• Loss of body (axillary and pubic) hair or reduced shaving
• Reduced volume (especially <5 mL; normal adult male testicular volume 15 mL) or
shrinking testes
• Inability to father children, or low or zero sperm count
• Height loss, low trauma fracture, or low bone mineral density
• Hot flushes or sweats
Other less specific symptoms and signs
• Decreased energy, motivation, initiative, and self-confidence
• Feeling sad or blue, depressed mood, or dysthymia
• Poor concentration and memory
• Sleep disturbance or increased sleepiness
• Mild anaemia (normochromic, normocytic, or in the female range for assay used)
• Reduced muscle bulk and strength
• Increased body fat or body-mass index
• Diminished physical or work performance
Adapted from Bhasin and colleagues,51 by permission of Endocrine Society.
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glucagon stimulation test, measurement of overnight
metyrapone stimulation, and corticotropin-releasing
hormone testing.63
TSH deficiency
TSH deficiency leads to central hypothyroidism.
Presenting symptoms are similar to those for primary
hypothyroidism. Differences include absence of goitre
and reduced severity of symptoms. Central hypo-
thyroidism nearly always presents alongside other
pituitary hormonal deficiencies, and as a result the
phenotype is difficult to define.64
Measurement of both serum TSH and free thyroxine
concentrations is needed for diagnosis. Low thyroxine
and low or normal TSH concentrations confirms the
diagnosis in the absence of non-thyroidal illness.64
Reference ranges for TSH and thyroxine for healthy
individuals (ie, set points) are narrower than those for
the general population. Many patients with deficiency
who have TSH and free thyroxine concentrations that are
within the reference range but have substantially reduced
over time from their individual set point will probably
not be classed as TSH deficient according to these
criteria.65 Models of individual TSH and thyroxine indices
might be useful in this context, but clinical usefulness
has not been validated.66,67
A B
C D
Figure: MRI of the pituitary gland
(A) T1-weighted and (B) T2-weighted MRI of normal pituitary gland in sagittal planes before contrast
administration. The high signal intensity of the posterior lobe is visible. (C) T1-weighted and (D) T2-weighted
MRI in sagittal planes before contrast administration in a 36-year-old man with central diabetes insipidus. The
high signal intensity of the posterior lobe is not visible. Reproduced from Bladowska and Sąsiadek,76 under
CC BY 3.0 licence.
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Prolactin deficiency
Hypoprolactinaemia prevents adequate lactation in
women. Severe hypoprolactinaemia (serum prolactin
concentrations <100 pmol/L) is rare, but has been
suggested to be a reliable marker of severe hypo-
pituitarism,68 independently associated with low serum
IGF-1,69 and in that context low serum IGF-1 might be
associated with specific humoral immune dysfunction.70
ADH deficiency
The classic presentation of complete central diabetes
insipidus due to ADH deficiency is polyuria (>3 L per day)
and concomitant polydipsia. Providing thirst sensation is
intact, normal serum sodium concentrations and
osmolality are maintained through increased fluid intake.
An initial finding of hypotonic polyuria is needed for
diagnosis. No diagnostic gold standard exists.71 A water
deprivation test should be done in the first instance,
although when this test was used in isolation only 70% of
patients were classified in the correct diagnostic
category.72 A urine osmolality of more than 800 mOsm/kg
after fluid deprivation excludes diabetes insipidus. A
urine osmolality of less than 300 mOsm/kg in the
presence of fluid deprivation and subsequent response to
arginine vasopressin (AVP) is suggestive of central
diabetes insipidus. The use of 3% saline stimulation and
measurement of AVP concentrations are alternative
options, but are limited by difficulties in accurate AVP
measurement73,74 and uncertainty regarding the normal
range for AVP in relation to plasma osmolality.72
Copeptin, the C-terminal moiety of AVP, is a stable
marker of AVP concentrations, and the combination of a
fluid deprivation test with hypertonic saline challenge
using copeptin measurements recently provided an
accurate diagnosis in 96% of patients presenting with
polyuria and polydipsia.75 Radiologically, in diabetes
insipidus the normal high-intensity posterior pituitary
signal might be absent on MRI (figure).
In symptomatic patients with a clear underlying cause
for diabetes insipidus, a therapeutic trial of desmopressin
can be warranted in lieu of clear-cut diagnostics.
Diabetes insipidus in patients with altered thirst
perception is more difficult to diagnose and manage.
Adipsic diabetes insipidus is rare, but has a substantially
increased morbidity and mortality compared with
patients with diabetes insipidus with intact thirst
perception. Thirst perception must be assessed in all
patients who present with signs and symptoms of
central diabetes insipidus.77,78
Management
Included in the management of a patient with hypo-
pituitarism are replacement of hormone deficiencies,
regular screening for the development of new pituitary
hormone deficiencies, surveillance of the underlying
cause (usually a tumour), and monitoring and
management of other consequences of hypopituitarism,
www.thelancet.com Vol 388 November 12, 2016

such as cardiometabolic risk factors, bone health, and
wellbeing of the patient.
ACTH deficiency
Most patients with secondary adrenal insufficiency have
other pituitary hormone deficiencies.6,79 Replacement
treatment for cortisol deficiency must meet the day-to-day
basic maintenance needs and include rescue treatment
when patients increase their dose during physical and
mental stress to prevent an adrenal crisis. The aim of
replacement treatment is to achieve a physiological daily
dose for each patient and to mimic the circadian serum
cortisol profile. Hydrocortisone or cortisone acetate are
most commonly used for replacement treatment.80 The
recommended mean daily dose of hydrocortisone should
be lower than 30 mg,81 on the basis of findings from
studies that showed a cortisol production rate of
15·5–19 mg/day in healthy adults82 and adverse metabolic
risk in patients with hypopituitarism who received doses
greater than 20 mg/day.83
In patients with partial cortisol insufficiency, use of
conventional doses of hydrocortisone will result in overly
high cortisol exposure.84 Clinical judgment should be
used to decide whether to start with lower than
conventional doses for replacement (5–10 mg/day) or to
use only rescue treatment when needed.
Commonly used doses are hydrocortisone 10 mg in the
morning in the fasting state together with 5 mg at 1200 h,
often with an additional 5 mg later in the day (before
1800 h). This regimen attempts to simulate the normal
physiological exposure to cortisol, higher in the morning
and lower in the afternoon and evening. A dose
administered too late during the day results in higher
cortisol exposure during late evening, which might affect
sleepiness and have a more adverse metabolic effect.85,86
New products for the treatment of adrenal insufficiency
have been developed and provide a more physiological
cortisol profile,87–89 which might have some beneficial
effects over conventional replacement treatment with
hydrocortisone.89
Adrenal crisis occurs when cortisol availability is
reduced or low at a time of increased need for cortisol,
such as during a severe infection. During adrenal crisis,
patients develop fever, abdominal pain, nausea and
vomiting, diarrhoea, reduced blood pressure, and
eventually circulatory failure, with a risk of death unless
treated promptly with cortisol and saline infusion.
Common precipitating disorders that cause adrenal
crisis are gastroenteritis, other infections, and mental
stress.90 Therefore, to prevent adrenal crisis patients are
instructed to immediately double or triple their daily
dose of hydrocortisone during an illness, whereas the
dose adjustment during a stress not related to illness,
such as mental stress and physical exercise, is less and
needs to be tailored more individually to prevent excess
cortisol exposure. All patients with hypopituitarism and
cortisol insufficiency should carry a steroid card that
www.thelancet.com Vol 388 November 12, 2016
Seminar
provides information for the patient regarding the
intercurrent illness regimen and information for health-
care personnel on how to manage adrenal crisis. Patients
should also have an emergency kit for self-administration
of parenteral hydrocortisone in case of a sudden severe
disease, such as gastroenteritis, when extra doses of oral
hydrocortisone are less likely to be efficacious. Parenteral
administration is needed if the patient requires general
anaesthesia or when oral administration is not possible.
Patients with hypopituitarism who have untreated
severe GHD have increased local 11β-hydroxysteroid
dehydrogenase type 1 activity in adipose tissues, resulting
in increased local cortisol exposure.91,92 Therefore, when
growth hormone replacement is started, tissue exposure
of cortisol is reduced; this can push some patients with
partial cortisol insufficiency into overt deficiency.93 To
avoid the occurrence of problems with cortisol deficiency,
the hydrocortisone dose might need to be increased in
those on a low replacement dose at the start of growth
hormone replacement.
ACTH deficiency also leads to androgen deficiency,
including dehydroepiandrosterone (DHEA) deficiency.94
Studies on DHEA replacement have been done in women
with secondary adrenal insufficiency, and findings from
some, but not all, showed beneficial effects on wellbeing
and sexuality.95,96 DHEA replacement might also be of
some benefit in men.97 Addition of 20–50 mg DHEA can
be considered in women with hypopituitarism and low
serum concentrations of DHEA who report reduced
wellbeing and libido,95 which might also reduce the need
for growth hormone.98 Side-effects that can occur are
increased sweating, acne, and undesired hair growth.
TSH deficiency
In patients with central hypothyroidism, the extent of
insufficiency cannot be defined as well as in patients with
primary hypothyroidism, in whom the magnitude of
increase in TSH is associated with the severity of the
insufficiency. Therefore, the starting dose and dose titration
should be chosen with caution in all elderly patients and
those with known ischaemic heart disease. In patients with
hypopituitarism with central hypothyroidism, the status of
the hypothalamic–pituitary–adrenal axis should always be
assessed and cortisol insufficiency corrected before starting
treatment with L-thyroxine. Otherwise, overt cortisol
insufficiency or even adrenal crisis can occur because of
the accelerated metabolic clearance of cortisol and
increased cortisol need as a result of an increased basal
metabolic rate after thyroxine replacement.
Growth hormone replacement increases the conversion
of thyroxine to triiodothyronine.99 Therefore, careful
monitoring of thyroid function is mandatory during
growth hormone treatment because it might uncover
central hypothyroidism or suggest the need for changes
in the dose of L-thyroxine.
Finding the appropriate L-thyroxine replacement dose
in central hypothyroidism is based on measurement of
2409
 Seminar
the free thyroxine concentration before the daily intake
of L-thyroxine. Serum free thyroxine concentrations
should be in the upper normal range for the assay
used.100–103 This suggestion is supported by findings from
two large trials104,105 of adults with hypopituitarism that
showed more prevalent cardiometabolic risk factors
among patients with free thyroxine concentrations in
the lower normal range and that BMI and total and LDL
cholesterol improved with an increased dose of
L-thyroxine. Findings from other prospective dose-
titration studies have suggested that an adult replace-
ment dose of L-thyroxine should be 1·6 μg/kg per
day,101,102,105 with a dose of 1·1–1·4 μg/kg per day in patients
older than 60 years and 1·41–1·7 μg/kg per day in those
younger than 60 years.106
Gonadotropin deficiency
Oral oestrogen with cyclic addition of progestin to mimic
the normal menstrual cycle is the most common
replacement regimen in women with hypopituitarism.
Younger women need higher oestrogen doses and
women approaching the age of menopause might need a
lower dose. After age 50 years (ie, the mean age of
menopause), oestrogen treatment is usually withdrawn.
Oral, by contrast with transdermal, oestrogen has
clinically significant effects on lipid metabolism,
coagulation factors, systemic inflammation, and various
circulating binding globulins important for carrying
hormones.107 Oral oestrogen during its first passage
through the liver suppresses the hepatic IGF-1 response
to growth hormone and might also attenuate other
metabolic responses to growth hormone.107
Ovulation and fertility can be achieved in women
with hypopituitarism by gonadotropin treatment. The
outcome of such treatment in general is not known, but
in some patients, pregnancy and successful births have
been achieved.108,109
For men with hypopituitarism, testosterone can be
replaced using depot formulation for intramuscular
injections or transdermal or oral preparations. The oral
formulations are often less effective and are more likely
to induce hepatic toxicity than are other formulations
that are likely to be otherwise similar in terms of safety
and efficacy. Before initiation of testosterone replacement,
and on a regular basis during treatment, patients need to
be screened for prostate cancer, polycythaemia, and
sleep apnoea.
Spermatogenesis can be induced in men with hypo-
pituitarism using human chorionic gonadotropin or
recombinant FSH, or both,110 but this takes months and
in some cases 2–3 years. Small testicular volumes at the
start of treatment is a negative predictor of success.111
Growth hormone deficiency
In adults, the goal of growth hormone replacement is to
improve wellbeing, reduce cardiovascular risk, increase
bone density, and normalise body composition.112
2410
Well-documented effects of growth hormone replacement
in adults include reductions in total and LDL cholesterol
and diastolic blood pressure,113 and changes in body
composition, with increases in lean body mass and
reductions in fat mass, particularly abdominal
adiposity.113,114 Findings from randomised controlled trials
have also shown improvements in quality of life,
wellbeing, and cognitive function,115,116 although these
were not found in all studies.117
Recombinant human growth hormone is available for
daily subcutaneous injections. In adults, the treatment
dose needs to be low initially and then titrated gradually
against serum IGF-1 concentration and clinical response
every 2–4 weeks.118,119 Effects on wellbeing, with increased
energy, are usually reported after 3–12 months of
treatment and are sustained by continued treatment.120
The growth hormone dose should be titrated towards a
normal serum IGF-1 concentration against proper age-
adjusted reference values. Using a larger initial dose of
growth hormone and undertaking dose titration too fast
places patients at risk of side-effects related to fluid
retention, such as muscle and joint stiffness and pain,
peripheral oedema, and carpal tunnel syndrome.10
Dose adjustment of growth hormone needs to be done
in women who change their oestrogen replacement
treatment. Since oral oestrogen replacement attenuates
the serum IGF-1 response to growth hormone, a dose
reduction is needed when withdrawing oestrogen
replacement or switching to a transdermal route of
replacement. Thyroid and adrenal function need to be
monitored before and after the start of growth hormone
replacement because this treatment can unmask central
hypothyroidism and secondary adrenal insufficiency,
which would result in the need for dose adjustments in
those receiving replacement treatment with L-thyroxine
and glucocorticoid.93,99
Adults with hypopituitarism and untreated GHD are
insulin resistant.121,122 Growth hormone directly reduces
insulin sensitivity and therefore the possibility that
growth hormone replacement might induce diabetes
mellitus in adults with hypopituitarism is concerning.
Findings from two large prospective surveillance studies
showed either no change123 or an increase124 in the
incidence and prevalence of diabetes mellitus among
adults who underwent growth hormone replacement.
Available data do not suggest an increased risk of de-novo
malignancies125 or recurrence or regrowth of pituitary
tumour during long-term growth hormone replacement
treatment.121,126,127
Diabetes insipidus
Desmopressin is a modified form of the normal human
hormone AVP. For maintenance, desmopressin tablets
divided into two or three daily doses, or nasal preparations
administered one to two times daily are used. The
parenteral form is available for emergency use and when
oral or nasal administration is not possible.
www.thelancet.com Vol 388 November 12, 2016

Patients with central diabetes insipidus who are
conscious can compensate for the excess loss of free
water from the kidney by drinking more fluids. However,
in decompensated patients with increased serum sodium
concentrations, slow correction of serum sodium should
be done to avoid cerebral oedema. In patients who are
unconscious, management of diabetes insipidus needs
to be monitored carefully, with assessment of fluid
balance, serum sodium concentrations, and appropriate
replacement of AVP.
The aim of replacement treatment in diabetes
insipidus is to reduce the daily urinary production of
free water to prevent excessive thirst, persistent
polyuria, and nocturia. Ideally, treatment with
desmopressin should be started with a dose at bedtime
to prevent nocturia. Thereafter, the most appropriate
morning and, sometimes, midday dose should be
added. The duration of antidiuresis after nasal
administration varies from 6 h to 12 h, whereas the oral
dose can have a shorter duration. Most patients need
twice daily dosing, but a third oral dose might be
needed. Patients should learn to sense signs and
symptoms suggestive of reduced efficacy, such as
increased thirst and increased urinary output, and also
signs suggestive of overdose such as headache, fatigue
(caused by hyponatraemia), and low urinary output.
Biochemical monitoring consists of measurement of
serum sodium and urea concentrations.
Patients with diabetes insipidus and hypothalamic
lesions that have resulted in loss of thirst sensation are at
risk of developing severe hypertonic hypernatraemia.
This can be managed by a constant intake of
desmopressin each day and calculation of variable daily
fluid intake to balance renal and insensible losses. Daily
weighing and frequent monitoring of serum sodium and
urea is needed in these patients, in particular in the early
stages of treatment.
Pregnancy
Before conception, endocrine replacement treatment in
women with hypopituitarism should be optimised,
including growth hormone replacement and adjustment
of the L-thyroxine dose to obtain high normal free
thyroxine concentrations. The hypothalamic–pituitary–
adrenal axis should be assessed carefully before
pregnancy, because this is difficult during pregnancy
owing to the marked increase in cortisol binding globulin.
During pregnancy, the L-thyroxine dose needs to be
increased in the first trimester and regular and careful
clinical assessment of glucocorticoid status should be
done because an increase in the dose might be needed in
some women during the last trimester. In many women,
growth hormone treatment is discontinued when
pregnancy is confirmed, whereas in others treatment is
continued until placental production of variant growth
hormone is clinically evident (usually around the
12th week of gestation), after which the growth hormone
www.thelancet.com Vol 388 November 12, 2016
Seminar
dose is gradually reduced and then discontinued around
gestational week 20.108
Data on the outcome of pregnancy in women with
hypopituitarism are limited;108,109,128 however, there is no
evidence to suggest that appropriately treated hypo-
pituitarism is associated with decreased frequency of
livebirths, increased risk of malformation, or variation in
gestational week of delivery or birthweight.
Controversies, uncertainties, and future needs
Pathology
The varying sensitivity of the different anterior pituitary
hormones to pathological damage remains unexplained.
Thus, the reason why growth hormone secretion is
adversely affected early and TSH later after pathological
changes such as radiation or increased sellar pressure
from a pituitary tumour is unknown. Equally unknown
is the explanation for why radiation-induced damage,
primarily hypothalamic in most instances, does not
cause diabetes insipidus. Similarly, the specific
vulnerability of gonadotropin secretion to iron deposition
in the pituitary and ACTH secretion to lymphocytic
hypophysitis are unexplained. Without an explanation
for these findings, new hypopituitarism-avoidance
strategies cannot be developed.
Treatment
Different strategies exist for endocrine replacement in
adults. In the UK, growth hormone treatment is offered
to adults with severe GHD on the basis of a single
biological endpoint: impaired quality of life. Elsewhere in
the world, growth hormone replacement is offered on
holistic grounds in the belief that it improves adverse
markers of vascular risk, reduces the risk of fractures,
offers metabolic benefit, and improves quality of life.129
In general, the enthusiasm of the endocrinologist for
starting thyroxine and hydrocortisone replacement
diminishes for lesser amounts of TSH and ACTH
deficiency, whereas partial GHD does not warrant growth
hormone replacement in adults.127 Furthermore, the
replacement dose (eg, thyroxine for TSH deficiency) is
less frequently optimised than it is when used for
treatment of failure of the primary target gland.130
In the future, modified-release forms of growth
hormone administered about once weekly or even less
frequently might replace once daily preparations.
Similarly, in selected patients, sustained-release forms of
hydrocortisone might replace thrice daily conventional
hydrocortisone to improve quality of life through a more
physiological cortisol profile.
Continuation of care
Care of patients with childhood-onset hypopituitarism,
once growth is completed, varies substantially. Attempts
to offer transitional care involving shared management
between paediatric and adult endocrinologists have had
mixed success, depending on the health-care system of
2411
 Seminar
the country and the local circumstances of endocrine
practice in the vicinity of the patient. Thus, although
guidelines are clear in their recommendations for the
management of this period in life,131 the success of the
integration of the adult and paediatric contributions is
often dependent on the beliefs and personalities of the
local adult and paediatric endocrinologists.
Finally, the strategy for repeated assessment over the
long term in patients with predictable slowly evolving
hypopituitarism also needs more thought regarding who
to screen and how often, and which are the best screening
instruments in terms of labour, cost, and endocrine yield.
However, in the meantime, many patients in the
community undoubtedly have untreated hypopituitarism
and are suffering greatly because of this absence of a
process of follow-up.132
Contributors
All authors contributed equally to this work.
Declaration of interests
GJ has served as a consultant to Viropharma/Shire and AstraZeneca and
has received lecture fees from Merck Serono, Novartis, Novo Nordisk,
Otsuka, Pfizer, and Shire. SMS has received fees for lecturing and
ad-hoc advisory board consultancy from Pfizer, Novo Nordisk, Ipsen,
Sandoz, Merck, and Eli Lilly. CEH declares no competing interests.
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