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Hypopituitarism Maria Fleseriu, Mirjam Christ-Crain, Fabienne Langlois, Mônica Gadelha, Shlomo Melmed
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Hypopituitarism Maria Fleseriu, Mirjam Christ-Crain, Fabienne Langlois, Mônica Gadelha, Shlomo Melmed
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SeminarHypopituitarism
Maria Fleseriu, Mirjam Christ-Crain, Fabienne Langlois, Mônica Gadelha, Shlomo Melmed
Partial or complete deficiency of anterior or posterior pituitary hormone production leads to central hypoadrenalism, Published Online
central hypothyroidism, hypogonadotropic hypogonadism, growth hormone deficiency, or arginine vasopressin May 9, 2024
https://doi.org/10.1016/
deficiency depending on the hormones affected. Hypopituitarism is rare and likely to be underdiagnosed, with an S0140-6736(24)00342-8
unknown but rising incidence and prevalence. The most common cause is compressive growth or ablation of a
Department of Medicine,
pituitary or hypothalamic mass. Less common causes include genetic mutations, hypophysitis (especially in the Division of Endocrinology,
context of cancer immunotherapy), infiltrative and infectious disease, and traumatic brain injury. Clinical features Diabetes and Clinical Nutrition
vary with timing of onset, cause, and number of pituitary axes disrupted. Diagnosis requires measurement of basal (Prof M Fleseriu MD),
Department of Neurological
circulating hormone concentrations and confirmatory hormone stimulation testing as needed. Treatment is aimed at
Surgery (Prof M Fleseriu), and
replacement of deficient hormones. Increased mortality might persist despite treatment, particularly in younger Pituitary Center
patients, females, and those with arginine vasopressin deficiency. Patients with complex diagnoses, pregnant patients, (Prof M Fleseriu), Oregon Health
and adolescent pituitary-deficient patients transitioning to adulthood should ideally be managed at a pituitary tumour and Science University,
Portland, OR, USA; Department
centre of excellence. of Endocrinology, Diabetology
and Metabolism, University
Introduction However, rates of radiation-associated hypopituitarism Hospital Basel, University of
Hypopituitarism, defined as partial or complete could fall with decreased use of radiotherapy in many Basel, Basel, Switzerland
(Prof M Christ-Crain MD);
deficiency of anterior or posterior pituitary hormones, countries. Department of Medicine,
results from compromised production of anterior Division of Endocrinology,
pituitary or hypothalamic hormones, or from the failure Mortality Centre intégré universitaire de
of hypothalamic hormone transport to the pituitary Mortality rates among patients with hypopituitarism santé et de services sociaux de
l’Estrie, Centre Hospitalier
via the portal system (figure 1).1–5 Deficiencies in are higher than those in the general population.2,11 A meta- Universitaire de Sherbrooke,
adrenocorticotropic hormone (ACTH) leading to central analysis of 13 studies comprising more than 23 000 patients Sherbrooke, QC, Canada
adrenal insufficiency (central hypoadrenalism), in reported a weighted standardised mortality ratio of 1·55 (F Langlois MD); Endocrine Unit
thyroid-stimulating hormone (TSH) leading to central (95% CI 1·14–2·11), which persisted even after hormone and Neuroendocrinology
Research Center, Medical
hypothyroidism, and in the gonado tropins, follicle- replacement.12 Younger age and female sex,11 history of School and Hospital
stimulating hormone (FSH) and luteinising hormone, brain irradiation or craniotomy, AVP-D, hypogonadism, Universitário Clementino Fraga
leading to central hypogonadism (hypo gona dotropic and craniopharyngioma diagnosis are all associated with Filho, Universidade Federal do
hypogonadism) are all common, as are growth hormone increased mortality.12,13 Hypothalamic obesity, when Rio de Janeiro, Rio de Janeiro,
Brazil (Prof M Gadelha MD);
deficiency and arginine vasopressin deficiency (AVP-D), present, also increases mortality as it is associated with Department of Medicine and
formerly called central diabetes insipidus.1–4,6 Clinically increased risk of cardiovascular complications.14 Pituitary Center, Cedars-Sinai
important oxytocin and prolactin deficiencies7 are not Although growth hormone deficiency could increase Medical Center,
Los Angeles, CA, USA
well described.8 We present here the wide range of causes mortality risk in some patients,15 growth hormone
(Prof S Melmed MBChB)
of hypopituitarism, including newly emerging causes, as replacement does not always decrease excess risk.11 Hypo
Correspondence to:
well as clinical features, diagnosis, and recommended adrenalism increases risks for cardiac and cerebrovascular Prof Maria Fleseriu, Pituitary
treatment strategies, including geographical variations, events, respiratory failure, infection, and adrenal crisis, Center, Oregon Health and
with a focus on adult hypopituitarism. all of which could contribute to mortality risk.16,17 Science University, Portland, OR
A Swiss database study showed a mortality rate of 97239, USA
fleseriu@ohsu.edu
Epidemiology 5·9% among those with hypopituitarism admitted to the
Epidemiological data on hypopituitarism are scarce. It hospital for non-pituitary indications versus 4·9% among
is probably underdiagnosed given the heterogeneous those without. Hypopituitarism patients were more likely
clinical features at presentation and complexities in to be admitted to the intensive care unit (odds ratio [OR]
testing for partial or transient hypopituitarism. A 1·5), have a longer hospital stay (OR 2·44), and have a
Spanish population-based study reported a prevalence of higher re-admission risk within 30 days (OR 1·31) and at
approximately 45·5 cases of hypopituitarism per 1 year (OR 1·29) than those without hypopituitarism.18 As
100 000 adults, with similar rates between females in outpatient settings, AVP-D was an adverse prognostic
and males, and an annual incidence of 4·21 per factor.
100 000 adults.9 Congenital hypopituitarism incidence is
estimated at one in 4000 to one in 10 000 livebirths per Causes
year.10 Improved detection of clinically relevant pituitary Hypopituitarism is typically classified based on onset of
adenomas on MRI,5 often performed for non- hormone deficiency (congenital or acquired) and whether
pituitary indications, suggests that hypopituitarism such deficiency results from structural injury or, more
prevalence has increased over the past two decades, rarely, pituitary or hypothalamic dysfunction1–4,19,20
possibly, in part, due to newer causes, including cancer (table 1). In high-income countries, hypopituitarism in
immunotherapy and traumatic brain injury (TBI). adults most frequently occurs in the setting of a pituitary
www.thelancet.com Published online May 9, 2024 https://doi.org/10.1016/S0140-6736(24)00342-8 1
, Seminar
is partly reversible after drug cessation.3,4,25 Non-thyroidal
• Expanding mass • Cortical inputs illnesses can lead to functional hypothyroidism.25 Obesity
• Iatrogenic • Hypothalamic
• Traumatic • Neural can reduce gonadotropins and growth hormone
• Infectious • Drugs concentrations that recover after weight loss, although
• Congenital or genetic • Infiltrative
• Developmental • Functional
insulin-like growth factor 1 (IGF-1) levels usually remain
• Vascular normal3 (table 1; appendix p 4).
Structural causes
Mass lesions
Pituitary adenomas and their treatment represent the
Adrenal main cause of hypopituitarism in adults5,26 (appendix p 6),
Cortisol
Androgens as adenomas account for approximately 17% of all
intracranial lesions in adults versus less than 3% of
Mammary ACTH
paediatric brain tumours.27,28 Prevalence of clinically
Lactation
Kidney apparent pituitary adenomas is low,29 ranging from one in
PRL AVP
Water reabsorption 865 to one in 1322 people,26 although rates have been
Gonads increasing, most likely due to improvements in MRI
Oestradiol LH, FSH
Progesterone OX
Uterus and breast detection.30 Anterior hypopituitarism can be seen in
Contractions
Testosterone 34–89% of adults with compressive non-functioning
TSH
pituitary adenomas (NFPAs). Rates of anterior hypo
Brain
Thyroid
GH Behavioural pituitarism are considerably lower with untreated micro
Thyroxine
Tri-iodothyronine
Metabolic adenomas.31 Hypogonadism is most common (>80%),
followed by deficiencies in growth hormone, TSH, and
Liver ACTH.32 Diminished secretion of gonadotropins is seen
IGF-1
Peripheral tissues with hyperprolactinaemia due to pituitary stalk com
pression, which suppresses hypothalamic gonadotropin-
Figure 1: Causes of hypopituitarism releasing hormone (GnRH) pulses, mainly via kisspeptin
The anterior pituitary lobe produces ACTH, PRL, LH, FSH, TSH, and GH largely under hypothalamic control. AVP and suppression.33 AVP-D is extremely rare in patients with
OX are produced in the hypothalamus and stored in the posterior lobe. Pituitary hormones, in turn, act on their pituitary adenomas,34 but it may be seen in as many as
respective peripheral target organs or tissues. Pituitary hormones are regulated by hypothalamic hormones, which
50% at presentation in patients with pituitary metastases.35
are under neuroendocrine control by integration of hormonal, neural, and cortical inputs. Peripheral hormone
feedback loops suppress their respective trophic hormone production. Each axis is tightly regulated to maintain Hypopituitarism due to hypothalamic and pituitary
homoeostasis. Alteration in the synthesis of pituitary hormones could be due to congenital or genetic defects abnormalities can also be seen with variable frequency in
affecting one or multiple cell lineages, an injury to the gland, local compression by an intrasellar mass, interrupted patients with non-pituitary sellar, suprasellar, and para
blood supply, hypophyseal cell dysfunction induced by an inflammatory, infiltrative, or infectious process, a drug,
sellar lesions (appendix p 6). For example, hypoadrenalism
or acute illness. ACTH=adrenocorticotropic hormone. AVP=arginine vasopressin. FSH=follicle-stimulating
hormone. GH=growth hormone. IGF-1=insulin-like growth factor 1. LH=luteinising hormone. OX=oxytocin. occurs more frequently in patients with Rathke’s cleft
PRL=prolactin. TSH=thyroid-stimulating hormone. cysts,36 and patients with craniopharyngioma. The latter
account for 6–13% of intracranial tumours in children.37,38
See Online for appendix adenoma and treatments affecting the pituitary or Pituitary surgery induces new anterior hypopituitarism
hypothalamus. Infection, snakebite, and postpartum in less than 10% of patients. Risk is potentially higher
Sheehan syndrome are more commonly encountered in following transcranial resection than trans-sphenoidal
low-income countries.21 Hypopituitarism reversibility is resection (risk ratio 4·90, 95% CI 2·94–7·82), particularly
more likely in patients with sellar and hypothalamic for persistent AVP-D (2·50, 1·05–5·35), while 30% show
tumours treated surgically and in those with functional improved pituitary function (95% CI 12–57).39 Transient
hypopituitarism. or permanent postoperative AVP-D can be as high
as 30%, and is substantially higher with large suprasellar
Medication, endogenous hormone excess, and tumours, such as craniopharyngiomas.40
functional hypopituitarism Predictors of postoperative hypopituitarism can vary
Medications that suppress one or more hormone axes by adenoma type. Preoperative hypopituitarism in
can lead to hypopituitarism.3,4 For example, exogenous patients with NFPA was associated with higher risk
glucocorticoid therapy, especially in high doses, of postoperative deficiencies compared to those without
suppresses the hypothalamic–pituitary–adrenal (HPA) preoperative defiencies (p=0·001),41 and a machine-
axis. Careful functional HPA axis restoration is critical to learning model identified 1-year postoperative hormonal
avoid hypoadrenalism.22 Long-standing endogenous status as a strong predictor of subsequent panhypo
Cushing’s syndrome has a similar suppressive effect.23 pituitarism after 5 years and 10 years. Age, adenoma
Opioids suppress several pituitary axes,24 and drug- volume, and use of radiotherapy also correlated with
induced hyperprolactinaemia and chronic or illicit hypopituitarism.42 By contrast, a meta-analysis including
testosterone use suppress gonadotropin function, which more than 4500 patients with acromegaly found
2 www.thelancet.com Published online May 9, 2024 https://doi.org/10.1016/S0140-6736(24)00342-8
, Seminar
Cause Underlying cause
Medication-induced Suppression of specific axis, possibly reversible with High-dose glucocorticoid treatment (oral, injectable, inhaled, topical, or intranasal) or long-standing endogenous
or endogenous medication discontinuation Cushing’s syndrome; medications including opiates, drugs causing hyperprolactinaemia, androgens, thyroid
hormonal excess hormones, somatostatin receptor ligands, intravenous dopamine, interferon, ribavirin, or other
Functional Reversible isolated or combined deficiency due to Acute or chronic severe illness, anorexia nervosa, extreme exercise, obesity or malnutrition, or pseudotumour
systemic disorder cerebri
Mass effect and Compressive sellar or suprasellar lesion; treatment Pituitary adenoma (functioning or non-functioning), pituitary cysts (Rathke, arachnoid, epidermoid, or dermoid),
treatment-related to the sellar area, basal brain, or nasopharynx craniopharyngioma, germinoma, metastasis (breast, lung, or other), meningioma, glioma, ependymoma, or other;
effects surgery and radiation therapy to the sellar area
Inflammatory Hypophysitis or inflammatory process, or both, Lymphocytic, granulomatous, IgG4 related, peritumoural, secondary to immunotherapy (anti-CTLA-4, anti-PD-1,
in the anterior or posterior pituitary, stalk, or anti-PD-L1), granulomatosis with polyangiitis, giant cell granuloma, secondary to other vasculitis or connective
or hypothalamus tissue disorders, xanthomatous, necrosis, or paraneoplastic syndromes (anti-POMC or anti-PIT1)
Infiltrative Pituitary or stalk infiltration, or both, often systemic Haemochromatosis, sarcoidosis, amyloidosis, or histiocytosis (Langerhans cell or Erdheim-Chester disease)
Infectious or toxic Mostly in immunosuppressed or endemic COVID-19; tuberculosis; viral, bacterial, fungal, or parasitic infection; syphilis; AIDS; or snakebite venom
populations
Vascular Infarction or haemorrhage Pituitary apoplexy, pituitary haemorrhage, Sheehan syndrome, cavernous carotid artery aneurysm, cavernous
sinus thrombosis, or subarachnoid haemorrhage
Traumatic Mechanical or vascular injury to the sellar area Head injury or contact sports (eg, boxing, kickboxing, or American football)
Developmental Syndromic or non-syndromic genetic alterations in Septo-optic dysplasia, absent pituitary gland, hypoplastic pituitary gland, empty sella, or stalk interruption
pituitary development (table 2; appendix p 2)
Other Unknown Idiopathic
This is a non-exhuastive list of hypopituitarism causes. Genetic causes of hypopituitarism are discussed in table 2. CTLA-4=cytotoxic T-lymphocyte associated protein 4. PD-1=programmed death 1.
PD-L1=programmed death ligand 1. PIT1=pituitary-specific transcription factor 1. POMC=pro-opiomelanocortin.
Table 1: Causes of hypopituitarism by category
postoperative hypoadrenalism rates were slightly higher Rates of hypopituitarism are lower with SRS (10–30%)
and hypothyroidism and hypo gonadism were slightly when compared with conventional radiotherapy,
lower in those with hypopituitarism than those without.43 especially with a distance of 3·95 mm or more between
Among patients with Cushing’s disease, postoperative the pituitary stalk centre and lower mass margin SRS
hypopituitarism risk is increased by up to 50%, especially isodose47 (hazard ratio 4·5, 95% CI 1·6–12·6; p=0·004).51
after repeat surgery.44 The degree of pituitary axis deficit at 1 year after
Surgeon experience can minimise postoperative radiotherapy predicts long-term pituitary function.52
hypopituitarism risk.44 Postoperative recovery of all four Surgery plus radiotherapy leads to higher hypo
hormonal axes after sellar decompression was shown in pi
tuita
rism rates. A meta-analysis of 24 studies com
approximately 30% of patients with NFPA, with ACTH prising 1381 patients with pituitary adenomas showed
and cortisol showing the highest degree of recovery.45 hypopituitarism in 11% of people treated with primary
In most countries, radiotherapy is less commonly used Gamma Knife radiosurgery versus 18–32% treated post-
than surgery in treating pituitary adenomas. Nevertheless, surgery.53
both stereotactic radiosurgery (SRS) and conventional
fractionated radiotherapy can induce hypopituitarism, Inflammatory, infiltrative, and infectious lesions
and radiotherapy remains a major cause of hypo Lymphocytic hypophysitis frequently causes hypo
pituitarism among patients with aggressive adenomas adrenalism (60–80%) and AVP-D (50%), a pattern
and brain or nasopharyngeal malignancies. A meta- markedly different from that seen with pituitary
analysis and systematic review of 18 studies with more adenomas.54,55 Thyroid and gonadal axes are also
than 800 patients with non-pituitary tumours found a frequently affected (30–60%), whereas growth hormone
pooled prevalence of 66% for hypopituitarism with concentrations are rarely abnormal (14–37%).3 Other
radiotherapy use, with deficiencies of growth hormone in forms of hypophysitis are described in table 1 and
45%, gonadotropins in 30%, TSH in 25%, and ACTH in depicted in the appendix (p 6). Pregnancy-related
22%.46 Rates vary from 10% to 50% for new deficiencies at hypophysitis is associated with a lower AVP-D rate versus
5 years depending on the treatment approach, radiation non-pregnancy autoimmune hypophysitis (12% vs 54%,
dose, and tumour type and volume.47,48 In adults, doses p<0·0001),56 whereas panhypopituitarism is frequent
more than 30 Gy, and especially more than 50 Gy, to the (~40%) in patients with IgG4-related hypophysitis.57
pituitary gland require close surveillance.48 Children Diagnoses of hypophysitis have increased in the past
treated with radiation doses 18 Gy or more to the decade with increased use of cancer immunotherapies,
hypothalamus or pituitary are at increased risk for growth specifically CTLA-4, PD-1, and PD-L1 inhibitors.54 These
hormone deficiency, and doses more than 30–40 Gy therapies induce autoimmune destruction of the
increase risk for other deficiencies.49,50 anterior pituitary, potentially due to early development of
www.thelancet.com Published online May 9, 2024 https://doi.org/10.1016/S0140-6736(24)00342-8 3
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