Clinical Review: Hypopituitarism

Contributed by Dr Rajeev Raghavan, specialist registrar, and Dr Karin Bradley, consultant endocrinologist, University Hospitals Bristol NHS Foundation Trust.

MRI showing a large pituitary adenoma (arroows) with upward extension, impinging on the optic chiasm
MRI showing a large pituitary adenoma (arroows) with upward extension, impinging on the optic chiasm

Section 1: Epidemiology and aetiology

Hypopituitarism evolves secondary to a spectrum of disorders which lead to insufficiency of pituitary hormones. Pathology may be intrinsic or extrinsic; either directly affecting the pituitary or indirectly via the hypothalamus.

Panhypopituitarism refers to the loss of secretion of at least three pituitary hormones. Several studies have demonstrated an increase in mortality by 1.3to 2.2-fold in hypopituitarism.1-3 Morbidity is variable and may result from the hormone deficiency or the underlying pathology.3 The incidence of hypopituitarism is around 2.5 per 100,000 with a prevalence of about 45.5 per 100,000 population.4

No age or racial predilection exists but pituitary failure is more common in women due to post-partum pituitary failure.

Aetiology
The causes of hypopituitarism vary with the age of onset and can be divided into sub-groups (see table left). Depending on the aetiology the syndrome can present acutely or insidiously and be either transient or permanent. There can be isolated (IPHD) or multiple pituitary hormone deficiencies (MPHD).

Classification
Disturbances in pituitary function commonly arise from a pituitary adenoma and dysfunction is usually proportional to tumour size (microadenoma <10mm diameter="" macroadenoma="">10mm).

The prevalence of pituitary adenomas is thought to be as high as 16.7 per cent5 and macroadenomas are estimated to occur in 1 in 600. 6

Pituitary dysfunction following radiotherapy is well researched in survivors of childhood cancer7 and is dependent upon the cumulative dose; doses less than 20Gy are rarely detrimental.

Typically the growth hormone (GH) axis is most sensitive followed by gonadotrophins and then the HPA (hypothalamic-pituitary-adrenal) axis. Hypothalamic damage can cause disturbances in thirst, appetite and temperature regulation, as well as aggressive behaviour and learning difficulties.

Cranial diabetes insipidus (DI) is seen more often in infiltrative conditions and traumatic brain injury. 8 Lymphocytic hypophysitis is an infiltrative disorder associated with pregnancy.9 It is characterised by headaches and visual field defects, and can cause MPHD.

CLASSIFICATION OF CAUSES
Aetiology Diseases/disorders
Congenital
  • Single hormone defects
  • Multiple hormone defects

Neoplastic

  • Pituitary adenomas
  • Cystic lesions
  • Peri-pituitary tumour
  • Prolactinomas, Cushing's disease
  • Rathke's cleft cyst, retention cyst
  • Meningioma, craniopharyngioma
  • Glioma, germ cell tumour, metastases
Vascula
  • Sheehan's syndrome, aneurysms
Inflammation/infiltration
  • Wegener's granulomatosis
  • Langerhans' cell histiocystosis
Infection
  • TB, fungal infections, syphilis
Post-irradiation
  • Acromegaly, TSH tumours
  • Craniopharyngioma, glioma
  • Nasopharyngeal carcinoma
  • Lymphomas, leukaemias
Miscellaneous
  • Traumatic brain injury
  • Empty sella syndrome
Source: www.endotext.com

Section 2: Making the diagnosis

Many symptoms and signs of hypopituitarism may be insidious or non-specific and may overlap with non-endocrine conditions, including depression, so careful clinical evaluation is essential.

Hypopituitarism during childhood may lead to delayed or deficient growth and upset in pubertal development, and may have lifelong consequences. Congenital syndromes associated with hypopituitarism, such as Bardet-Biedl syndrome, have distinct features (obesity, developmental delay, polydactyly, strabismus) that typically arouse suspicion.

Increased morbidity is correlated with earlier onset of disease and MPHD. Some symptoms of anterior pituitary dysfunction are summarised in the table.

Prolactin deficiency does not cause specific symptoms apart from a failure of lactation and hyperprolactinaemia is the more common abnormality seen. Hyperprolactinaemia may be secondary to a disruption of the hypothalamic pituitary connection with consequent lack of the normal dopamine suppression of prolactin.

Hyperprolactinaemia can cause breast congestion, galactorrhoea, oligomenorrhoea, secondary amenorrhoea, loss of libido, and sexual dysfunction.

Posterior pituitary dysfunction typically causes polydipsia and polyuria, resulting in weight loss, dehydration, hypernatraemia and renal impairment if untreated.

Symptoms that are variable or are mainly confined to the daytime are less consistent with a diagnosis of cranial DI (vasopressin deficiency).

Failure of lactation (the only symptom of oxytocin deficiency) may be one of the first indicators of post-partum pituitary insufficiency (Sheehan's syndrome).

SIGNS AND SYMPTOMS
Hormones affected Signs and symptoms
Hypoadrenalism Postural symptoms, hypoglycaemia, hypotension and
shock, hypothermia, asthenia, poor appetite and
weight loss
Hypothyroidism Low energy, fatigue, constipation, dry skin, hair
loss and cold intolerance
Hypogonadism Low libido/impotence, low energy, hot flushes,
reduced body hair (men), amenorrhoea/
olgiomenorrhoea, poor breast development, atrophy
and dyspareunia
Growth hormone Poor growth in children, poor concentration and
memory, fatigue and somnolence
Primary pathology related Headaches, double vision, weight loss, night
related sweats, visual field defects, nasopharyngeal
symptoms and neurological deficits

Investigations and diagnosis
Once pituitary insufficiency is suspected, then along with an examination which includes assessment of secondary sexual characteristics, investigations should include visual field testing and 'baseline' pituitary function: free thyroxine (fT4), TSH, prolactin, FSH, LH, estradiol (women), 9am testosterone (men), insulin-like growth factor 1 (IGF-1), and a 9am cortisol and/or synacthen test.

It is crucial to assess fT4, as TSH can be misleadingly 'normal'. It is important to be aware of the circadian rhythmicity of various hormones when arranging and interpreting tests and to appreciate that in hypopituitarism of acute onset early testing may be falsely reassuring.

Further dynamic testing is frequently indicated and early specialist input supports the selection and validity of testing.

Additional tests for the pituitary and to screen for underlying systemic disease include paired serum/urine osmolality and U&Es (hyponatraemia, DI); haemochromatosis-serum ferritin, sarcoid-serum ACE, Wegener's; MRI of the pituitary; an assessment of bone density (hypogonadism, GH deficiency, Cushing's disease or iatrogenic over-replacement of thyroid or adrenal axes); abdominal/pelvic ultrasound (fatty liver, gallstones, ascites, uterine and adnexal pathology); echocardiography (increased cardiovascular disease in acromegaly or possible increased risk of cardiac valvular fibrosis - long-term high dose dopamine agonist therapy), and colonoscopy (in acromegaly due to increased risk of colonic polyps and neoplasia).

Section 3: Managing the condition

The rationale behind HRT is to minimise morbidity, reduce long-term complications and to ensure good outcomes during fertility therapy, pregnancy and major illness or surgery.

In general, the relevant target hormone is replaced rather than the specific pituitary component of the feedback cycle. Patient choice and education is an integral feature of good management.

Steroid replacement

  • Prompt replacement is essential as any significant deficiency is life-threatening.
  • Current treatments poorly mimic normal physiology but hydrocortisone (10mg on waking, 5mg at midday and 5mg at approximately 5pm) is currently the most logical initial approach.
  • Prednisolone is sometimes used but has a long duration of action and dexamethasone is less favoured due to varying rates of metabolism.
  • It is vital that steroid replacement is commenced preferably 24 to 28 hours before the thyroid axis is replaced.
  • Steroid replacement may unmask latent DI as cortisol is required for renal filtration and free water excretion.
  • Patients should be advised to carry a 'steroid alert' card.
  • Normal steroid doses should be doubled with comorbid illness or major stress. Parenteral administration may be necessary. A home-emergency pack (vial of 100mg of hydrocortisone and injection paraphernalia) should be available.

Thyroid hormone replacement
The typical adult replacement dose is 75-150microgram/day. Lower doses titrated slowly may be necessary in the elderly or in cardiac comorbidity. fT4 levels and symptomatology rather than TSH levels should guide replacement.

Treatment of GH deficiency
GH replacement is generally straightforward in children. Therapy is titrated against indices of growth until expected growth or peak bone mass is achieved. Subsequent GH withdrawal and confirmation of ongoing GH deficiency in adulthood is required before ongoing prescribing.10

GH therapy in adults is more controversial. Evidence supports beneficial effects on lean-to-fat mass ratio, lipid profile, and bone resorption but fracture, cardiovascular, or mortality endpoints remain elusive.

Prescribing is NICE governed and involves specialist assessment along with a quality of life assessment and a need to demonstrate benefit from any trial of therapy.10

Serum IGF-1 levels are used to guide therapy and nurse specialist input is needed. GH therapy is contraindicated in active malignancy.

Sex-hormone replacement
In women, estrogen replacement is a key area for GPs. Since deficiency is being replaced until age of menopause there is no increase in cancer risk.

In men, the intramuscular route is the most reliable. Treatment is guided by 'trough' testosterone levels (aim for lower third of the reference range), and clinical response. Testosterone gels can also be used.

Treatment of DI
Desmopressin is available in various forms. Drug therapy should be built up and weaned slowly. A 'drug holiday' is recommended once a week.

Surgery
Trans-sphenoidal surgery can cure syndromes of hormone excess, restore pituitary function and protect vision depending on the size and location of the causative pathology but there is an associated risk of iatrogenic hypopituitarism.11

Cranial DI occurs in a small proportion of postoperative patients but may be transient.

Follow-up
Life-long specialist follow-up is required; the frequency of specialist review is determined by the complexity of the underlying problem, the treatment regimen and need for ongoing dynamic testing. The following are important aide memoirs:

  • Hormone deficiencies may manifest many years after the initial diagnosis of pituitary pathology.
  • Fertility issues should be reviewed periodically as appropriate.
  • Imaging frequency is usually dictated by the underlying aetiology.

Section 4: Prognosis

A study in 2001 followed up 1,014 individuals with hypopituitarism over an eight-year period.3 The most common underlying aetiologies were non-functioning adenomas in 57 per cent of patients. Observed deaths (118) vs expected deaths (96.7) revealed a standardised mortality rate of 1.87 (99% CI 1.62-2.16, p<0.0001).

Mortality was higher in women with hypopituitarism, younger patients, those with craniopharyngiomas and those treated with radiotherapy.

The main causes of increased mortality included cardiovascular, respiratory and cerebrovascular disease in descending order. Untreated gondaotrophin deficiency contributed to excess mortality. The excess cardiovascular risk is not well characterised but further work has shown that after optimal correction of all anterior pituitary hormone deficiencies, adult GH deficiency can still lead to excess cardiovascular morbidity and mortality.12

Some expected advances in hormone formulation will allow more physiological HRT but much work still needs to be done to help minimise the morbidity and mortality associated with this condition.

The role of primary care
Given the chronicity of hypopituitarism, the primary care physician retains a critical role in co-ordinating care, appreciating whether hormone replacement is optimal and often may be better placed to explore fertility, sexual health, employment or other pertinent issues.

Given the varied pathology and the number of potential care-givers, clear communication between healthcare professionals, and careful patient education and empowerment is vital to a successful outcome.

Section 5: Case report

A 39-year-old vicar presented to his GP with headaches, lethargy, and blurred peripheral vision. Referral to ophthalmology led to confirmation of a bitemporal hemianopia.

An MRI scan demonstrated a 28x32mm pituitary lesion stretching the optic chiasm, extending into the cavernous sinuses bilaterally and eroding the sphenoid bone.

Following a baseline assessment, a non-functioning adenoma causing hypogonadism was diagnosed (testosterone: 4.6nanomoles/L). Trans-sphenoidal adenomectomy (TSA) restored his vision and postoperative biochemistry revealed an improvement in testosterone levels. Two years after his original presentation, annual imaging revealed enlargement of the residual tumour with renewed encroachment on the optic chiasm. The therapeutic options of further surgery or radiotherapy were considered and a revised TSA was undertaken.

Postoperative imaging revealed a reduction in tumour volume but the patient experienced transient DI. He was discharged on hydrocortisone replacement. A two-month postoperative short synacthen test was normal (peak cortisol 996nanomoles/L) and steroids were withdrawn.

Later problems
The patient presented three years later with headaches, nausea, vomiting, lethargy and flushing and sweating and he was admitted to hospital.

A low random cortisol of 53nmol/L prompted steroid replacement and reassessment of his pituitary profile. A repeat MRI showed a pituitary mass impinging on the optic chiasm and visual fields demonstrated a left upper temporal field defect.

Secondary hypogonadism and secondary hypothyroidism were diagnosed and the patient was treated with IM testosterone 250mg four-weekly and thyroxine 100 microgram daily.

Further pituitary surgery restored the patient's visual fields but established hypogonadism and hypothyroidism were confirmed. Conventional radiotherapy was administered for the indication of aggressive local tumour recurrence.

An assessment for adult GH deficiency was prompted by marked fatigue and arginine-GH releasing hormone stimulation confirmed severe GH deficiency with a peak GH of 1.4microgram/L. The patient had impairment in quality of life. This patient's testosterone, thyroxine and GH replacement are likely to be lifelong and appropriate dose titration and associated monitoring will be required. Careful monitoring for further enlargement of the tumour remnant is ongoing.

Section 6: Evidence base

Clinical trials

  • Tomlinson JW, Holden N, Hills RK, et al. Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet 2001; 357: 425-31.
  • Abs R, Feldt-Rasmussen U, Mattsson AF, et al. Determinants of cardiovascular risk in 2589 hypopituitary GH-deficient adults - a KIMS database analysis. Eur J Endocrinol 2006; 155: 79-90.

Guidelines

  • The Endocrine Society. Evaluation and treatment of adult growth hormone deficiency: An endocrine society clinical practice fuideline. J Clin Endocrinol Metab 2006; 91: 1621-34.
  • Ghigo E, Masel B, Aimaretti G, et al, Consensus guidelines on screening for hypopituitarism following traumatic brain injury. Brain Inj 2005; 19: 711-24. Consensus on screening and treatment of pituitary insufficiency following traumatic brain injury.
  • Cook DM, Yuen KCJ, Biller BMK, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in growth hormone-deficient adults and transition patients - 2009 update. Endocr Pract 2009; 15 Suppl 2: 1-29. This is an updated version of the guideline which was published in 2003 by the American Association of Clinical Endocrinologists.
  • BMJ Best Practice guide on hypopituitarism.

Key texts

  • 'The pituitary' In: Turner H, Wass J. Oxford Handbook of Endocrinology and Diabetes. Oxford, Oxford University Press, 2009. This is a handy brief textbook reference.
  • 'Neuroendocrinology and The Pituitary' In: De Groot LJ, Jameson JL. Endocrinology (5th Ed.). Philadelphia. Elsevier Health. 2005. This is a comprehensive textbook resource.

Online

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    REFERENCES

    1. Rosen T, Bengstsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990; 336: 285-8.

    2. Bulow B, Hagmar L, Mikoczy Z, et al. Increased cerebrovascular mortality in patients with hypopituitarism. Clin Endocrinol 1997; 46: 75-81.

    3. Tomlinson JW, Holden N, Hills RK. Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet 2001; 357: 425-31.

    4. Regal M, Paramo C, Sierra JM, et al. Prevalence and incidence of hypopituitarism in an adult Caucasian population in northwestern Spain. Clin Endocrinol 2001; 55: 735-40.

    5. Ezzat S, Asa SL, Couldwell WT, et al. The prevalence of pituitary adenomas: a systematic review. Cancer 2004; 101: 613-19.

    6. Nammour GM, Ybarra J, Naheedy MH, et al. Incidental pituitary macroadenoma: A population-based study. Am J Med Sci 1997; 314: 287-91.

    7. Chemaitilly W, Sklar CA. Endocrine complications in long-term survivors of childhood cancers. Endocr Relat Cancer 2010; 17: R141-59.

    8. Aimaretti G, Ambrosio MR, Di Somma C, et al. Traumatic brain injury and subarachnoid haemorrhage are conditions at high risk for hypopituitarism: screening study at 3 months after the brain injury. Clin Endocrinol 2004; 61: 320-6.

    9. Gutenberg A, Hans V, Puchner MJ, et al. Primary hypophysitis: clinical-pathological correlations. Eur J Endocrinol 2006; 155: 101-7.

    10. NICE. Human growth hormone (somatotrophin) in adults with growth hormone deficiency. TA64, London, NICE, 2003.

    11. Webb SM, Rigla M, Wagner A, et al. Recovery of hypopituitarism after neurosurgical treatment of pituitary adenomas. J Clin Endocrinol Metab 1999; 84: 3696-700.

    12. Abs R, Feldt-Rasmussen U, Mattsson AF,et al. Determinants of cardiovascular risk in 2589 hypopituitary GH-deficient adults - a KIMS database analysis. Eur J Endocrinol 2006; 155: 79-90.

    Visit our GP Curriculum Centre for hundreds of articles linked to key topics in the RCGP curriculum.

    - Contributed by Dr Rajeev Raghavan, specialist registrar, and Dr Karin Bradley, consultant endocrinologist, University Hospitals Bristol NHS Foundation Trust.

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