Hypopituitarism

A 35-year-old woman presents with fatigue, weight loss, and amenorrhea for 6 months. She has a history of postpartum hemorrhage 5 years ago. On examination, she has dry skin, sparse body hair, and a low blood pressure.

Pathophysiology

Hypopituitarism results from the deficient production of one or more hormones by the anterior and/or posterior pituitary gland.

The hypothalamus plays a crucial role in regulating pituitary hormone secretion through releasing and inhibiting hormones. Consequently, disorders affecting the hypothalamus can also lead to hypopituitarism.

The specific clinical manifestations depend on which hormones are deficient and the severity of the deficiency.

Aetiology

Hypopituitarism can result from a variety of causes, including:

• Pituitary tumours: Both functioning and non-functioning pituitary adenomas can compress and damage surrounding pituitary tissue. Craniopharyngiomas are also associated with hypopituitarism.
• Pituitary surgery or irradiation: Treatment for pituitary tumours or other conditions may damage the pituitary gland.
• Pituitary infarction: Pituitary apoplexy, infarction of the pituitary gland due to haemorrhage or ischaemia, is a medical emergency. Sheehan’s syndrome, pituitary infarction following postpartum haemorrhage, is a specific example.
• Infiltration: Infiltrative diseases, such as sarcoidosis, haemochromatosis, and Langerhans cell histiocytosis, can damage the pituitary gland and cause hypopituitarism.
• Trauma: Head injuries and basal skull fractures can damage the pituitary stalk or gland.
• Infection: Meningitis, tuberculosis, and pituitary abscesses can affect pituitary function.
• Empty sella syndrome: the pituitary gland appears flattened or absent within the sella turcica.
• Congenital causes: Genetic mutations and developmental defects can lead to hypopituitarism.
• Autoimmune hypophysitis: This rare inflammatory condition, characterised by lymphocytic infiltration, can affect both anterior and posterior pituitary function, potentially leading to hypopituitarism and diabetes insipidus.
• Russell Viper Envenomation: affecting ~30% survivors of bites from D. russellii.

Epidemiology and Risk Factors

The prevalence of hypopituitarism is difficult to estimate due to its often insidious presentation. However, it is considered a relatively uncommon condition. Risk factors depend on the underlying cause, as highlighted in the aetiology section. For example, individuals with pituitary tumors, a history of head trauma, or certain autoimmune diseases are at increased risk.

Clinical Features

The clinical presentation of hypopituitarism is diverse and depends on the specific hormone deficiencies. The loss of pituitary hormones typically follows a characteristic order: GH and gonadotropins (FSH and LH) are usually affected first, followed by TSH and ACTH. Prolactin deficiency is relatively rare, except in cases like Sheehan's syndrome. ADH secretion is usually unaffected by pituitary adenomas, but is uncommonly deficient in cases caused by trauma or infiltrative disease.

• GH deficiency: reduced lean body mass, reduced exercise tolerance, impaired attention and cognition
• FSH and LH: loss of libido, infertility, osteoporosis
  • In men: testicular atrophy, erectile dysfunction, gynaecomastia, loss of facial/pubic/axillary hair
  • In women: oligomenorrhoea, dyspareunia
• TSH deficiency: as for hypothyroidism
• ACTH deficiency: as for Addison's disease, except lack of hyperpigmentation and no hyperkalaemia
• PRL deficiency: lactation failure
• ADH deficiency: as for diabetes insipidus

Investigations

Pituitary Function Tests: These tests help assess the function of the pituitary gland and identify hormone deficiencies:

• Basal hormone levels: Measurement of serum hormone levels, including 9am cortisol, TSH, free T4, LH, FSH, testosterone (in men) or oestradiol (in women), prolactin, and IGF-1.
• Dynamic function tests: These tests involve stimulating or suppressing hormone production to assess pituitary reserve. Examples include:
  • Insulin tolerance test (ITT): This test assesses GH and ACTH reserve. Hypoglycemia induced by insulin injection should stimulate GH and cortisol release.
  • Short Synacthen test: Evaluates the adrenal axis by measuring cortisol response to synthetic ACTH.
  • Glucagon stimulation test: An alternative to the ITT for assessing GH and ACTH reserve.
  • GHRH challenge: Assesses GH reserve by measuring GH response to GHRH administration.
  • LHRH challenge: Evaluates gonadotropin reserve by measuring LH response to LHRH administration.
• Corticotroph function should be replete prior to assessing posterior pituitary function, as ACTH deficiency reduced GFR and therefore ability to excrete water load which can mask diabetes insipidus in a water deprivation test.

Imaging:

• Magnetic resonance imaging (MRI): The preferred imaging modality to visualise the pituitary gland and identify structural abnormalities, such as tumours, cysts, or infiltrative lesions.

Management

The management of hypopituitarism involves two key aspects:

1. Hormone replacement therapy: The cornerstone of management is replacing deficient hormones to restore normal function and prevent complications. Specific hormone replacement therapies include:
   • Hydrocortisone: Replaces cortisol deficiency, essential for maintaining blood pressure, blood sugar, and responding to stress.
   • Levothyroxine: Replaces thyroid hormone deficiency, crucial for regulating metabolism, energy levels, and other bodily functions.
   • Testosterone (for men): Replaces testosterone deficiency, important for maintaining muscle mass, bone density, libido, and sexual function.
   • Oestrogen and progesterone (for women): Replaces oestrogen and progesterone (in those with a uterus) deficiency, essential for regulating menstrual cycles, maintaining bone health, and other female-specific functions.
   • Growth hormone (GH): May be considered in children and adults with GH deficiency to improve growth, body composition, and quality of life.
2. Treatment of the underlying cause: Addressing the underlying cause of hypopituitarism is crucial whenever possible. For example, this may involve:
   • Surgical removal of a pituitary tumour: Transsphenoidal surgery is commonly used for pituitary adenomas.
   • Radiation therapy: May be used for residual tumours or inoperable cases.
   • Treatment of infiltrative diseases: Specific therapies depend on the underlying disease.

Complications and Prognosis

Untreated hypopituitarism can lead to serious complications, including:

• Adrenal crisis: A life-threatening condition resulting from severe cortisol deficiency, characterized by low blood pressure, shock, and coma.
• Myxoedema coma: Severe hypothyroidism leading to decreased mental status, hypothermia, and other complications.
• Infertility
• Osteoporosis
• Increased cardiovascular risk

The prognosis for hypopituitarism depends on the underlying cause, the severity of hormone deficiencies, and the timeliness of diagnosis and treatment. With appropriate hormone replacement therapy and management of the underlying condition, most individuals can lead relatively normal lives. However, lifelong monitoring and hormone adjustments are often necessary.