14th September 2024

Disorders of the Anterior Pituitary

Hypopituitarism

The pituitary gland is located centrally at the base of the brain, within the sella turcica, a depression in the sphenoid bone. It is connected to the hypothalamus by the pituitary stalk and a fine vascular network. On either side of the gland are the cavernous sinuses, through which pass important neurovascular structures, including the internal carotid arteries and cranial nerves III, IV, V, and VI.

The majority of the blood supply to the anterior pituitary comes from the hypothalamic-hypophyseal portal system, which originates from the superior and inferior hypophyseal arteries. The remaining blood supply comes from the pituitary capsular vessels, which also arise from the superior hypophyseal arteries. Venous drainage occurs through the internal jugular veins via the cavernous and petrosal sinuses.

The anterior pituitary releases several hormones with distinct secretion patterns. Prolactin is secreted in a pulsatile circadian rhythm with approximately 14 pulses per 24 hours, peaking during sleep and, to a lesser extent, in the evening. Growth hormone is also secreted in pulses, primarily at night, and its secretion is influenced by age and sex. LH and FSH (gonadotropins) have a pulsatile secretion that depends on the frequency of GnRH secretion. Thyroid-stimulating hormone (TSH) has a 24-hour pulsatile secretion and can cause cross-reactivity during the first trimester of pregnancy, potentially increasing thyroid hormone release and mimicking hyperthyroidism. ACTH is also released in a pulsatile manner.

The hypothalamic-pituitary-hormonal axis is a complex system which has a central role in maintaining homeostasis. The main anterior pituitary hormone axis is shown below.

Causes of hypopituitarism

Hypopituitarism refers to the partial or complete deficiency of one or more hormones produced by the pituitary gland. It can result from a combination of these hormone deficiencies, which may be caused by primary pituitary disease or hypothalamic disorders that disrupt hypothalamic control of the pituitary.

Clinical features

The clinical features of anterior pituitary deficiencies depend on the type and degree of the hormonal deficits. The most common types of hypopituitarism include GH and gonadotrophin deficiencies, followed by TSH and ACTH at a later stage. Prolactin deficiency is rare and is mainly seen in relation to Sheehan syndrome.

Investigations

Basal and dynamic tests are used to assess the function of the hypothalamic-pituitary-hormonal axis. This includes cortisol, prolactin, TSH, Free T4, LH/FSH, testosterone or oestradiol, IGF-1, 9am Cortisol, and ACTH. Baseline posterior pituitary function should also be assessed (covered in another chapter). Dynamic stimulation tests are used to assess hormone under-secretion, including:

• Insulin tolerance test (ITT) for ACTH and GH reserves
• Glucagon test for GH and ACTH reserves
• GHRH and arginine test for GH reserves
• Short synacthen test for ACTH reserves
• CRH stimulation test for adrenal insufficiency
• TRH stimulation test for T3/T4 reserves (for secondary and tertiary hypothyroidism)

For suspected over-secretion in pituitary disorders, use suppression tests such as:

• Oral glucose tolerance test for GH reserves (used for acromegaly)
• Low dose dexamethasone suppression for cortisol levels (used for Cushing’s syndrome)

For other systemic illnesses: serum ACE levels, ferritin, hCG, and alpha-fetoprotein, and perform MRI of the pituitary for optimal imaging.

Management

The mainstay of management of anterior pituitary hormone deficiency is adequate target hormone replacement and management of the underlying cause. Exceptions are growth hormone replacement in adults and when fertility is required (GnRH therapy is given instead of testosterone or oestrogen).

Patients with ACTH deficiency need glucocorticoid replacement only and do not need mineralocorticoid in contrast to patients with primary adrenal disease. GH is replaced in adults when symptomatic, affecting the quality of life as compared to children where regular replacement is required for growth. Thyroid hormone replacement-in pituitary disease, thyroid replacement is monitored via clinical and Free T4 levels as TSH measurement cannot be used to assess adequate replacement due to the TSH deficiency.

Pituitary apoplexy

Haemorrhage directly into the pituitary gland, known as pituitary apoplexy, tends to occur in individuals with a preexisting pituitary adenoma. Patients typically experience a sudden headache, diplopia, and hypopituitarism. Urgent MRI is required for diagnosis and treatment consists of initial steroid replacement and neurosurgical evaluation. Additional hormone replacement may be necessary, depending on the clinical picture.

References

• Snyder P, Martin K. UpToDate [Internet]. Cooper D, editor. UpToDate. Available from: https://www.uptodate.com/contents/causes-of-hypopituitarism
• Chung TT, Monson JP. Hypopituitarism. [Updated 2022 Nov 27]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK278989/

Growth hormone deficiency

GH, also referred to as somatropin, is released from somatotroph cells, which make up 45-50% of the anterior pituitary. GH release is positively regulated by growth hormone-releasing hormone and negatively regulated by IGF-1 and somatostatin. The target organs for GH include the liver, cartilage, muscle, fat, and skin. GH influences linear and somatic growth and metabolism, including the metabolism of lipids, proteins, and carbohydrates.

Causes of GH deficiency

Clinical features

Typical symptoms and signs related to body composition include increased body fat, particularly central adiposity, decreased muscle mass and decreased muscle function.

Features related to cardiovascular and metabolic health include poor thermoregulation, decreased insulin sensitivity, increased total and LDL cholesterol and Apo B, decreased HDL cholesterol, accelerated atherogenesis, impaired cardiac function and decreased exercise capacity.

Growth hormone deficiency can cause decreased bone mineral density, which is associated with an increased risk of fractures. Quality of life can also be affected, resulting in depressed mood, reduced concentration, increased anxiety, fatigue and low self-esteem.

Investigations

Both insulin and glucagon stimulate GH and tests have derived from giving these hormones and measuring a lack of GH level rise. The insulin stress test and glucagon stimulation test are widely used methods to assess GH reserves, unless there are contraindications to insulin or glucagon use such as epilepsy, ischemic heart disease, untreated hypothyroidism or basal cortisol levels below 100 nmol/l. The growth hormone-releasing hormone test, also known as the arginine stimulation test, serves as a 2nd line option for those where the insulin tolerance and glucagon tests are contraindicated.

Low IGF-1 levels support the diagnosis of GH deficiency, but normal IGF-1 levels do not exclude it. A pituitary MRI should be performed to rule out a pituitary tumour that could be compressing GH-producing cells and causing GH deficiency.

Management

All patients with GH deficiency should be considered for growth hormone replacement therapy, especially those who are symptomatic with impaired quality of life, reduced mineral density, adverse cardiovascular risk profile, and reduced exercise capacity.

IGF-1 level is monitored to avoid over replacement, aiming to keep the values within the age-matched reference range. GH treatment is associated with impairment of insulin sensitivity, lipid metabolism and bone density. Therefore, these should be monitored at regular intervals. It can be useful to monitor quality of life using the adult growth hormone deficiency assessment (AGHDA) questionnaire.

Adverse effects of growth hormone replacement include sodium and water retention, weight gain, carpal tunnel syndrome, hyperinsulinemia, arthralgia (possibly due to intra-articular cartilage swelling), myalgia and benign intracranial hypertension which resolves on stopping treatment.

References

• Cook D, Yuen K , Miller B et al Guidelines for use of growth hormone in clinical practice, Ncbi.nlm.nih.gov, OHST-Endocrinology by Kalhan
• Feldt-Rasmussen U, Klose M. Adult Growth Hormone Deficiency- Clinical Management. [Updated 2022 May 23]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK425701/

Acromegaly

Acromegaly is a disorder characterised by excessive secretion of growth hormone (GH), leading to increased hepatic production of insulin-like growth factor 1 (IGF-1). Most cases are diagnosed from 40 to 60 and are caused by anterior pituitary adenomas, which include both macroadenomas (>1 cm) and microadenomas (<1 cm). Hereditary conditions such as multiple endocrine neoplasia type 1, which involves hyperplasia of endocrine organs, and McCune-Albright syndrome, characterised by autonomous endocrine function, can lead to acromegaly. Additionally, other iatrogenic tumours, including lymphoma and pancreatic islet cell tumours, can result in excess GH production. When GH excess occurs before the end of puberty, while the epiphyseal growth plates are still open, the condition is termed gigantism.

Clinical features

There are a wide range of features caused by excess GH and the direct effects of adenoma. The onset tends to be slow, taking years to manifest. Below is a concise summary of the main features and complications.

Investigations

An oral glucose tolerance test (OGTT) is used to confirm the diagnosis. This test involves administering a 75 g oral glucose load, which should suppress GH in normal individuals. IGF-1 levels are used as a screening test and can aid in the diagnosis. IGF-1 is preferred over GH due to its lower variability.

If the blood tests confirm elevated GH levels through the OGTT, an MRI is the preferred imaging method for detecting a pituitary tumour. If no adenoma is identified, cross-sectional imaging of the body should be conducted to identify an ectopic source.

Additionally, pituitary function tests should be performed as acromegaly may affect other pituitary hormones and formal visual testing to assess the extent of the visual field defect. Echocardiogram, sleep studies and isotope bone scans should be considered as acromegaly has many systemic complications.

Management

Transsphenoidal surgery is typically the first line treatment option in micro and macroadenomas.  If levels of these hormones are still too high or begin to rise again, further treatment with radiotherapy and medications is required.

The three main types of medications used are the following:

• Somatostatin analogues (octreotide, lanreotide)
• Dopamine agonists (bromocriptine)
• Growth hormone-receptor antagonists (pegvisomant)

Post-operative complications of transsphenoidal surgery include vasopressin deficiency, which occurs in the first few days, and SIADH, which tends to occur after a week and is mostly transient.

References

• Melmed S, Katznelson L. UpToDate [Internet]. Snyder P, Martin K, editors. UpToDate. 2024. Available from: https://www.uptodate.com/contents/causes-and-clinical-manifestations-of-acromegaly#references

Cushing’s disease

Cushing’s disease is characterised by increased ACTH production, leading to excess cortisol and adrenal hyperplasia. It is a rare disease, and the majority of cases are caused by a pituitary adenoma, typically a microadenoma. To a lesser extent, the condition can arise from excess CRH production by the hypothalamus. Cushing’s disease is the second most common cause of Cushing syndrome, with the leading cause being the exogenous use of corticosteroids.

Clinical features

As mentioned, Cushing disease is typically caused by a microadenoma and thus the local mass effects on surrounding structures can occur, but it is rare.

Although much less common than GH-secreting tumours, macroadenomas that secrete can also present with mass effects on surrounding structures.

Investigations

High levels of cortisol can be identified in the saliva, blood, and urine. A 24-hour urinary free cortisol, a late-night salivary cortisol test and the low dose dexamethasone suppression test which should suppress cortisol so if it is high, it is in keeping with Cushing syndrome. After this is confirmed, further localisation tests need to be performed which include:

• Plasma ACTH and cortisol levels at 9am and midnight.
  • If ACTH is high the cause is ACTH dependent (exogenous steroid or adrenal tumour)
  • If ACTH is low the cause is ACTH independent (Cushing disease or ectopic ACTH secretion)
• High dose dexamethasone suppression test (if cortisol suppressed then it indicates Cushing disease/pituitary adenoma)
• CRH stimulation test (if cortisol rises then it indicates a pituitary source)
• Petrosal sinus sampling measures the difference in ACTH level found in the inferior petrosal sinus (where the pituitary gland drains) compared to the periphery

By using these tests, healthcare providers can accurately diagnose Cushing disease and determine its underlying cause.

Management

Transsphenoidal microadenomectomy is the first-line treatment choice, with radiotherapy being a second-line option for patients in whom surgery is contraindicated or was not successful. Medications are often used either prior to surgery or after to aid with suppression of cortisol suppression. Two agents licensed for this include metyrapone and ketoconazole. Post-operative vasopressin deficiency and SIADH can occur.

References

• Kairys N, Anastasopoulou C, Schwell A. Cushing Disease. [Updated 2023 Feb 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK448184/
• Nieman L. Establishing the cause of Cushing syndrome [Internet]. Lacroix A, Rubinow K, editors. UpToDate. 2023. Available from: https://www.uptodate.com/contents/establishing-the-cause-of-cushing-syndrome#H1760641735
• NICE Treatment summaries. Cushing’s syndrome [Internet]. NICE. 2024. Available from: https://bnf.nice.org.uk/treatment-summaries/cushings-syndrome/

Prolactinomas

Prolactin, secreted by the anterior pituitary gland, is regulated by TRH and various physiological factors. This hormone increases after childbirth and in combination with oestrogen enables women to produce breast milk. Dopamine significantly inhibits prolactin, making dopamine agonists the first-line treatment for prolactin-related conditions, including prolactinomas. Prolactinomas are the most common pituitary tumours in multiple endocrine neoplasia type 1 (MEN1) syndrome.

High prolactin levels can stem from various causes, which must be identified to effectively treat the underlying condition.

Causes of hyperprolactinaemia

Clinical features

In women, elevated prolactin levels can cause amenorrhea, oligomenorrhea, breast enlargement, breast pain, hirsutism, and infertility. Men may experience gynaecomastia and impotence. Both may present with galactorrhoea and loss of libido.

Investigations

Diagnosing a prolactinoma involves elevated prolactin levels and MRI evidence of a pituitary mass. Macroadenomas are detectable, while microadenomas are often not visible. Prolactin levels help determine the aetiology.

• A prolactin level of 1000 – 3000 mU/l is likely to be medication induced, hypothyroidism and physiological reasons listed above.
• A prolactin level >3000 mU/l is suggestive of a microprolactinoma or medication induced.
• A prolactin level >6000 mU/l is indicative of a macroprolactinoma.

Generally, higher prolactin levels correlate with larger adenomas. Measuring TRH can also be helpful as it stimulates prolactin secretion.

Management

First-line treatment for both microprolactinomas and macroprolactinomas includes dopamine agonists such as cabergoline (first line) and bromocriptine. Transsphenoidal surgery is considered for patients who do not respond to medication or cannot tolerate it, especially those with psychiatric histories affected by dopamine agonists.

References

• Snyder P. High prolactin levels and prolactinomas (Beyond the Basics) [Internet]. Cooper D, Martin K, editors. UpToDate. 2023. Available from: https://www.uptodate.com/contents/high-prolactin-levels-and-prolactinomas-beyond-the-basics#H8
• Snyder P. Causes of hyperprolactinemia [Internet]. Cooper D, Martin K, editors. UpToDate. 2023. Available from: https://www.uptodate.com/contents/causes-of-hyperprolactinemia

Non-functioning pituitary tumours

Non-functioning adenomas (NFA) are pituitary tumours that do not cause hypersecretory syndromes (GH excess, hypercortisolism, hyperprolactinaemia). Approximately one third of pituitary adenomas are categorised as non-functioning. The majority are macroadenomas, often detected incidentally during MRI scans for other reasons.

Clinical features

NFAs can cause pituitary hypofunction due to compression of pituitary tissue and symptoms from the local mass effect. Hyperprolactinemia may occur if the adenoma compresses the pituitary stalk, reducing hypothalamic dopamine and increasing prolactin. A concise summary of clinical features is provided in the table below.

Investigations

A complete pituitary hormone profile should be checked to check hypopituitarism and if there is hyperprolactinaemia. If not already performed, an MRI of the pituitary gland to determine the extent of the tumour and how it affects the surrounding structures. Formal visual field testing to assess the visual field defects due to compression of the optic chiasm.

Management

Initial treatment involves transsphenoidal surgery, followed by blood tests, visual field testing and repeat imaging to monitor for tumour regrowth and adequacy of hormone replacement therapy. Radiotherapy is often used post-surgery to slow tumour growth. Complications from radiotherapy include hypopituitarism and neurological deficits.

References

• Snyder P. Clinical manifestations and diagnosis of gonadotroph and nonfunctioning pituitary adenomas [Internet]. Cooper D, Martin K, editors. UpToDate. 2024. Available from: https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-gonadotroph-and-nonfunctioning-pituitary-adenomas#H177771375
• Snyder P. Treatment of gonadotroph and other clinically nonfunctioning adenomas [Internet]. Cooper D, Martin K, editors. UpToDate. 2023. Available from: https://www.uptodate.com/contents/treatment-of-gonadotroph-and-other-clinically-nonfunctioning-adenomas#H8