23rd May 2025

Disorders of Excess Hormone Production

Acromegaly

Acromegaly is an insidious chronic and progressive disorder caused by the overproduction of GH and characterised by features of gigantism. It is usually caused by a somatotroph adenoma in the adenohypophysis. The incidence of acromegaly is between 40-130 cases per million adults. An excess of GH leads to increased secretion of insulin-like-growth factor-1 (IGF-1) leading to multi-systemic symptoms.

Clinical effects 

• Facial: Frontal bossing, macroglossia, prognathism, large nose
• Skin: Hyperhidrosis, increased skin thickness 
• Respiratory: Sleep apnoea
• Joint: Osteoarthritis, arthropathy, bone enlargement 
• Cardiovascular: Hypertension, arrhythmias, valvular heart disease, congestive cardiac failure, ischaemic heart disease
• Metabolic and electrolyte: diabetes mellitus, impaired glucose tolerance, hypercalciuria 
• Organomegaly 
• Increased height

Image Source: Wikimedia Commons (2008). Acromegaly facial Features, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/w/index.php?curid=15072125 (Accessed 13 May 2025).

Investigations

Biochemical

• Excluded in most cases of normal IGF-1 levels
• Random GH >1 microgram/L or >2.5 micrograms/L 
• Glucose tolerance test with 75g oral glucose and measuring plasma glucose and GH every 30 mins for 2 hrs. Lack of GH suppression <1 microgram/L (<1 nanogram/mL) suggestive of acromegaly 
• Other pituitary hormone plasma levels: cortisol, prolactin, thyroid-stimulating hormone and free thyroxine, follicle-stimulating hormone, luteinising hormone, oestradiol, or testosterone
• Consider genetic testing for AIP

Imaging 

• MRI with contrast of pituitary gland 
• In <1% of the cases, the above is negative. In this case a CT Thorax, Abdo, Pelvis will likely be needed to locate ectopic hormones producing GH/GHRH

Management

• Transsphenoidal surgery is first-line for enclosed somatotroph microadenomas (< 10mm diameter) and macroadenomas (>10mm diameter)
• If surgery fails, or the tumour is unresectable, somatostatin analogues (SSAs) are used e.g., octreotide with an initial dose of 20mg every month
• If there is mixed GH/PRL release, or IGF-1 levels are <1.5 the upper limit of normal a dopamine agonist, e.g., cabergoline, can be used as an additional treatment
• Pegvisomant, a growth hormone receptor antagonist, is considered in patients who are unsuitable or who have not responded to the above
• If medical and surgical treatments fail, radiotherapy can be attempted 

Monitoring

Lifelong monitoring of GH and IGF-1 will be required

Complications

• Cardiovascular (including HTN) (30-40%) 
• Sleep apnoea (60-80%)
• Joint (70%)
• Endocrine (50%)
• Pre-cancerous polyps 
• Carpal tunnel (64%)
• Hypopituitarism

Prognosis

Surgery is effective in 70-90% of microadenomas and 30-60% of macroadenomas. SSAs control disease in 30-40% of cases.

Cushing Syndrome

Cushing syndrome is a rare disorder characterised by an excess production of cortisol, often secondary to an excess of ACTH production. It has an incidence of 0.7-2.4 per million population per year. It affects females more than males at a ratio of 3:1. Cushing’s disease is Cushing syndrome caused by an ACTH secreting pituitary tumour, affecting more males than females at a ratio of 5:3. 

Risk factors

• Hypertension 
• Uncontrolled diabetes
• Osteoporosis
• Adrenal masses

Causes

ACTH Dependent causes are due to an overproduction of ACTH which stimulates increased synthesis of cortisol. Causes include:

• Cushing’s disease (70-80%). This has been linked to a mutation in the gene ubiquitin-specific protease 8 on chromosome 15 (USP8) which increases risk of developing pituitary adenoma 
• Adrenal adenoma (10%). Linked to mutations in the cAMP/PKA pathway
• Ectopic secretion of ACTH or CRH by non-pituitary tumours (~10%)
• Adrenal carcinoma (1%)

ACTH Independent causes result in overproduction of cortisol by the adrenal glands despite suppressed ACTH levels. Causes include:

• Adrenal adenoma
• Bilateral adrenal hyperplasia 
• Adrenal carcinomas (rare). Often presents as a rapidly growing adrenal mass
• Primary pigmented nodular adrenocortical disease (PPNAD)  

Exogenous corticosteroids, e.g., prednisolone, can also cause features of Cushings.

Clinical Features

• Facial plethora and facial rounding 
• Skin: Purple striae, atrophy, hyperpigmentation (due to increased ACTH rather than cortisol), acanthosis nigricans, cutaneous fungal infections e.g., tinea versicolor
• Metabolic: Diabetes/glucose intolerance, obesity with supraclavicular fullness (due to deposition of subcutaneous fat)
• Cardiovascular: Increased risk of hypertension, venous thromboembolism, heart failure and dilated cardiomyopathy
• Musculoskeletal: Osteoporosis, proximal muscle wasting and weakness,  
• Mood changes 
• Irregular menstruation
• Signs of androgen excess in females, whose main source of androgens are the adrenals, such as: hirsutism, acne, changes in libido, temporal balding, deep voice, virilization. Note the testes are the main source of androgens for men so they do not show signs of androgen excess.

Image Source: Wikimedia Commons (2020). Patient with Cushing-Syndrom, Licensed under a Creative Commons licence. Available for free at: https://commons.wikimedia.org/w/index.php?curid=90182292 (Accessed 13 May 2025).

Diagnosis

• First line is the dexamethasone suppression test. For the low dose test, 1mg of dexamethasone is given at 11pm and plasma cortisol and dexamethasone level are measured at 8am. The latter is measured to ensure adequate levels are achieved, especially in extremely obese patients. For a positive result, morning cortisol levels must be >1.8 micrograms/dL
• If the patient is taking drugs affecting the metabolism of dexamethasone e.g., phenytoin, carbamazepine, rifampicin, and cimetidine, 24-hour urinary free cortisol can be measured.
• Late-night salivary cortisol. Saliva sample taken between 11pm-12am. Can be repeated twice on two separate nights for greater sensitivity. Elevated cortisol levels suggest Cushings.
• Once a diagnosis has been established, morning plasma ACTH testing can be done. Suppressed ACTH (levels <1 picomol/L) suggest ACTH-independent Cushings due to adrenal pathology. No suppression (levels >4 picomol/L) indicates ACTH-dependent Cushings due to pituitary tumour or ectopic source of ACTH production. 
• To differentiate between Cushing’s disease and pseudo-Cushing syndrome (physiological hypercortisolism) a CRH stimulation test is done. 0.5mg of oral dexamethasone is administered 6 hourly for 48 hours. Two hours after the last dose, 1 mcg/kg of CRH is given IV. Serum cortisol is measured 15 minutes later. If glucocorticoid suppression is overcome, a diagnosis of Cushing’s disease rather than pseudo-Cushing syndrome is suspected.

Other investigations

• Urine pregnancy test to exclude pregnancy
• Serum glucose
• Elevated plasma dehydroepiandrosterone sulphate (DHEAS) levels could suggest adrenal carcinoma
• Pituitary MRI if ACTH dependent Cushings
• If confirmed pituitary lesion, can attempt inferior petrosal sinus sampling. Blood sample taken from sinus and plasma at the same time. If central/peripheral ACTH ratio is >2:1 the causative pathology lies in the pituitary gland. Otherwise, the source is ectopic 
• Adrenal CT if ACTH independent Cushings 
• Can consider CT TAP and/or PET scan if considering ectopic source of pathology

Management

Treating ACTH secreting pituitary tumour:

• 1st line: transsphenoidal pituitary adenectomy. 
• Note, medical therapy with: somatostatin analogue e.g., Pasiretoride; dopamine agonist e.g., cabergoline; steroidogenesis inhibitor e.g., osilodrostat, or glucocorticoid antagonists  e.g., mifepristone or ketoconazole, could be used prior to surgery for severe Cushings
• Post-surgical corticosteroid replacement therapy with hydrocortisone
• Other hormones may also need to be replaced with levothyroxine testosterone/oestradiol, recombinant somatropin, desmopressin
• If hormone replacement fails, repeat transsphenoidal pituitary adenectomy can be considered 
• If no success, pituitary radiotherapy can be attempted 
• If the disease is still uncontrolled and/or the patient is not suitable for reoperation, a bilateral adrenalectomy can be done. However, this can increase the risk of Nelson syndrome 

Treating ectopic ACTH/CRH tumours:

• 1st: Surgical resection/ablation of tumour
• Steroidogenesis inhibitor therapy or a glucocorticoid receptor antagonist can be used prior to surgery in severe Cushing’s, e.g. ketoconazole
• If surgical resection cannot be performed, bilateral adrenalectomy can be considered. After this, permanent post-surgical corticosteroid therapy will be required
• Chemo/radiotherapy, or medical therapy alone, can be considered

Treating adrenal pathology:

• 1st: Unilateral adrenalectomy/tumour resection. If disease is bilateral, a bilateral adrenalectomy is first line.
• Like the above, medical therapy with steroidogenesis inhibitors can be considered before surgery in severe cases 
• Chemo/radiotherapy, or medical therapy alone, can be considered

Prognosis and Monitoring

• Patients in the first week post-pituitary adenectomy require monitoring of morning cortisol levels (sample taken 24 hrs post last dose of corticosteroid). Low levels of cortisol predict remission
• Recurrence of ACTH dependent Cushings occurs in 5-26% of patients within 5 years
• Therefore, screening at 6-12 months using one of the diagnostic tests listed above is required. Late night salivary cortisol is the most sensitive test to detect recurrence.

Prolactinoma

Prolactinomas are a type of anterior pituitary adenoma that secrete prolactin (PRL) and lead to hyperprolactinaemia. They are benign tumours of lactotroph cells. Hypersecretion of PRL has inhibitory effects on GNRH and pituitary gonadotrophins. 

They commonly occur in women aged 20-50 years. The ratio of incidence between females and males is 10:1. 

Aetiology

• Sporadic
• Multiple endocrine neoplasia syndrome type 1 (MEN-1) 
• Familial isolated pituitary adenoma (FIPA)

Tumour Classification

This is based on tumour size

• Microadenoma
  • <10mm diameter
  • Commonest
  • Unlikely to get larger
• Macroadenoma
  • >10mm diameter
  • Often locally invasive to suprasellar/parasellar areas
  • Can compress vital structures
  • Often benign and do not metastasise to outside the pituitary sella

Clinical Presentation

• Premenopausal women: Hypogonadotropic hypogonadism- infertility, oligo/amenorrhea, galactorrhoea, reduced bone density
• Men: Hypogonadotropic hypogonadism- reduced energy, decreased libido, lowered muscle mass, reduction in body hair, galactorrhoea, decreased bone density
• Postmenopausal women: Tumour often detected as an incidental finding on brain imaging. Or, mass effects from tumour produce symptoms, e.g., unilateral/bi-temporal hemianopia, which prompt investigation

Investigations

• Random serum prolactin level. The concentration often reflects the size of the tumour
  • Any PRL level above the normal age range suggests prolactinoma
  • PRL > 250 micrograms/L: prolactinoma likely
  • PRL > 500 micrograms/L: macroadenoma likely
  • Note: medications such as risperidone and metoclopramide can increase PRL levels
• Pituitary MRI
• Formal visual field testing for macroadenomas 
• Consider genetic screening in patients <30 years with macroadenomas for
  • MEN-1
  • Aryl hydrocarbon receptor-interacting protein (AIP) gene mutations present in FIPA
• Consider other tests for hypopituitarism such as IGF-1, ACTH, TSH
• U&Es to assess kidney function as CKD can lead to a decrease in PRL clearance

Management

• Pre-menopausal women with asymptomatic microadenomas: observation
• Pre-menopausal women with symptomatic microadenomas that do not wish to be pregnant:
  • 1st: Dopamine agonist e.g., Cabergoline
  • 2nd: Combined oral contraceptive pill, especially if only symptom menstrual changes
  • 3rd: transsphenoidal surgery
  • 4th: sellar radiotherapy
• Pre-menopausal women with symptomatic microadenomas that do wish to be pregnant OR microadenomas in men OR macroadenomas in any patient:
  • 1st: dopamine agonist
  • 2nd: transsphenoidal surgery
  • 3rd: sellar radiotherapy
• Microadenomas in post-menopausal women: observation

Monitoring and follow-up

• Pituitary MRI every year initially 
• Regular perimetry
• Regular measurements of PRL levels
• ECHO monitoring for patients on high dose cabergoline due to side effect of valve pathology

Complications

• Bi-temporal hemianopia
• Hypopituitarism 
• Cabergoline associated valvular pathology
• Pituitary apoplexy

Craniopharyngioma 

Craniopharyngiomas are benign non-glial epithelial tumours arising from remnants of Rathke’s pouch. These tumours often grow above the pituitary gland in the sellar/suprasellar space adjacent to the optic chiasm and often lead to a deficiency of anterior pituitary hormones. They account for 5-10% brain tumours in children and 1-3% of all adult intracranial tumours. The aetiology is unknown.

Classification

Craniopharyngiomas are classified based on pathology:

• Adamantinous type (>80%): Adamantinous epithelium, keratin nodules, poorly demarcated from brain tissue, associated withs CTNNB1 gene mutation
• Squamous papillary type (<20% of tumours): Squamous epithelium with papillaries, well demarcated from brain tissue, rare in children, associate with BRAF oncogene mutation

Clinical Features

• Visual disturbances 
• Headache
• Intracranial hypertension: nausea, vomiting, double vision
• Endocrine: Symptoms of hypogonadotrophic hypogonadism (as listed above, galactorrhoea 
• Paediatric: macrocephaly and hydrocephalus (prior to fusion of intracranial sutures) and growth failure

Investigations

• Visual field testing
• MRI brain with contrast
• Serum: PRL, GH, IGF-1, LH, FSH, TSH, morning testosterone, morning ACTH and cortisol, U&Es
• Paired urine serum osmolality 
• Can consider tissue histology following surgical biopsy/resection

Image Source: Wikimedia Commons (2011). Craniopharyngioma, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/w/index.php?curid=15959020 (Accessed 13 May 2025).

Management

• The exact type of surgical management (biopsy only, cyst aspiration, CSF shunting, or tumour resection) depends on tumour size and location
• Post-operative ophthalmology review will be required
• Hormonal replacement therapy
• Follow-up is done every 6-12 months and involves MRI brain scans as well as endocrinology review

Complications

• Pituitary hormone deficiencies
• Diabetes insipidus 
• Visual impairment 
• Rarer complications include: seizures, hypothalamic injury, cognitive dysfunction