Pituitary Disease

Home , Hyperprolactinaemia, Hypophysitis, Pituitary disease

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Pituitary disease

An update

Warrick J Inder, Christina Jang PITUITARY TUMOURS are surprisingly hypothalamus – arginine vasopressin common – at least 10% of people harbour (also known as antidiuretic hormone) an asymptomatic lesion in their pituitary and oxytocin. Background 1 Pituitary lesions are present in >10% that never causes a problem. Most of of the population. Approximately one in these lesions are small microadenomas 1000 people has a symptomatic pituitary or cystic lesions, discovered incidentally Epidemiology tumour, which may cause clinical when brain imaging is done for another The prevalence of symptomatic problems from mass effect, hormonal indication. However, there is a broad range pituitary tumours in the population is hypersecretion and impairment of of pathologies that may present as a sellar approximately one in 1000 people.2,3 normal pituitary function. or parasellar mass, as outlined in Table 1. Pituitary adenomas may be functional Objective Biochemical testing is used to or non-functioning. A breakdown of The aim of this article is to outline determine function (ie to confirm or pituitary adenoma subtypes is presented the potential causes of a sellar and exclude both hormonal hypersecretion in Table 2. Prolactinomas are the most parasellar mass, with an emphasis and hypopituitarism), while radiology common pituitary tumours, comprising on the presenting clinical features (preferably magnetic resonance over 50% in some series,3 while clinically and screening investigations that are applicable to doctors working imaging [MRI]) is used to assess the non-functioning pituitary adenomas 3,4 in the primary care setting. structure, extent of mass effect and make up approximately 30% of cases. tumour invasion. Pituitary adenomas are defined as Discussion The normal anterior pituitary secretes microadenomas if <10 mm in maximum There is a broad range of causes six main hormones from five separate of a sellar/parasellar mass. Pituitary diameter, macroadenomas if ≥10 mm in adenomas and Rathke’s cleft cysts cell lineages: maximum diameter, and ‘giant’ pituitary are the most frequently encountered. • adrenocorticotrophic hormone (ACTH) adenomas if >4 cm in maximum diameter Prolactinomas are the most common from corticotroph cells (Figure 1). Natural history studies functioning tumour and tend to present • thyroid stimulating hormone (TSH) examining the behaviour of incidentally as macroadenomas in men, while from thyrotroph cells discovered microadenomas indicate that hyperprolactinaemia is associated with growth hormone (GH) from fewer than 5% grow significantly.5 The 15% of secondary amenorrhoea in • women. Acromegaly and Cushing’s somatotroph cells growth rate of tumours in the first two disease are rare but important diagnoses • prolactin from lactotroph cells years can be used to predict the need for to detect. Pituitary disease is optimally • follicle stimulating hormone (FSH) later intervention.6 Incidentally discovered managed in a specialist centre in the and luteinising hormone (LH) from pituitary tumours found on imaging for context of an established gonadotroph cells. other indications should be worked up multidisciplinary team. The posterior pituitary releases two as outlined in this article, looking for hormones, which are synthesised in the features of both hyper- and hypofunction,

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and referred to an endocrinologist for field defects) and hypopituitarism. women of reproductive age,11 and the evaluation and follow-up. Typically, they are not fast growing and measurement of serum prolactin should therefore may have been present for be undertaken in all women presenting several years before becoming apparent with menstrual disturbance or infertility. Pituitary adenoma subtypes clinically. Treatment is surgery for those The treatment of choice for the majority of Clinically non-functioning pituitary with significant mass effect or growing patients with prolactinoma is a dopamine adenomas tumours, while small, stable lesions can agonist, most commonly cabergoline. Clinically non-functioning pituitary be monitored without intervention.6,7 This normalises hyperprolactinaemia adenomas are characterised by an absence Some non-functioning tumours may in 85% of cases and results in shrinkage of any clinically significant hormonal behave aggressively, requiring more than in 80% of cases.8 In experienced hands, hypersecretion and usually arise from one operation and/or forms of radiation surgery can be considered for primary gonadotroph cells.7 Secretion of the intact therapy,7 but malignant tumours are rare. therapy for patients with microadenomas hormones (FSH or LH) is rare, but elevated and for women with macroadenomas alpha or beta subunits may be detected Prolactinomas contemplating pregnancy,12 but it is in the circulation. Tumours derived from It is important to appreciate that usually reserved for patients either other pituitary cell lineages can present hyperprolactinaemia may be due to resistant to or experiencing significant as non-functioning adenomas, such as a range of other conditions such as side effects from the dopamine agonist.8 ‘silent’ corticotroph, ‘silent’ somatotroph stress, pregnancy, lactation, nipple or ‘silent’ lactotroph tumours.7 These stimulation and medications (particularly Acromegaly tumours lack the intracellular mechanisms anti-emetics and antipsychotics). Acromegaly is the clinical syndrome to actively secrete the hormone Up to 20% of cases may be due to caused by excessive GH secretion. If GH systemically. Non-functioning pituitary ‘macroprolactin’, a biologically inactive excess occurs prepubertally, gigantism adenomas cause clinical problems due immune complex between prolactin and arises, characterised by excessive to mass effect (eg headaches, visual immunoglobulin G.8 There is a significant growth.13 The key issue for general sex difference between the presentations practitioners (GPs) is recognition; of prolactinoma. Women have a higher the clinical features of acromegaly Table 1. Differential diagnosis of the prevalence of microprolactinoma, which are listed in Table 3. For a patient sellar and parasellar mass27 usually results in menstrual disturbance or with suggestive clinical features, the galactorrhoea (alone or in combination). screening test is measurement of serum Pituitary • Non-functioning Conversely, men are more likely to have insulin-like growth factor-1 (IGF1).14 adenomas • Functioning larger macroadenomas and have visual Circulating IGF1 arises predominantly Cystic lesions • Rathke’s cleft cyst field defects and hypopituitarism at from the liver and reflects integrated 9 • Arachnoid cyst presentation. The explanation for the size GH secretion. In contrast, measuring difference is not simply due to delayed a random GH alone is not helpful as, • Epidermoid cyst presentation in men,9 since natural because of its pulsatile nature, ‘high’ • Dermoid cyst history studies of microprolactinomas levels may indicate a secretory pulse in Non-adenomatous • Craniopharyngioma suggest most do not increase in size, an unaffected individual. A significantly tumours • Germ cell tumour even if untreated.10 Hyperprolactinaemia elevated IGF1 (>1.1 times the upper • Meningioma is discovered in approximately 15% limit of the age-matched reference • Glioma of cases of secondary amenorrhea in range) should then be a trigger for • Pituicytoma • Chordoma Table 2. Pituitary adenoma subtypes27 • Metastasis • Sarcoma Clinically non-functioning • Silent gonadotroph adenoma • Lymphoma pituitary tumours • Other non-secretory adenomas from corticotroph, lactotroph • Hypothalamic and somatotroph cell lineage hamartoma • Null cell adenoma

Inflammatory/ • Hypophysitis Functioning pituitary • Prolactinoma infiltrative lesions • Sarcoidosis tumours • GH-secreting adenoma (acromegaly) • Langerhans cell • ACTH-secreting adenoma (Cushing’s disease) histiocytosis • Rare functioning tumours – thyrotropinoma, FSH-secreting • Pituitary abscess pituitary adenoma

Other • Aneurysm ACTH, adrenocorticotrophic hormone; FSH, follicle stimulating hormone; GH, growth hormone

referral to an endocrinologist for further However, a positive test does not diagnose investigation and management. The Cushing’s syndrome, and referral to treatment of choice is usually surgery, an endocrinologist is recommended but since the majority of cases are caused for evaluation that is more detailed. by macroadenomas (often invasive), Instances in which the 1 mg DST is not multimodality treatment – including suitable include when a patient is taking radiation therapy and medical therapy – CYP3A4 enzyme–inducing medications is frequently required.13 Long-acting such as carbamazepine (increased injectable somatostatin analogues are metabolism of dexamethasone, leading the most frequently used medications. to non-suppression of cortisol) or they They act directly on the tumour, reducing are taking oral oestrogens, including the GH secretion and often inducing tumour oral contraceptive pill (increased serum shrinkage. An alternative is pegvisomant, cortisol from oestrogen stimulation of A a GH receptor antagonist administered by corticosteroid-binding globulin).19 In these a daily injection that blocks the effects of cases, 24-hour urinary free cortisol or late GH but does not reduce GH secretion.13 night salivary cortisol are preferred, but at Young people aged under 30 years with least two samples are required. Cushing’s acromegaly or gigantism should undergo syndrome may be caused by pituitary, genetic testing.15 Patients with acromegaly adrenal and ectopic sources. The key are best managed in the setting of a steps are: 1) establishing that the patient well-established multidisciplinary team.16 has a pituitary source, 2) determining if a post-surgical remission has been Cushing’s disease achieved and 3) managing patients for The most common cause of a Cushingoid whom surgery does not result in remission. appearance is secondary to exogenous Recurrence rates are high, even after administration of glucocorticoids. successful surgery (approximately 25% B Approximately 70% of cases of overall); therefore, lifelong follow-up is endogenous Cushing’s syndrome required.20 Management of Cushing’s are caused by an ACTH-secreting disease is optimal in a specialised pituitary adenoma (known as Cushing’s multidisciplinary pituitary service. disease).17 Again, the key issue here for GPs is recognition and screening. The Rare functioning pituitary adenomas predominant clinical features of Cushing’s Rarely, pituitary tumours may secrete TSH disease are listed in Table 3, with the or FSH. Patients with thyrotropinomas first five being more specific. Patients present with hyperthyroidism with a with simple obesity, hypertension and normal or elevated TSH in the presence type 2 diabetes should not be routinely of an elevated free thyroxine level, screened for Cushing’s disease unless in contrast to autonomous thyroid they display some of the specific features. function.21 FSH-secreting adenomas Measures of morning cortisol and ACTH are very rare and present in women C are not useful for diagnosing Cushing’s of pre-menopausal age with ovarian syndrome, but once Cushing’s syndrome hyperstimulation, sometimes with marked Figure 1. Magnetic resonance imaging of pituitary tumours is confirmed, measurement of ACTH is ovarian and uterine enlargement, and 22 a. Right-sided pituitary microadenoma essential to guide further investigations dysfunctional uterine bleeding. (yellow arrow). The normal pituitary (red because a suppressed ACTH indicates an arrow) and optic chiasm (blue arrow) autonomous adrenal source. While the are indicated; b. Left-sided pituitary Endocrine Society Guidelines suggest Non-adenomatous pituitary macroadenoma (yellow arrow) with mild 18 suprasellar extension. The normal pituitary three possible screening tests, for most and parasellar masses is displaced to the right (red arrow). The patients in the primary care setting, As outlined in Table 1, there is a wide optic chiasm (blue arrow) is well clear of the 1 mg overnight dexamethasone range of causes of a sellar or parasellar the superior margin of the tumour; c. Giant suppression test (1 mg DST) is the best mass. These may present with symptoms pituitary adenoma (yellow arrow). Neither the normal pituitary nor the optic chiasm screening test. A post-dexamethasone of mass effect such as visual loss or are visible. morning cortisol of <50 nmol/L pituitary dysfunction, or be discovered essentially excludes Cushing’s syndrome, incidentally on imaging for non-related and rarely is further testing required. reasons. The Rathke’s cleft cyst, resulting

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from failure of the obliteration of Rathke’s Red flags that indicate that a lesion is Hypopituitarism pouch during embryological development, unlikely to be a pituitary adenoma include: Pituitary hormonal dysfunction is is one of the common non-adenomatous • diabetes insipidus (thirst and polyuria, unusual in microadenomas but more lesions.23 Small Rathke’s cleft cysts may with inability to concentrate the urine) common as tumour size increases. The be managed conservatively, with surgery • upper cranial nerve palsies III, IV and usual mechanism is obstruction (by the reserved for those causing symptomatic VI, causing ptosis/eye movement tumour itself or increased intrasellar mass effect or pituitary dysfunction.23 disorders. Generally this will only occur pressure) of hypothalamic releasing A detailed discussion of the other lesions in patients with pituitary adenomas who factors. These factors are transported is beyond the scope of this article. have undergone pituitary apoplexy. via the hypothalamic–hypophyseal portal circulation to the normal anterior pituitary gland.24 Therefore, Table 3. Clinical features of hormonal excess in functioning pituitary adenomas27 many patients have the potential to regain hormone function following Condition Clinical features tumour resection by a skilled pituitary Prolactinoma • Galactorrhoea surgeon. Sometimes treatment of a • Menstrual disturbance (oligomenorrhoea/amenorrhoea) pituitary or parasellar tumour with • Male hypogonadism (low libido, erectile dysfunction) surgery or radiotherapy may result in Acromegaly • Enlargement of hands and feet loss of pituitary function due to direct • Frontal bossing damage to the normal anterior pituitary/ hypothalamus. Each hormonal axis must • Splayed dentition be assessed individually and replaced if • Mandibular enlargement – jaw malocclusion found to be deficient. • Enlarged tongue A standard pituitary function panel • Skin tags drawn in the morning before 9.00 am is • Oily skin outlined in Box 1. • Sweating Results that may point to the presence • Hirsutism (women) of a pituitary lesion, whereby the absence • Obstructive sleep apnoea of a pituitary hormone response to low • Osteoarthritis target organ hormone levels indicates • Carpal tunnel syndrome secondary (pituitary/hypothalamic) • Hypertension hypofunction, include: • Cardiomyopathy • low thyroxine with inappropriately • Goitre low or normal TSH, which indicates • Liver/spleen enlargement secondary hypothyroidism, in contrast • Colonic polyps to the elevated TSH seen in primary • Diabetes hypothyroidism • Tall stature (prepubertal onset = gigantism) • low testosterone or oestrogen with inappropriately low or normal FSH/ Cushing’s disease • Thin skin LH, or pre-menopausal FSH/LH • Easy bruising levels in a woman post-menopause. • Proximal myopathy • Broad (>1 cm) purple striae (abdomen, flanks, breasts, thighs, arms) • Osteoporosis/fracture (particularly vertebral fracture) Box 1. Pituitary function test panel • Central adiposity • Electrolytes/urea/creatinine/glucose • Dorsocervical (‘buffalo hump’) and supraclavicular fat pads • Cortisol (± ACTH) • Facial plethora • Free thyroxine, TSH • ‘Moon’ facies • Prolactin • Hirsutism (women) • FSH/LH • Menstrual disturbance • Oestradiol (women), testosterone (men) • Psychiatric/mood disorders • Insulin-like growth factor 1 (± GH) • Hypertension • Diabetes ACTH, adrenocorticotrophic hormone; FSH, follicle stimulating hormone; GH, growth • Pityriasis versicolor hormone; LH, luteinising hormone; TSH, thyroid • Short stature/growth failure (children) stimulating hormone

This is secondary hypogonadism, and Key points Clin Endocrinol (Oxf) 2016;84(2):222–28. doi: 10.1111/cen.12879. while functional causes exist with no • Pituitary conditions cover a broad 7. Yavropoulou MP, Tsoli M, Barkas K, Kaltsas G, structural pituitary abnormality, it still spectrum of aetiologies. Grossman A. The natural history and treatment requires further investigation. It is critical that GPs have an appropriate of non-functioning pituitary adenomas (non- • functioning PitNETs). Endocr Relat Cancer • isolated mild-to-moderate index of suspicion and are familiar 2020;27(1):R375–R90. doi: 10.1530/ERC-20- hyponatraemia – commonly seen in with the basic hormone screen for 0136. 8. Vilar L, Abucham J, Albuquerque JL, et al. secondary adrenal insufficiency. It is hypopituitarism. Controversial issues in the management of important to measure morning cortisol • Screening tests for causes of pituitary hyperprolactinemia and prolactinomas – An levels in patients with hyponatraemia. hyperfunction includes prolactin for overview by the neuroendocrinology department of the Brazilian society of endocrinology Assessing for secondary adrenal galactorrhoea/amenorrhoea in women and metabolism. Arch Endocrinol Metab insufficiency and GH deficiency is or low testosterone with low or normal 2018;62(2):236–63. doi: 10.20945/2359- 3997000000032. more involved than assessing the other FSH/LH in men, IGF1 for acromegaly 9. Duskin-Bitan H, Shimon I. Prolactinomas in males: axes, often requiring stimulation tests. and 1 mg DST for Cushing’s syndrome. Any differences? Pituitary 2020;23(1):52–57. Reference ranges and diagnostic cut-offs • Referral to an experienced pituitary doi: 10.1007/s11102-019-01009-y. 10. Sisam DA, Sheehan JP, Sheeler LR. The natural for cortisol in particular vary considerably centre for multidisciplinary history of untreated microprolactinomas. Fertil according to the assay used. The short management is recommended. Steril 1987;48(1):67–71. doi: 10.1016/s0015- Synacthen test is available through private 0282(16)59292-9. 11. Lee DY, Oh YK, Yoon BK, Choi D. Prevalence of pathology laboratories. While it is not Authors hyperprolactinemia in adolescents and young 100% accurate for diagnosing secondary women with menstruation-related problems. Warrick J Inder MBChB, MD, FRACP, Endocrinologist, Am J Obstet Gynecol 2012;206(3):213.e1–5. adrenal insufficiency, particularly Department of Diabetes and Endocrinology, Princess doi: 10.1016/j.ajog.2011.12.010. Alexandra Hospital, Qld; Associate Professor, Faculty if it has a recent onset, it is the most 12. Honegger J, Nasi-Kordhishti I, Aboutaha N, of Medicine, The University of Queensland, Qld commonly used test of pituitary–adrenal Giese S. Surgery for prolactinomas: A better Christina Jang MBBS, MD, FRACP, Senior Lecturer, 24,25 choice? Pituitary 2020;23(1):45–51. doi: 10.1007/ function. GH is now reimbursed by Faculty of Medicine, The University of Queensland, s11102-019-01016-z. Qld; Endocrinologist, Queensland Diabetes and the Pharmaceutical Benefits Scheme 13. Colao A, Grasso LFS, Giustina A, et al. Endocrine Centre, Mater Health, Qld for adults with GH deficiency, but a Acromegaly. Nat Rev Dis Primers 2019;5(1):20. Competing interests: WJI has received speaker doi: 10.1038/s41572-019-0071-6. stimulation test is required to confirm the honoraria from Pfizer and Ipsen and been on an 14. Katznelson L, Laws ER, Jr, Melmed S, et al. advisory board for Pfizer. The Princess Alexandra diagnosis; this should be performed in a Acromegaly: An endocrine society clinical Hospital Department of Diabetes and Endocrinology practice guideline. 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