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|Hyperprolactinaemia/galactorrhoea |

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|Hyperprolactinaemia is a common abnormality which usually presents with hypogonadism and/or galactorrhoea (lactation in the|

|absence of breastfeeding). Since prolactin stimulates milk secretion but not breast development, galactorrhoea rarely |

|occurs in men and only does so if gynaecomastia has been induced by hypogonadism . |

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|Prolactin usually circulates as a free (monomeric) hormone in plasma, but in some individuals prolactin becomes bound to an|

|IgG antibody. This complex is known as macroprolactin and such patients have macroprolactinaemia (not to be confused with |

|macroprolactinoma, a prolactin-secreting pituitary tumour > 1 cm in diameter). Since macroprolactin cannot cross blood |

|vessel walls to reach prolactin receptors in target tissues it is of no pathological significance. |

|Causes of hyperprolactinaemia |

|Physiological |

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|Stress (e.g. post-seizure) |

|Pregnancy |

|Lactation |

|Nipple stimulation |

|Sleep |

|Coitus |

|Exercise |

|Baby crying |

Drug-induced Dopamine antagonists

|Antipsychotics (phenothiazines and butyrophenones) |

|Antidepressants |

|Antiemetics (e.g. metoclopramide, domperidone) |

Dopamine-depleting drugs

|Reserpine |

|Methyldopa |

Oestrogens

|Oral contraceptive pill |

Pathological Common

|Disconnection hyperprolactinaemia (e.g. non-functioning pituitary macroadenoma) |

|Prolactinoma (usually microadenoma) |

|Primary hypothyroidism |

|Polycystic ovarian syndrome |

|Macroprolactinaemia |

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Uncommon

|Hypothalamic disease |

|Renal failure |

|Pituitary tumour secreting prolactin and growth hormone |

Rare

|Chest wall reflex (e.g. post-herpes zoster) |

|Ectopic source |

Clinical assessment

In women, in addition to galactorrhoea, hypogonadism associated with hyperprolactinaemia causes secondary amenorrhoea and anovulation with infertility important points in the history includes drug use, recent pregnancy and menstrual history. The quantity of milk produced is variable, and it may be observed only by manual expression. In men there is decreased libido, reduced shaving frequency and lethargy. Unilateral galactorrhoea may be confused with nipple discharge, and careful breast examination to exclude malignancy or fibrocystic disease is important.

|Investigations |

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|Pregnancy should first be excluded before further investigations are performed in women of child-bearing potential. The |

|upper limit of normal for many assays of serum prolactin is approximately 500 mU/L (14 ng/mL). In non-pregnant and |

|non-lactating patients, monomeric prolactin concentrations of 500-1000 mU/L are likely to be induced by stress or drugs, |

|and a repeat measurement is indicated. Levels between 1000 and 5000 mU/L are likely to be due to either drugs, a |

|microprolactinoma or 'disconnection' hyperprolactinaemia. Levels above 5000 mU/L are highly suggestive of a |

|macroprolactinoma. |

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|Patients with prolactin excess should have tests of gonadal function and T4 and TSH measured to exclude primary |

|hypothyroidism causing TRH-induced prolactin excess. Unless the prolactin falls after withdrawal of relevant drug therapy, |

|a serum prolactin of > 1000 mU/L is an indication for MRI or CT scan of the hypothalamus and pituitary. Patients with a |

|macroadenoma also need tests for hypopituitarism . |

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|Management |

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|If possible, the underlying cause should be corrected (for example, cessation of offending drugs and giving thyroxine |

|replacement in primary hypothyroidism). If this is not possible, then in almost all cases of hyperprolactinaemia, dopamine |

|agonist therapy will normalise prolactin levels with return of gonadal function. If gonadal function does not return |

|despite effective lowering of prolactin, then there may be associated gonadotrophin deficiency or, in the female, the onset|

|of the menopause. Troublesome physiological galactorrhoea can also be treated with dopamine agonists. |

|Prolactinoma |

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|Most prolactinomas in pre-menopausal women are microadenomas because the symptoms of prolactin excess usually result in |

|early presentation. In men and post-menopausal women, however, the presentation is often much more insidious and due to |

|mass effects rather than hyperprolactinaemia, with the result that these tumours are almost invariably macroadenomas at the|

|time of diagnosis. Prolactin-secreting cells of the anterior pituitary share a common lineage with growth hormone-secreting|

|cells, so occasionally prolactinomas can secrete excess growth hormone and cause acromegaly. In prolactinomas there is a |

|relationship between prolactin concentration and tumour size: the higher the level, the bigger the tumour. Some |

|macroprolactinomas can elevate prolactin concentrations > 100 000 mU/L. |

Management

|Medical |

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|Dopamine agonist drugs are first-line therapy for the majority of patients .They usually reduce serum prolactin |

|concentrations and cause significant tumour shrinkage. It is possible to withdraw dopamine agonist therapy without |

|recurrence of hyperprolactinaemia after a few years of treatment in some patients with a microadenoma. Also, after the |

|menopause, suppression of prolactin is only required in microadenomas if galactorrhoea is troublesome, since hypogonadism |

|is then physiological and tumour growth unlikely. In patients with macroadenomas, drugs can only be withdrawn after |

|curative surgery or radiotherapy and under close supervision. |

|Dopamine agonist therapy: drugs used to treat prolactinomas |

|  |Oral dose* |Advantages |Disadvantages |

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|Bromocriptine |2.5-15 mg/day |Available for parenteral use |Ergotamine-like side-effects (nausea, |

| |8-12-hourly |Short half-life; useful in treating |headache, postural hypotension, constipation) |

| | |infertility |Frequent dosing so poor compliance |

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|  |  |Proven long-term efficacy |Rare reports of fibrotic reactions in various |

| | | |tissues |

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|Cabergoline |250-1000 μg/week |Long-acting, so missed doses less |Limited data on safety in pregnancy |

| |2 doses/week |important |Associated with cardiac valvular fibrosis in |

| | |Reported to have fewer ergotamine-like |Parkinson's disease |

| | |side-effects | |

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|Quinagolide |50-150 μg/day |A non-ergot with few side-effects in |Untested in pregnancy |

| |Once daily |patients intolerant of the above | |

|Surgery and radiotherapy |

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|Surgical decompression is usually only necessary when a macroprolactinoma has failed to shrink sufficiently with dopamine |

|agonist therapy and this may be because the tumour has a significant cystic component. Surgery may also be performed in |

|patients who are intolerant of dopamine agonists. Microadenomas can be removed selectively by trans-sphenoidal surgery with|

|a cure rate of about 80%; the cure rate for surgery in macroadenomas is substantially lower. |

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|External irradiation may be required for some macroadenomas to prevent regrowth if dopamine agonists are stopped. |

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|Pregnancy |

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|Hyperprolactinaemia often presents with infertility, so dopamine agonist therapy may be followed by pregnancy. Patients |

|with microadenomas should be advised to withdraw dopamine agonist therapy as soon as pregnancy is confirmed. In contrast, |

|macroprolactinomas may enlarge rapidly under oestrogen stimulation and these patients should continue dopamine agonist |

|therapy and need measurement of prolactin levels and visual fields during pregnancy. All patients should be advised to |

|report headache or visual disturbance promptly. |

|Acromegaly |

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|Acromegaly is caused by growth hormone (GH) secretion from a pituitary tumour, usually a macroadenoma |

|Clinical features |

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|If GH hypersecretion occurs before puberty then the presentation is with gigantism. More commonly, GH excess occurs in |

|adult life and presents with acromegaly. If hypersecretion starts in adolescence and persists into adult life, then the two|

|conditions may be combined. The most common complaints are headache and sweating. Additional features include those of any |

|pituitary tumour |

|Investigations |

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|The clinical diagnosis must be confirmed by measuring GH levels during an oral glucose tolerance test .In normal subjects, |

|plasma GH suppresses to below 0.5 μg/L (approximately 2 mU/L). In acromegaly, GH does not suppress and in about 50% of |

|patients there is a paradoxical rise. The rest of pituitary function should be investigated as described previously |

|Prolactin concentrations are elevated in about 30% of patients due to co-secretion of prolactin from the tumour. |

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|The diagnosis of acromegaly is more difficult in patients with insulin deficiency, either type 1 or long-standing type 2 |

|diabetes mellitus. GH may fail to suppress following a glucose load in these patients because inadequate insulin secretion |

|results in failure of glucose to stimulate IGF-1 from the liver. It is IGF-1 that, in turn, suppresses GH secretion. This |

|is important because acromegaly can cause diabetes mellitus by exacerbating insulin resistance. However, measuring IGF-1 |

|usually resolves matters; in diabetic patients without acromegaly, IGF-1 concentrations are low, while in acromegalic |

|patients IGF-1 levels are high. |

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|Additional tests in acromegaly may include screening for colonic neoplasms with colonoscopy. |

|Management |

|Surgical |

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|Trans-sphenoidal surgery is usually the first line of treatment and may result in cure of GH excess, especially in patients|

|with microadenomas. More often, surgery serves to debulk the tumour and further second-line therapy is required, according |

|to post-operative imaging and glucose tolerance test results. |

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|Radiotherapy |

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|External radiotherapy is usually employed as second-line treatment if acromegaly persists after surgery, to stop tumour |

|growth and lower GH levels. However, GH levels fall slowly (over many years) and there is a risk of hypopituitarism. |

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|Medical |

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|In patients with persisting acromegaly after surgery, medical therapy is usually employed to lower GH levels to < 1.5 μg/L |

|(approximately < 5 mU/L) and to normalise IGF-1 concentrations. Medical therapy may be discontinued after several years in |

|patients who have received radiotherapy. Somatostatin analogues (such as octreotide or lanreotide) can be administered as |

|slow-release injections every few weeks. Somatostatin analogues can also be used as primary therapy for acromegaly either |

|as an alternative or in advance of surgery, given evidence that they can induce modest tumour shrinkage in a proportion of |

|patients. Dopamine agonists are less potent in lowering GH but may be helpful, especially in patients with associated |

|prolactin excess. Pegvisomant is a peptide GH receptor antagonist which is administered by daily self-injection and may be |

|indicated in some patients whose GH and IGF-1 concentrations fail to suppress sufficiently following somatostatin analogue |

|therapy. |

|Craniopharyngioma |

|Craniopharyngiomas are benign tumours that develop in cell rests of Rathke's pouch, and may be located within the sella |

|turcica, or commonly in the suprasellar space. They are often cystic with a solid component that may or may not be |

|calcified In young people, they are diagnosed more commonly than pituitary adenomas. They may present with pressure |

|effects on adjacent structures, hypopituitarism and/or cranial diabetes insipidus. In addition, other clinical features |

|that are directly related to hypothalamic damage may also occur. These include hyperphagia and obesity loss of the |

|sensation of thirst and disturbance of temperature regulation. |

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|Craniopharyngiomas can rarely be reached by the trans-sphenoidal route and so surgery may involve a craniotomy, with a |

|relatively high risk of hypothalamic damage and other complications. If the tumour has a large cystic component it may be |

|safer to place in the cyst cavity a drain which is attached to a subcutaneous access device, rather than attempt a |

|resection. Whatever form it takes, surgery is unlikely to be curative and radiotherapy is usually given, although there is |

|uncertainty about its efficacy. Unfortunately, craniopharyngiomas often recur, requiring repeated surgery. They often cause|

|considerable morbidity, usually from hypothalamic obesity, water balance problems and/or visual failure. |

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