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Review Article

Hyperprolactinemia: A Systematic Review of Diagnosis and Management Nazma Akter1, Nazmul Kabir Qureshi2, Tangera Akter3

Abstract Hyperprolactinemia is a common endocrine disorder that can be associated with significant morbidity. It can result from a number of causes, including use of medication, and pituitary disorders. Depending on the cause and consequences of hyperprolactinemia, selected patients require treatment considering the underlying cause, age sex, and reproductive status. We describe a systematic review of hyperprolactinemia, including microadenomas and macroadenomas, in various clinical settings, with emphasis on newer diagnostic strategies and the role of various therapeutic options, including treatment with selective agonists. Through this review, we aimed to compare efficacy and adverse effects of medications, surgery and radiotherapy in the treatment of hyperprolactinemia. Keywords: Hyperprolactinemia; diagnostic strategies; therapeutic options.

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Search strategy Introduction We searched electronic databases, reviewed is a pituitary-derived that plays bibliographies of included articles and sought a pivotal role in a variety of reproductive articles addressing hyperprolactinemia or functions. It is an essential factor for normal prolactin-secreting tumours that were treated by production of following . dopamine agonists, surgery or radiotherapy, and Furthermore, prolactin negatively modulates the which focused on outcomes from those secretion of pituitary responsible for treatments. We searched in MEDLINE, The New gonadal function, including luteinizing hormone England Journal of Medicine, Bio Med Central and follicle-stimulating hormone. An excess of Journal and Pub Med from March 2016 to June prolactin, or hyperprolactinemia, is a commonly 2016. Search was limited to articles published encountered clinical condition.1 It is the most in English. common disorder of the hypothalamic-pituitary

1. Resident Physician & Consultant, Dept. of Endocrinology & Metabolism, MARKS Medical College & Hospital, Dhaka, Bangladesh. 2. FACE Consultant, Dept. of Endocrinology & Medicine, National Health Care Network (NHN), DAB, Bangladesh. 3. Assistant Professor (C.C.), Dept. of Surgery, Delta Medical College, Dhaka, Bangladesh. Correspondence: Dr. Nazma Akter. e-mail: [email protected]

90 Delta Med Col J. Jul 2018;6(2) Review Article axis. Patients typically present with galactorrhea or , and men with , infertility or, in the case of hypogonadism, impotence or infertility must have macroadenomas, symptoms related to mass effect serum prolactin levels measured.1 It is estimated at (headache and visual field defects). Management 9% among women with amenorrhea, 17% among of this condition depends on the cause and on the women with polycystic ovary syndrome, 25% effects it has on the patient. Commonly cited among women with galactorrhea and as high as indications for treatment of microprolactinomas 70% among women with amenorrhea and include infertility, hypogonadism, prevention of galactorrhea.2 The prevalence is about 5% among bone loss and bothersome galactorrhea.2,3 The men who present with impotence or infertility.1 primary aim of treatment in patients with pituitary macroadenoma is to control the compressive effects of the tumour, including compression of Prolactin molecule optic chiasm, with a secondary goal to restore Prolactin is a 23 kDa polypeptide hormone (198 gonadal function. However, indications and amino acids) synthesized in the lactotroph cells of modalities of treatment of hyperprolactinemia due the anterior . Its secretion is to pituitary microadenomas are less well defined.2 pulsatile and increases with sleep, stress, food Medications in the form of dopamine agonists are ingestion, , chest wall stimulation, and the first line of treatment, with surgery and trauma. Macroprolactinemia denotes the situation radiotherapy reserved for refractory and in which there is high level of the circulating ‘big medication-intolerant patients.2 Treatment with prolactin’ molecules of 50 and 150 kDa (PRL-IgG dopamine agonists can restore normal prolactin complexes); which have high immunogenic levels and gonadal function. However, the choice properties, but poor or no biological effect. When of which is most efficacious and these big variants circulate in large amounts, the produces the least adverse effects is unclear. To condition is referred to as “macroprolactinemia”, provide evidence-based recommendations to identified as hyperprolactinemia by the commonly practicing clinicians facing these common used immune assays. Many commercial assays do therapeutic dilemmas, in this review we not detect macroprolactin. Macroprolactin in the summarize advances in our understanding of the serum can be detected by Polyethylene glycol clinical significance of hyperprolactinemia and its precipitation.4 In these situations even though high pathogenetic mechanisms, including the influence levels of circulating prolactin hormone are of concomitant medication use, effects with detected, the biological prolactin is normal and so medications, surgery and radiotherapy in there are no clinical symptoms, although a smaller hyperprolactinemic patients. proportion of patients with macroprolactinemia may have symptoms.5-8 It should be suspected when typical symptoms of hyperprolactinemia are Prevalence absent.9,10 As macroprolactinemia is common in An excess of prolactin above a reference hyperprolactinemia, routine screening for laboratory’s upper limits, or “biochemical macroprolactinemia could eliminate unnecessary hyperprolactinemia,” can be identified in up to diagnostic testing as well as treatment in cases of 10% of the population.1 The prevalence of asymptomatic hyperprolactinemic subjects.6 hyperprolactinemia ranges from 0.4% in an unselected adult population to as high as 9-17% in Regulation of prolactin secretion women with reproductive diseases. Its prevalence was found to be 5% in a family planning clinic.4 The main biological action of prolactin is inducing Women with oligomenorrhea, amenorrhea, and maintaining . However, it also exerts

Delta Med Col J. Jul 2018;6(2) 91 Review Article metabolic effects, takes part in reproductive Etiology of hyperprolactinemia16 mammary development and stimulates immune 1. Physiologic hypersecretion responsiveness.11,12 Plenty of mediators of central, Pregenency pituitary, and peripheral origin take part in Lactation regulating prolactin secretion through a direct or Chest wall stimulation 5 indirect effect on lactotroph cells. Like most Sleep anterior pituitary hormones, prolactin is under Stress dual regulation by hypothalamic hormones 2. Idiopathic hyperprolectinaemia (40%) delivered through the hypothalamic–pituitary 3. Hypothalamic-pituitary stalk damage portal circulation. The predominant signal is tonic Tumours: Craniopharyngioma, meningioma, inhibitory control of hypothalamic dopamine dysgerminoma, dermoid cyst, pineal gland tumours which traverses the portal venous system to act Empty sella upon pituitary lactotroph D2 receptors. Other Lymhocytic hypophysitis prolactin inhibiting factors include gamma amino Rathke’s cyst butyric acid (GABA), somatostatin, acetylcholine, Irradiation and norepinephrine. The second signal is Trauma stimulatory which is provided by the Pituitary stalk lesion hypothalamic peptides, thyrotropin releasing hormone (TRH), vasoactive intestinal peptide Suprasellar surgery (VIP), epidermal growth factor (EGF), and 4. Pituitary hypersecretion antagonists.13,14 Actual serum prolactin level is the result of a complex balance Metastatic tumors between positive and negative stimuli derived Tuberculosis from both external and endogenous environments. Serotonin physiologically mediates nocturnal Histiocytosis surges and suckling-induced prolactin rises and is Acromegaly a potent modulator of prolactin secretion. Cushing disease Histamine inhibits the system and Addison’s disease has a predominantly stimulatory effect. 5. Systemic disorders stimulates pituitary lactotroph proliferation Chronic renal failure especially during pregnancy. However, during Hypothyroidism pregnancy lactation is inhibited by high levels of Ectopic production estrogen and progesterone. In the postpartum Cirrhosis period, estrogen and progesterone rapidly decline which allows lactation to commence. During Pseudocyesis lactation and breastfeeding, ovulation may be Epileptic seizures suppressed due to the suppression of 6. Drug induced gonadotropins by prolactin, but may resume Dopamin receptor blocker before menstruation resumes.15 Dopamin depleting agents Histamin receptor antagonists Stimulator of serotonergic pathway Causes of hyperprolactinemia Estrogens, antiandrogens Hyperprolactinemia can be physiological or Serotonin reuptake inhibitors pathological. Calcium channel blockers

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Physiological hyperprolactinemia is usually mild prolactin excess. Clinical presentation in women or moderate. During normal pregnancy, serum is more obvious and occurs earlier than in men. prolactin rises progressively to around 200-500 Women can present with symptoms of ng/mL. Many common medications cause mild oligomenorrhea, amenorrhea, galactorrhea, hyperprolactinemia where prolactin levels rise up decreased libido, infertility, and decreased to less than 100 ng/mL. Pathological bone mass. hyperprolactinemia can be caused by both Table I: Clinical presentations of hyperprolactinemia hypothalamic- () as Premenopausal women well as non-hypothalamic-pituitary disease. The • Marked prolactin excess (>100 μg/L [normally <25 μg/L]) is commonly associated with presence of a secondary cause and fluctuating hypogonadism,* galactorrhea and amenorrhea degrees of hyperprolactinemia should raise the • Moderate prolactin excess (51–75 μg/L) is associated with oligomenorrhea suspicion of a non tumourous cause. • Mild prolactin excess (31–50 μg/L) is associated with short luteal phase, decreased libido and Prolactinomas account for 25-30% of functioning infertility 19 pituitary tumours and are the most frequent cause • Increased body weight may be associated with prolactin-secreting pituitary tumour • Osteopenia is present mainly in people with associated hypogonadism of chronic hyperprolactinemia.17 Prolactinomas • Degree of bone loss is related to duration and severity of hypogonadism*20 are divided into two groups: (1) microadenomas Men (smaller than 10 mm) which are more common in • Hyperprolactinemia presents with decreased libido, impotence, decreased sperm production, premenopausal women, and (2) macroadenomas infertility, and, rarely, galactorrhea (10 mm or larger) which are more common in men • Impotence is unresponsive to treatment and is associated with decreased muscle 21 and postmenopausal women. Pituitary adenomas mass, body hair and osteoporosis co-secreting prolactin hormone also raise *The degree of hypogonadism is generally proportionate to the degree of prolactin elevation. prolactin levels. Hypothalamus and pituitary stalk Diagnostic evaluation lesions such as nonfunctioning adenomas, Normal serum prolactin levels vary between 5 and gliomas, and craniopharyngiomas also result in 25 ng/mL in females although physiological and prolactin elevation.18 The hyperprolactinemia of 22 hypothyroidism is related to several mechanisms. diurnal variations occur. Serum prolactin levels In response to the hypothyroid state, there is a are higher in the afternoon than in the morning, compensatory increase in the discharge of central and hence should preferably be measured in the hypothalamic thyrotropin releasing hormone morning. Hyperprolactinemia is usually defined as which results in increased stimulation of prolactin fasting levels of above 20 ng/mL in men and above secretion. Furthermore, prolactin elimination from 25 ng/mL in women12 at least 2 hours after the systemic circulation is reduced. There may be waking up. For evaluation of hyperprolactinemia, diffuse pituitary enlargement in primary physiologic causes, including pregnancy in hypothyroidism, which is reverseible with women of childbearing age should be considered. appropriate hormone replacement Interpretation of postpartum hyperprolactinemia therapy.13 depends on interval after delivery and status of lactation. Prolactin levels normalize within approximately 6 months after delivery in nursing Clinical presentations mothers and within weeks in non-nursing The clinical manifestations of prolactin excess mothers.23 Elevations in prolactin levels due to (Table I) can be categorized into two groups, those stalk compression rarely exceed 150 μg per liter, that are due to prolactin excess and those but the use of agents or representing the consequences of the resulting can increase prolactin levels to hypogonadism. The clinical manifestations of more than 200 μg per liter. Clinical manifestations conditions vary significantly depending on the age of drug-induced hyperprolactinemia are similar to and the sex of the patient and the magnitude of the those of prolactinomas, except for tumour mass

Delta Med Col J. Jul 2018;6(2) 93 Review Article effects.24,25 Most patients with prolactin levels more than 150 μg per liter have associated symptoms though the Ssymptoms do not correlate well with prolactin levels. Macroprolactin, can cause spurious hyperprolactinemia because of delayed clearance.6 Unless the prolactin levels are markedly elevated, the investigation should be repeated before labeling the patient as hyperprolactinemic. Even one normal value should be considered as normal and an isolated raised one should be discarded as spurious. Other common conditions which must be excluded when considering raised prolactin levels are non-fasting sample, excessive exercise, history of drug intake, chest wall surgery or trauma, renal disease, cirrhosis, and seizure within 1-2 hours. These conditions usually cause prolactin elevation of Fig 1: Overview of diagnosis and management <50 ng/mL. Plain radiographs have been replaced of hyperprolactinemia by cross-sectional imaging techniques such as CT scanning and MRI. Currently, MRI remains the method of choice for evaluation of pituitary Management tumors. Lesions that are iso-dense with The objective of hyperprolactinemia treatment is surrounding structures may not be identified well to correct the biochemical consequences of the with CT scan.26 In patients with microadenomas hormonal excess. pituitary function is typically normal. In 29 amenorrheic women, serum levels of Objectives of treatment of hyperprolactinemia follicle-stimulating hormone should be measured Restoration and maintenance of normal to rule out primary ovarian failure, and serum gonadal function. testosterone levels should be assessed in men with Restoration of normal fertility. hyperprolactinemia; infertility (in patients desiring fertility) is an indication for therapy. Bone Prevention of osteoporosis. density should be evaluated in patients with If a pituitary tumour is present: hypogonadism. Patients with macroadenomas adjacent to the optic chiasm or compressing it Correction of visual or neurological require visual-field testing as visual compromise abnormalities. needs rapid treatment.27 The hyperprolactinemia Reduction or removal of tumour mass. is referred to as “idiopathic” in cases where other Preservation of normal pituitary function. causes of hyperprolactinemia have been excluded and no adenoma can be visualized with MRI Prevention of progression of pituitary or (Figure 1).28 hypothalamic disease.

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For management purpose, hyperprolatinemics can Table II: Advantages, disadvantages and cost of be broadly divided into three groups. various dopamine agonist agents available Agent Main advantages Disadvantages Typical dose Management of hyperprolactnemia based on Longest track record High frequency of 2.5 mg/day etiology30 gastrointestinal upset and sedation Group 1 High efficacy; less adverse Experience during 0.5 mg/week events; indicated in cases pregnancy relatively Dopamine agonist is the mainstay of management of bromocriptine resistance limited or intolerance in patients desiring fertility, with symptoms of Quinagolide Pituitary selectivity; Daily use; limited access 0.075 mg/day estrogen deprivation or with galactorrhea. indicated in cases of bromocriptine resistance or Idiopathic hyperprolactinemia intolerance Occasionally beneficial in High frequency of adverse 0.25 mg/day Bromocriptine is the first option for this condition resistant cases events and is the drug used for the longest period of time. Dopamine agonists have been in clinical use for It is best to give as continuous therapy and many years and remain the cornerstone for therapy prolactin levels reduce in about a week; ovulation of prolactinomas.30,31 All (except quinagolide) are and menstruation resumes in 4-8 weeks. Most ergot alkaloids. Current recommendations popular method to confirm resumption of advocate dopamine agonist therapy according to ovulatory function in oligo or amennorrhic women patient's requirement. Most commonly used is weekly assessment of progesterone. Ovulation dopamine agonists are bromocriptine and rates achieved by medical therapy with dopamine cabergoline. Others are , pergolide, agonist alone are approximately 80-90% if there is quinagolide, , and . Patients no other cause for anovulation other than who are intolerant or fail to respond to one agent hyperprolactinemia.30,31 In the remaining women, may do well with another. exogenous gonadotropin stimulation can be added Side effects associated with these drugs are along with dopamine agonist to achieve ovulation. nausea, vomiting, headache, constipation, Microadenoma with hyperprolactinemia dizziness, faintness, depression, postural Medical management can be continued for 18 hypotension, digital vasospasm, and nasal stuffiness. These symptoms are most likely to months to 6 or more years. Tumour expansion may occur with initiation of treatment or when the dose occur during pregnancy in less than 2% of cases. is increased. One rare but notable side effect is No treatment is required in asymptomatic and very neuropsychiatric symptoms which present as slow growing tumours which do not metastasize. auditory hallucinations, delusion, and mood Follow-up is mandatory with yearly estimation of changes. It quickly resolves with discontinuation prolactin levels, MRI, and visual fields. However, of the drug.32 Previous concerns about valvular hormone replacement therapy (HRT) to replenish heart disease with the use of these agents have estrogen deficit should be given to all patients with largely been disproved by more recent reports.33-36 amenorrhea. Bromocriptine is a lysergic acid derivative with a Medical therapeutic options for the management bromine substitute at position 2.37 It is a strong of hyperprolactinemia dopamine agonist which binds to dopamine Medical therapy has traditionally involved receptor and directly inhibits PRL secretion. It agonists of the physiologic inhibitor of prolactin, decreases prolactin synthesis, DNA synthesis, cell dopamine (Table II).28 multiplication, and overall size of prolactinoma. It

Delta Med Col J. Jul 2018;6(2) 95 Review Article has a short half-life and so it requires twice daily Group 2 administration to maintain optimal suppression of Macroadenoma with hyperprolactinemia prolactin levels. Intolerance to bromocriptine is common and it is the main indication of using an The aim of the treatment is reduction in tumour alternative drug. Tolerance is better when started mass along with the correction of the biochemical with the lowest possible dose of 1.25 mg/day after consequences of the hormonal excess including dinner and then increased gradually by 1.25 mg restoration of fertility, prevention of bone loss, and 3 each week until prolactin levels are normal or a suppression of galactorrhea. dose of 2.5 mg twice daily is reached which is Dopamine agonists are the first line of treatment 38 effective in 66% cases. However, one can start with surgery and radiotherapy reserved for with 7.5 mg/day dosage to save time and 90% will refractory and medication intolerant patients.44 respond. Macroprolactinomas regress with medication but Another alternative is vaginal usage of the same the response is variable. Some show prompt drug which is well tolerated. Vaginal absorption is shrinkage with low doses while others may require nearly complete and lower therapeutic dosing is prolonged treatment with higher dosage. possible as it avoids the liver first pass Reduction in tumour size can take place in several metabolism.39 It is also available in a long acting days to weeks.17,45 form (depot-bromocriptine) for intramuscular Surgical removal of tumours associated with injection and a slow release oral form.40,41 prolactin excess requires careful consideration of Bromocriptine has good treatment results but after treatment objectives. It is indicated in patients discontinuation of treatment prolactin returns to with nonfunctional pituitary adenomas or other elevated levels in 75% of patients and there is no non-lactotroph adenomas associated with clinical or laboratory assessment to predict hyperprolactinemia and in patients in whom long-term beneficial result.42 medical therapy has been unsuccessful or poorly Cabergoline shares many characteristics and tolerated. adverse effects of bromocriptine but has a very Indications for pituitary surgery in patients long half-life allowing weekly dosing. This is with hyperprolactinemia27 more effective in suppressing prolactin and reducing tumour size.30 The low rate of side Increasing tumour size despite optimal effects and the weekly dosage make cabergoline a medical therapy. better choice for initial treatment. It can also be Pituitary apoplexy. given vaginally if nausea occurs when taken orally.43 A dose of 0.25 mg twice per week is Inability to tolerate dopamine agonist therapy. usually adequate for hyperprolactinemia. Dopamine agonist–resistant macroadenoma. Maximum dose that can be given is 1 mg twice a Dopamine agonist–resistant microadenoma in week. a woman seeking fertility. Though both drugs have been found to be safe in If ovulation induction is not appropriate. pregnancy, the number of reports studying bromocriptine in pregnancy far exceeds that of Persistent chiasmal compression despite cabergoline.38 optimal medical therapy.

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In women seeking fertility, macroadenoma in External radiation therapy is only reserved for close proximity to optic chiasm despite residual tumour in patients who have undergone optimal medical therapy (pre pregnancy surgery and there is incomplete resection. It is of debulking recommended). very limited benefit since the response is typically quite modest and delayed.47 There is also a risk of Cerebrospinal fluid leak during administration developing hypopituitarism. Bromocriptine has of dopamine agonist. been used in patients where surgery or combined Macroadenoma in a patient with a psychiatric surgery and radiation therapy is failed. condition for which dopamine agonists are contraindicated. Group 3 Transnasal transsphenoidal microsurgical excision Around 40% patients with primary of prolactinoma is a widely chosen as it is a safe hypothyroidism have mild elevation of PRL levels procedure. It is usually recommended for very that can be normalized by thyroid hormone large tumours, those with suprasellar and frontal replacement.16 Medications that can cause extension, and visual impairment persisting after hyperprolactinemia should be discontinued for medications. Besides the usual surgical risks, 48-72 hours if it is safe to do so and serum hypopituitarism is a potential long-term effect of prolactin level repeated. Sometimes the causative surgery and patients should be counseled properly agent is essential for the patient's health (for e.g., a beforehand. Unfortunately, relapse is common as psychotropic agent) but it may cause symptomatic excision is often incomplete but prolactin levels hypogonadism. In these patients, treatment with a are lower than before. Prolactin levels should be dopamine agonist should be avoided since it might monitored regularly. First after 4 weeks of starting compromise the effectiveness of the psychotropic therapy and then repeated after 3-6 months drug and the patient should simply be treated with depending on symptom reversal. Repeat MRI is replacement of sex steroids. done after 6 months of normalization of prolactin About 30% patients with chronic renal failure and levels. Further evaluation is done with 6 monthly up to 80% patients on hemodialysis have raised prolactin levels. Scanning should be repeated only prolactin levels. This is probably due to either if symptoms reappear or exacerbate. decreased clearance or increased production of There are several possible explanations for the prolactin as a result of disordered hypothalamic recurrence or persistence of hyperprolactinemia regulation of prolactin secretion. Correction of the after surgery as listed below: renal failure by transplantation results in normal a. Tumour may be multifocal in origin PRL levels. b. Complete resection is difficult because prolactin producing tumour looks like the Management of hyperprolactinemia in surrounding normal pituitary pregnancy c. There may be continuing abnormality of the The collaboration of various specialists, including hypothalamus giving rise to chronic an obstetrician, is required for the careful planning stimulation of the lactotrophs and recurrent of pregnancy in women with hyperprolactinemia. hyperplasia. However, pituitary tumours are Ideally, this should occur before conception, to monoclonal in origin as indicated by permit a full assessment of the risks and benefits molecular biology studies.46 of dopamine agonist therapy during pregnancy.

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Management of hyperprolactinemia in of medical therapy is the potential need for pregnancy48,49 lifelong treatment. The Pituitary Society has There is no evidence of increased teratogenicity published guidelines for the diagnosis and associated with bromocriptine or cabergoline use management of prolactinomas.2 These guidelines during pregnancy suggest that discontinuation of dopamine agonist therapy can be attempted in selected patients who Similarly, there is no evidence of increased have had normal prolactin levels for at least 2 risk of or multiple with years and minimal residual tumour volume. dopamine agonist use However, such patients need to be followed If the tumour size before pregnancy is<10 mm, carefully, since tumour recurrence is common, dopamine agonist therapy is stopped during particularly in the case of macroadenomas. Unless pregnancy because the risk of tumour there is evidence of growth of a prolactinoma or expansion is low related symptoms, such as headache, there is no If the tumour size before pregnancy is≥10 mm indication to continue dopamine agonist therapy before pregnancy, bromocriptine use is after menopause.42 After discontinuation of advised during pregnancy to avoid significant treatment, regular monitoring of clinical tumour expansion symptoms and prolactin levels is recommended. All patients should be evaluated every 2 Given the propensity for early recurrence, months during pregnancy prolactin levels should be measured monthly for Formal visual field testing is indicated in the first 3 months and every 6 months thereafter. patients with symptoms or a history of macroadenoma Conclusion If visual field defects develop despite dopamine agonist treatment, early delivery or It is important to establish the pathological pituitary surgery should be considered relevance of hyperprolactinemia before commencing treatment for this endocrinological In most women with prolactinomas, disorder. Pituitary function should be tested in hyperprolactinemia persists after delivery; patients with macroadenomas, and visual-field although spontaneous resumption of menses and testing is mandatory when tumours are adjacent to remission of hyperprolactinemia can occur.50 the optic chiasm. Although microadenomas may Prolactin levels and tumour size typically remain stable during nursing. In patients with a or may not require therapy, macro-adenomas do macroadenoma requiring treatment after delivery, require therapy. Most cases of true dopamine agonists are administered, and hyperprolactinemia are associated with therefore, nursing is not possible. amenorrhea or hormone deprivation in premenopausal women and can be managed by dopamine agonist or hormone replacement Monitoring and Follow-up therapy respectively. If a normal prolactin level is Biochemical and clinical improvements in maintained and if there is minimal residual tumour response to dopamine agonist therapy are readily during medical therapy, available data suggest that apparent in most patients. In addition, tumour it may be reasonable to discontinue therapy after 2 shrinkage can be expected in about 80% of years, although recurrence rates are high and close macroadenomas.50 However, a major drawback follow-up is necessary.

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