General approach to management of hyperprolactinaemia Dr. But Wai Man

Prolactin Polypeptide hormone consisted of 199 aminoacids with 3 intramolecular disulfide bonds Encoded by a single gene on chromosome 6, 5 coding exons Secreted by lactotrophic cells in anterior pituitary gland

Prolactin receptor Identified as a member of the cytokine receptor superfamily Single –chain transmembrane receptor Functions by binding a single prolactin molecule and then dimerizing with a second receptor molecule Like a pair of hands holding the hormone

Functions of prolactin Important role in a variety of reproductive functions Essential factor for normal production of breast milk following child birth Hyperprolactinaemia disrupts normal pulsatile secretion of gonadotrophic-releasing hormone, altered LH and FSH secretion and impaired gonadal steroidogenesis, leads to infertility and gonadal dysfunction

Control of prolactin secretion Secretion is mainly under inhibitory control by hypothalamic dopamine Circadian variation. Levels rise after the onset of sleep, nocturnal peak of 2x daytime concentration

Hyperprolactinaemia Clinical manifestations Galactorrhoea 90%: affect mammary gland development Amenorrhoea/Oligomenorrhoea: In women, prolactin-secreting tumors is usually small, headache and neurological deficits are rare

loss of libido and erection dysfunction In men, tend to be large, and may cause cranial-nerve dysfunction, visual loss and panhypopituitarism loss of libido and erection dysfunction Galactorrhea and gynaecomastia are uncommon N Engl J Med 78; 299: 847-52 In both men and women Low bone density Weight gain Mood and behaviour changes Related to low testosterone level in men

Causes Pregnancy 10X Dopamine antagonist drug therapy ( phenothiazines and metoclopramide, TCA, monamine oxidase inhibitors, oestrogen, verapamil, methyldopa Stress eg venepuncture/ exercise Polycystic ovarian syndrome Pituitary-secreting microadenomas/macroadenomas Pituitary stalk disruption by interfering with the normal suppression of prolactin by hypothalamic dopamine Chronic renal failure

Evaluation Biological evaluation of related hormonal axes: Careful drug history and physical examination TFT, RFT PCO and exclusion of pregnancy

Levels of prolactin <1000 m U/L <5000 m U/L > 10,000 m U/L stress Micro-prolactinoma Macroprolactinoma hypothyroidism Pituitary stalk disconnection PCOS

Macroprolactinaemia High molecular-weight prolactin-immunoglobulin complexes Polyethylene glycol precipitation of complexes allows the measurement of free monmeric prolactin Not thought to have pathological significance

Evaluation for hypothalamic-pituitary pathology Clinical examination: assessment of visual fields Imaging : MRI /CT Pituitary microadenoma < 10mm Pituitary macroadenoma > 10 mm Pituitary stalk lesions Hypothalamic tumours, granulomas

Pituitary microadenoma 20% of the normal population at autopsy 50% of MRI imaging No lesion suggesting microadenoma < 2mm, lactotroph hyperplasia Hypopituitarism in structural lesion

Prolactin secreting pituitary tumors Benign tumors Commonest pituitary tumors, 40% >90% are small, intrasellar tumors that rarely increase in size JCEM 89; 68: 412-8

Treatment of prolactin-secreting pituitary adenoma Medical Surgical Radiotherapy

Indication To suppressive abnormal lactation To restore ovarian function Protection against development of osteoporosis Rx may not be required in a few women with modest elevations of prolactin, may retain normal ovarian function and have few symptoms

Dopamine agonist Primary treatment of choice Normalise prolactin levels, restoration of pituitary function and tumor shinkage in 80-90% over several weeks JCEM 1997 82 996-1000 Tumour shinkage by at least 25% of volume in 80% of patients with large macroadenoma Improvement in pressure symptoms within 48 hrs In men, 50% may require testosterone replacement, withhold until prolactin levels are normalised

Bromocriptine Cabergoline Quinagolide 1st dopamine agonist since early 1970 New, high affinity for lactotroph dopamine receptors 2-3 x/day 5-30mg/day (7.5mg/d) 1-2x/week 0.5-2 mg/wk Once daily 0.05-0.25 mg Nausea, postural hypotension, dizziness, headache, depression Improved efficacy and few side effects NEJM 94; 331: 904-909 Start with low dose and increase dosage gradually. Start 0.625 mg Nocte Duration 2-6 years? Most effective in reducing tumor size JCEM 2000 85 2247-2252

Duration of treatment Early studies showed remission is rare after interruption of therapy, life long treatment Clin Endo 1991; 34: 173-174 Recent studies showed increase in remission and therapeutic withdrawal is recommended J Royal College of Physicians 1997; 31: 628-636

List of studies assessing dopamine agonist withdrawal Authors No Agent Duration (month) Type Remission FU Zarate 83 16 BRC 24 Micro 37.5% Moriondo 84 36 12 Macro 11% 30 Wang 87 21% 12-48 Rasmussen 87 75 All 44% >6 Ferari 92 127 CAB 14 31% 3-24 Muratori 97 26 19% 38-60 Colao 03 105 48 73% 24-60 Biswas 05 89 67- CAB 22- BRC 37 >12

Remission Long term follow up studies of untreated patients have shown that prolactinomas are very indolent Short term therapy appears to induce cytostatic effects including reduction in organelle size and reduction in the volume of prolactin cells JCEM 55, 11798-1183 Long-term therapy induces cytocidal effects such as necrosis, fibrosis and inflammatory cell infiltration JCEM 58, 1179-1183

Pregnancy Warned that restoration of ovulatory menstral cycle within weeks Advised to use mechanical form of contraception until 2 regular menstrual flow Stop dopamine agonist as soon as pregnancy is confirmed for microadenoma, risk of pituitary enlargement is low <2% Bromocriptine can cross placenta and suppress pituitary prolactin secretion, but no apparent risk of congenital abnormality or misscarriage JCEM 97 82 996-1000

For macroadenoma, bromocriptine is advised during pregnancy to avoid significant tumor expansion as risk of enlargement is 15-30% (J Reprod Med 99; 44: 1121-6) Some recommend debulking for macroadenoma which have extended beyond the sella before pregnancy and bromocriptime prescribed throughout pregnancy (Am J O&G 83; 146:935-8) Cabergoline should not be used as a therapy for infertility until more information is available

Surgery Not first line option as outcomes reported are variable Experienced center cure rate 85-90%, recurrence and complication <10% and hypopituitarism <1% JCEM 1995 81 1711-1719 Prolactin decrease to very low values immediately after surgery and gradually to low-normal over wks, recurrence rate is very low Meta 1986 35 905-912 Success is less likely (<50%) in macroadenoma which has extended beyond the sella JCEM 1995 81 1711-1719

Indications for pituitary surgery Resistance or intolerance to optimal medical therapy For patients with intrasellar tumor for whom long-term drug treatment is not acceptable Surgical decompression may be required for tumors pressing on optic chiasm Avoid in cases o f extrasellar expanding tumors without optic chiasm compression because of low success rate

Hormonal therapy Fertility is not a concern For hypogonadism Prevent progressive bone loss

Macroadenomas Tend to grow, absolute indication for therapy Managed with dopamine agonist Confined to the sella should be managed as micraoadenoma as unlikely enlarged sufficiently to cause serious complications

Higher doses Decrease in prolactin levels within 2-3 wks and precedes a decrease in the size of the tumor and restoration of anterior pituitary function Visual field assessment 1 month after the initiation of therapy MRI repeated 6 months later Prolactin measured yearly

Hyperprolactinaemia and antipsychotic drugs

Hyperprolactinaemia and antipsychotic drugs 34% of men and 75% of women showed hyperprolactinaemia (Curr Med Res Opin 2004;20:(2) 189-97) Hypogonadism is common. Mean levels were in the hypogonadal range for women and 6.4% of men were hypogonadal (Br J Psy 2004;184:503-8) Sexual dysfunction in 45% compared with 17% of GP clinic control (Br J Psy 2004;184:503-8)

Effects of long term prolactin raising antipsychotic medication on bone mineral density in patients with schizophrenia Male and post-menopausal female patients with schizophrenia on long-term prolactin –raising antipsychotic drugs (>10yr) British J of Psychiatry 2004; 184; 503-508

Results Hyperprolactinaemia was present in 62% of the overall group (60% in male and 64% in female) 57% of the men and 32% of the women had reduced bone mineral density

Antipsychotic drugs A new risk factor for osteoporosis in young women with schizophrenia To study the effect of prolactin-raising and prolactin-sparing antipsychotic drugs (olanzapine) on bone density of premenopausal females J of clinical psychopharmacology 2005; 25 (1):26-31

Results Low BMD in 65% of prolactin-raising group, compared with 17% in prolactin-sparing group Hyperprolactinaemia was associated with low BMD; 95% with low BMD had hyperprolactinemia and only 11% of the group with normal prolactin had abnormal BMD

Relative percentage distribution of low BMD in prolactin-sparing and prolactin –raising groups

Relative percentage distribution of bone loss in normal prolactin and hyperprolactinemia

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