General approach to management of hyperprolactinaemia

Dr. But Wai Man

Prolactin

Polypeptide hormone consisted of 199 aminoacids with 3 intramolecular disulfide bondsEncoded by a single gene on chromosome 6, 5 coding exonsSecreted by lactotrophic cells in anterior pituitary gland

Prolactin receptor

Identified as a member of the cytokine receptor superfamilySingle –chain transmembrane receptor Functions by binding a single prolactin molecule and then dimerizing with a second receptor molecule

Functions of prolactin

Important role in a variety of reproductive functionsEssential factor for normal production of breast milk following child birthHyperprolactinaemia 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

HyperprolactinaemiaClinical manifestations

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

In men, tend to be large, and may cause cranial-nerve dysfunction, visual loss and panhypopituitarismloss of libido and erection dysfunctionGalactorrhea and gynaecomastia are uncommon N Engl J Med 78; 299: 847-52

In both men and womenLow bone densityWeight gainMood and behaviour changes

CausesPregnancy 10XDopamine antagonist drug therapy ( phenothiazines and metoclopramide, TCA, monamine oxidase inhibitors, oestrogen, verapamil, methyldopa Stress eg venepuncture/ exercise Polycystic ovarian syndromePituitary-secreting microadenomas/macroadenomasPituitary stalk disruption by interfering with the normal suppression of prolactin by hypothalamic dopamineChronic renal failure

Evaluation Biological evaluation of related hormonal axes:

Careful drug history and physical examinationTFT, RFTPCO 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 complexesPolyethylene glycol precipitation of complexes allows the measurement of free monmeric prolactinNot thought to have pathological significance

Evaluation for hypothalamic-pituitary pathology

Clinical examination: assessment of visual fieldsImaging : MRI /CT Pituitary microadenoma < 10mmPituitary macroadenoma > 10 mmPituitary stalk lesionsHypothalamic tumours, granulomas

Pituitary microadenoma

20% of the normal population at autopsy50% of MRI imagingNo lesion suggesting microadenoma < 2mm, lactotroph hyperplasiaHypopituitarism in structural lesion

Prolactin secreting pituitary tumors

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

Treatment of prolactin-secreting pituitary adenoma

MedicalSurgical Radiotherapy

Indication

To suppressive abnormal lactationTo restore ovarian functionProtection against development of osteoporosisRx 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 choiceNormalise 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 hrsIn 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/day5-30mg/day (7.5mg/d)

1-2x/week0.5-2 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 NocteDuration 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 Duratio

n(month)

Type Remission

FU(month)

Zarate 83 16 BRC 24 Micro 37.5% 24

Moriondo 84

36 BRC 12 Macro 11% 30

Wang 87 24 BRC 24 Micro 21% 12-48

Rasmussen 87

75 BRC 24 All 44% >6

Ferari 92 127 CAB 14 All 31% 3-24

Muratori 97 26 CAB 12 Micro 19% 38-60

Colao 03 105 CAB 48 Micro 73% 24-60

Biswas 05 89 67- CAB22- BRC

37 Micro 31% >12

RemissionLong term follow up studies of untreated patients have shown that prolactinomas are very indolentShort 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 weeksAdvised to use mechanical form of contraception until 2 regular menstrual flowStop 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

SurgeryNot first line option as outcomes reported are variableExperienced 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 therapyFor patients with intrasellar tumor for whom long-term drug treatment is not acceptableSurgical decompression may be required for tumors pressing on optic chiasmAvoid in cases o f extrasellar expanding tumors without optic chiasm compression because of low success rate

Hormonal therapy

Fertility is not a concernFor hypogonadismPrevent progressive bone loss

Macroadenomas

Tend to grow, absolute indication for therapyManaged 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 functionVisual field assessment 1 month after the initiation of therapyMRI repeated 6 months laterProlactin 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 groupHyperprolactinaemia 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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