Hyper Pro Lac Tine Mia

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Diagnosis & Treatment

of Hyperprolactinemia:

An Endocrine Society Clinical Practice Guideline

Patawee Bonntanondha


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Natural history


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Factors inducing prolactin synthesisE

TRHEDGF

D2Rantagonist


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At autopsy, 12% of pituitary glands are show

to clinically inapparent adenoma

Clinical apparent prolactinoma range from 6-

10 per 100,000 to approximately 50 per100,000

Natural history


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Clinical symptomsFemale Oligo-amenorrhea

Infertility

Galactorrhea

Bone loss

Male Hypogonadism

Decrease libido

Erectile dysfunction

Infertility

Gynecomastia

Galactorrhea

Decrease bone mass Mass effect Headache, visual symptoms

Mass effect Delayed puberty

Children


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DiagnosisRecommendation 1.1

Single measurement of serum prolactin

level above UNL confirm the diagnosis

Serum sample was obtained without

venopuncture stress

Against dynamic testing of prolactin secretion


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Evidence Assay-specific normal values are higher in women

than in men and are generally lower than 25g/liter#

level >250 g/liter

the presence of a prolactinoma

But prolactin level > 200 g/liter in selected drug risperidone , metoclopramide

Diagnosis

# 1 g/liter is equivalent to 21.2 mIU/liter


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Serum prolactin can be drawn at any time of

the day

When in doubt, sampling can be repeated ona different day at 15- to 20-min intervals

Diagnosis


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Recommendation 1.2

Asymptomatic hyperprolactinemia, we

suggest assessing for macroprolactin

Diagnosis


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Recommedation 1.3

Discrepancy between a very large pituitary

tumor and a mildly elevated prolactin level,

we recommend serial dilution of serum

samples to eliminate an artifact that can occur

with some immunoradiometric assays leading

to a falsely low prolactin value (hook effect)

Diagnosis


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Evidence

Serum prolactin levels generally parallel tumor

size

Macroprolactinomas (>10 mm) are prolactin

levels greater than 250 g/liter

Diagnosis


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Macroprolactin

Hook effect

Endogenou serumheterophilicantibodies


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Discrepancy between a very large pituitary

tumor and a mildly elevated prolactin level

Large prolactinoma-Hook effect

Large nonfunctioning adenoma-stalk effect

Diagnosis


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Etiology of hyperprolactinemiaPhysiologic Breast stimulation

Exercise

Lactation

Pregnancy

Sleep

Stress

Pharmacological Anesthetics

Anticonvulsant

Antidepressants

Antihistamines (H2) Antihypertensives

Cholinergic agonist

Drug-induced hypersecretion

Catecholamine depletor

Dopamine receptor blockers

Dopamine synthesis inhibitor

Estrogens: oral contraceptives

Neuroleptics/antipsychotics

Neuropeptides

Opiates and opiate antagonists


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Etiology of hyperprolactinemiaHypothalamic-pituitary stalk

damage Granulomas

Infiltrations

Irradiation Rathkes cyst

Trauma: pituitary stalk section,suprasellar surgery

Tumors: craniopharyngioma,germinoma,

hypothalamic metastases,meningioma, suprasellarpituitary mass extension

Pituitary

Acromegaly

Idiopathic lymphocytic

hypophysitis Parasellar mass

Macroadenoma (compressive)

Macroprolactinemia

Plurihormonal adenoma

Prolactinoma

Surgery

Trauma


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Etiology of hyperprolactinemiaSystemic disorders

Chestneurogenic chestwall trauma, surgery, herpes

zoster Chronic renal failure

Cirrhosis

Cranial radiation

Epileptic seizures Polycystic ovarian disease

Pseudocyesis

Primary hypothyroidism


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Etiology of hyperprolactinemiaRecommendation 2.1

We recommend excluding medication use,

renal failure, hypothyroidism, and parasellar

tumors in patients with symptomatic

nonphysiological hyperprolactinemia


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Management Drug-induced hyperprolactinemia

Prolactinoma

Resistant prolactinoma Prolactinoma in pregnancy


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Drug-induced hyperprolactinemia

Recommendation3.1

In a symptomatic patient with suspected druginduced hyperprolactinemia,

Discontinuation of the medication for 3 days orsubstitution of an alternative drug, followed byremeasurement of serum prolactin

Discontinuation or substitution of an antipsychotic agent should not beundertaken without consulting the patients physician


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Drug-induced hyperprolactinemia If the drug cannot be discontinued and

onset of the hyperprolactinemia does notcoincide with therapy initiation

We recommend a pituitary magneticresonance image (MRI) to differentiatebetween Medication-induced hyperprolactinemia Hypothalamic - pituitary mass


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Neuroleptics/antipsychotic agents are the

ones most common cause

Prolactin levels ranging from 25-100 g/liter

metoclopramide, risperidone, phenothiazines

prolactin levels >200 g/liter

The mechanism is the dopamine antagonisteffect of these medications



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Drug-induced hyperprolactinemiaRecommendation 3.2

Not treat asymptomatic patients

Suggest the use of estrogen or testosterone in

patients with long-term hypogonadism

(hypogonadal symptoms or low bone mass)


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Drug-induced hyperprolactinemiaRecommendation3.3

First step is to stop the drug, if this is not

possible, a drug with a similar action that does

not cause hyperprolactinemia should be

substituted, if this is not feasible

we suggest considering the cautious

administration of a dopamine agonist inconsultation with the patients physician


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Treat a patient who has antipsychotic induced

hyperprolactinemia with a dopamine agonist

remains controversial

May lead to exacerbation of the underlyingpsychosis



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Management of ProlactinomaRecommendation 4.1

For patients harboring symptomatic prolactin-secretingmicroadenomas or macroadenomas. We recommenddopamine agonisttherapy to

lower prolactin levels, decrease tumor size,

restore gonadal function

Using cabergoline in preference to other dopamineagonists because it has higher efficacy in normalizing prolactin levels,

a higher frequency of pituitary tumor shrinkage


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The proportions (median; range) of patients with

improved outcomes are:

reduction in tumor size (62%; 20100%)

resolution of visual field defects (67%; 33100%),

resolution of amenorrhea (78%;40100%),

resolution of infertility (53%; 10100%),

improvement of sexual function (67%; 6100%), resolution of galactorrhea (86%; 33100%), and

normalization of prolactin level (68%; 40100%).

Management of Prolactinoma


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It is unclear why cabergoline is more effective than bromocriptine,

Cabergoline

has a higher affinity for dopamine receptor

incidence of unpleasant side effects is lower, increase drug

compliance

No clinical trials have directly compared the mass-reducing effects ofdifferent dopamine agonists.

Nevertheless, results of various studies indicate that Bromocriptine decreases pituitary tumor size by approximately 50% in

two thirds of patients,

90% decrease with cabergoline.



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Dopamine agonist therapy, follow-up includes

1) Periodic prolactin level starting 1 monthafter therapy

2) Repeat MRI in 1 yr

In 3 months in patients with macroprolactinoma

if prolactin levels continue to rise while patient is receivingdopaminergic agents

if new symptoms

3) Visual field examinations

4) Assessment and management of comorbidities



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Not treat asymptomatic patients harboring

microprolactinomas with dopamine agonists

Patients with amenorrhea caused by a

microadenoma, treatment with

dopamine agonist or

oral contraceptive


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Microadenomas rarely grow

No controlled trials have compared these two

options, dopamine agonist or oral contraceptive Oral contraceptives are less expensive and have

fewer side effects

Patients treated with oral contraceptives and

estrogen/progesterone replacement for 2 yr have notshown an increase in tumor size



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We suggest that with careful clinical and

biochemical follow-up

Therapy may be tapered and perhaps

discontinued in patients who have been treated

with dopamine agonists for at least 2 yr

Who no longer have elevated serum prolactin,and who have no visible tumor remnant on MRI


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The risk of recurrence after withdrawal ranges from 26to 69%

All studies have shown that recurrence is predicted by

prolactin levels at diagnosis and by tumor size. Recurrences are most likely to occur in the year after

withdrawal

A study the risk of recurrence was 18% per millimeter

of tumor mass Up to 28% of such patients may develop hypogonadism

suggesting the need for long-term surveillance andtreatment of these patients.



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Dopamine agonists have been tapered ordiscontinued, follow-up includes:

1) serum prolactin levels every 3 months for the first

year and then annually thereafter

2) MRI if prolactin increases above normal levels

In women with microprolactinomas, it may bepossible to discontinue dopaminergic therapywhen menopause occurs.



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Resistant ProlactinomaRecommendation 5.1

Symptomatic patients who do not achieve

normal prolactin levels or show significant

reduction in tumor size on standard doses of adopamine agonist

We recommend that the dose be increased to

maximal tolerable doses before referring thepatient for surgery


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dopamine agonist resistance includes

failure to achieve a normal prolactin level on

maximally tolerated doses of dopamine agonist

failure to achieve a 50% reduction in tumor size

failure to restore fertility in patients receivingstandard doses of dopamine agonist

Resistant Prolactinoma


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Mechanism of dopamine agonist resistance is notcompletely understood.

There is a decreased number of D 2 receptorsexpressed on resistant prolactinomas but this finding isnot invariable

Dopamine receptor binding is normal, and nodopamine receptor mutation has been identified inprolactinomas.

D2 receptor isoform ratios may differ, and molecularalterations may occur downstream of the D 2 receptor

Different mechanisms underlie dopamine agonistresistance in prolactinomas



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Caution with use of high-dose cabergolinethe potential risk of cardiac valvular regurgitation.

Patients with Parkinsons disease receiving at least 3 mg ofcabergoline daily are at risk for moderate to severe cardiac valve

regurgitation

In contrast, six of seven studies analyzing cardiac valves in over 500patients with prolactinomas receiving standard doses ofcabergoline

->shown no evidence of clinically significant valvular disease

The one study that did report a 57% incidence of tricuspidregurgitation in patients treated with cabergoline also notedsignificant tricuspid regurgitation in the control group



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Dose increases should be step wise and

guided by prolactin levels.

In patients receiving high doses for prolongedperiods, echocardiography may be necessary

to assess for valvular abnormalities.

Patients receiving typical doses of cabergoline(12 mg/wk) likely will not require regularechocardiographic screening



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We recommend that patients resistant to

bromocriptine be switched to cabergoline


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Clinicians offer transsphenoidal surgery tosymptomatic patients with prolactinomas who cannot tolerate high doses of cabergoline

not responsive to dopamine agonist therapy.

For patients who are intolerant of oralbromocriptine, intravaginal administration maybe attempted.

For patients who fail surgical treatment or whoharbor aggressive or malignant prolactinomas,we suggest radiation therapy


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In patients with malignant prolactinomas, wesuggest temozolomide therapy


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A malignant prolactinoma is defined as one that exhibitsmetastatic spread within or outside the central nervoussystem

Treatment of malignant tumors is difficult, and survival isusually approximately 1 yr

Surgery may be necessary to diminish the compressiveeffects

Chemotherapy has been used with little effect

Temozolomide , an alkylating agent

reduce prolactin levels and control tumor growth

if tumor specimens do not express methylguanine-DNAmethyltransferase



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Prolactinoma during pregnancyRecommendation 6.1

We recommend that women with

prolactinomas be instructed to discontinue

dopamine agonist therapy as soon as theydiscover that they are pregnant


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In selected patients with macroadenomas

who become pregnant on dopaminergic

therapy and who have not had prior surgical

or radiation therapy,

Continue dopaminergic therapy throughout

the pregnancy, especially if the tumor is

invasive or is abutting the optic chiasm

Prolactinoma during pregnancy


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Bromocriptine crosses the placenta

In the more than 6000 pregnancies achieved and

reported in women taking bromocriptine the

incidence of congenital malformations orabortions was not increased

Cabergoline also appears to be safe when

used to treat infertility in women withhyperprolactinemia, but there is far lesspublished experience with this drug



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In pregnant patients with prolactinomas,

we recommend against performing serum

prolactin measurements during pregnancy


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We recommend against the use of routine

pituitary MRI during pregnancy in patients

with microadenomas or intrasellar

macroadenomas unless

There is clinical evidence for tumor growth such

as visual field compromise


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Microadenomas the risk of symptomatic tumor growth is so low

pregnant patients may be followed by clinical examination duringeach trimester.

Macroadenomas-tomor growth is much higher patients who had undergone debulking, pituitary surgery pituitary

irradiation before pregnancy, the risk of symptomatic growth was only2.8%

macroadenoma who did not undergo surgery or irradiation beforepregnancy, the risk of symptomatic pituitary tumor enlargement was

31%

The onset of new or worsening headache, or a change in vision,

urgent performance of formal visual field testing

pituitary MRI without the use of gadolinium



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We recommend that women withmacroprolactinomas who

do not experience pituitary tumor shrinkageduring dopamine agonist therapy

cannot tolerate bromocriptine or cabergoline

Be counseled regarding the potential benefitsof surgical resection before attemptingpregnancy


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We recommend formal visual field assessment

followed by MRI without gadolinium in

pregnant women with prolactinomas whoexperience severe headaches and/or visualfield changes


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We recommend bromocriptine therapy in

patients who experience symptomatic growth

of a prolactinoma during pregnancy


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Thank you for your attention


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