Neue Aspekte in Diagnostik und Therapie der Hyperprolaktinämie

Prof. Dr. L. Wildt

Klinik für Gynäkologische Endokrinologie und Reproduktionsmedizin

Medizinische Universität Innsbruck

Hormonell - Aktuell Zypern 2008

Diagnosis, Symptoms and Aetiology of

Hyperprolactinaemia

Prolaktin/Laktotropin

Struktur• 199 AS - MG 23kD

Verwandtschaft• GH & hpL

Bildungsorte• Hypophysenvorderlappen• Endometrium• Dezidua (in der SS)• Lymphozyten

What is prolactin?• Monomeric peptide

hormone1 – 23 kDa (199 residues)– Closely related to

growth hormone and placental lactogen

• Secreted from lactotrophs in the anterior pituitary2

• Produced by Endometrium,

Decidua...

• Main role to promote milk secretion2

1From Li CH. In Greep RO (ed): Handbook of Physiology IV, part 2. Baltimore, Williams & Wilkins, 1974.

2Freeman et al. Physiol Rev 2000; 80(4): 1523–1631.

0

100

200

300

400

500

600

1 2 3 4 5 6 7 8 9 10 11 12

Fraction

Pro

lac

tin

(m

UI/

L)

23 kD

50 kD

170 kD

Monomeric prolactin demonstrated by column chromatography

HypothalamusNo dopamine

released

Pituitary lactotroph

HypothalamusDopamine released

Pituitary lactotroph

Prolactin released Prolactin inhibited

Prolactin released into bloodTargets mammary glands to

produce milk

GnRH TRH+ +

+

Prolactin release inhibited

+

Dopamine inhibits

the release of prolactin

D2 receptor

Role of Dopamine

Measurement of prolactin levels

• Avoid circadian increase

• Rule out use of drugs

• Minimise stress

• Avoid nipple stimulation

Prolactin at 0 minutes (μg/L)

Pro

lac

tin

at

30 m

inu

tes

(μg

/L) Time at which sample was taken (hours)

Pro

lac

tin

(μ

g/L

)

What is hyperprolactinaemia?

• Hyperprolactinaemia is an abnormally high level of prolactin in the blood:– Mild–moderate 26–100 μg/L– Severe >100 μg/L (Suspicious for

Prolaktinoma)

• Normal levels of prolactin in the blood:– 10–25 µg/L (women when not pregnant or

lactating)– 5–10 µg/L (men)

Rule out macroprolactinaemia• Prolactin molecules

can aggregate on non-specific antibodies (Defined as Macroprolactin)

• Macroprolactin is an inactive form of prolactin

• Column chromatography or polyethylene glycol precipitation can identify macroprolactin

• 30 % of cases. Does not require treatment

Column chromatography of prolactin molecules in four women

Fraction

Fraction

Fraction

Fraction

Pro

lac

tin

(μ

g/L

)

Pro

lac

tin

(μ

g/L

)

Pro

lac

tin

(μ

g/L

)

Pro

lac

tin

(μ

g/L

)

Monomeric

Rodriguez Espinosa et al. Gestion del laboratorio clínico MAPFRE Ed. Madrid 2000.

Macro-prolactinaemia

Monomericand

macro

Macroand

monomeric

Hyperprolactinaemia is common in women with reproductive disorders

Molitch ME and Reichlin S. Adv Intern Med 1980; 26: 37–65.

25.8%

74.2%

Galactorrhoea only

Normal prolactin levels

Hyperprolactinaemia

Amenorrhoea plus galactorrhoea

22.5%

77.5%

87.2%

12.8%

Amenorrhoea only

Effect of prolactin levels on menstruation

0

20

40

60

80

100

120

140

Normal cycle Irregular cycles Amenorrhoea

Pro

lact

in (

ng

/mL

)

*

*Upper limit has not been determined and may exceed 140 ng/mL prolactin

Aetiology of hyperprolactinaemia• Physiological1

– Pregnancy– Lactation– Stress, sleep,

exercise• Pituitary disorders

– Pituitary tumours2

– Acromegaly3

• Hypothalamic disorders – Primary

hypothyroidism3

• Medication4, 5 – Anti-psychotics– Anti-emetics– Anti-hypertensives

• Other – Macroprolactinaemia6 – Chest wall injuries7

– Renal or liver failure7

1Freeman et al. Physiol Rev 2000; 80(4): 1523–1631; 2Mah and Webster. Semin Reprod Med 2002; 20(4): 365–374; 3Asa and Ezzat. Nat Rev Cancer 2002; 2(11): 836–849; 4Marken et al. Clin Pharm 1992; 11(10): 851–856; 5Verhelst and Abs. Treat Endocrinol 2003; 2(1): 23–32; 6Yuen et al. Hong Kong Med J 2003; 9(2): 119–121; 7Serri et al. CMAJ 2003; 169(6): 575–581.

Prolactinomas

• Prolactinomas1,2

– Most frequent cause of persistent hyperprolactinaemia (~50%)

– Primarily benign

– Account for 25–30% of functional pituitary tumours

– <10 mm microprolactinomas

– ≥10 mm macroprolactinomas

1Mah and Webster. Semin Reprod Med 2002; 20(4): 365–374. 2Asa and Ezzat. Nat Rev Cancer 2002; 2(11): 836–849. Figure: http://www.mja.com.au/public/issues/180_08_190404/hur10511_fm-3.gif

OC=optic chiasm; arrow pointsto prolactinoma

Prolactinoma in the pituitary

Symptoms associated with hyperprolactinaemia

• Reproductive function symptoms1

– Premenopausal women • Hypogonadism (infertility,

irregular menstruation, oligomenorrhoea, amenorrhoea)

• Decreased libido

– Postmenopausal women • Disappearance/absence of

hot flushes

– Men2

• Decreased libido• Impotence• Infertility

• General symptoms– Galactorrhoea1

– Osteoporosis3

– Significant weight gain (up to 22 kg)

• Pressure symptoms– Headaches

– Visual field defects

– External ophthalmoplegia

– Hydrocephalus (rare)

1 Luciano. J Reprod Med 1999; 444(12 Suppl): 1085–1090.

2 Serri et al. CMAJ 2003; 169(6): 575–581.3 Vartej et al. Gynecol Endocrinol 2001; 15(1): 43–47.

HyperprolactinemicHypothalamic

Differential Diagnosis of Anovulation

FSH LH

LH/FSH-Ratio

Prolactin

TestosteroneSHBG/FAI

DHEAS

elevated elevatedelevated

Primary

normal

Hyperandrogenemic

PRL-Bestimmung

>100 ng/ml

andere Ursachen ausgeschlossen

(Med., Schwangersch. u.a.)

Wert bei Kontrollebestätigt

Weitere Diagnostik und Festlegungder Therapie durch Spezialisten

Klinischer Verdacht auf ein Prolaktinom

normal

Prolaktinomausgeschlossen

MRT der Hypophyse

erhöht, aber <100 ng/ml

Diagnosis• Measurement of serum prolactin levels

– Normal levels in women=10–25 ng/ml– Hyperprolactinaemia

• Mild–moderate 26–100 ng/ml• Severe >100 ng/ml (Suspicious for Prolaktinoma)

• Rule out macroprolactinaemia• Rule out hyperandrogenemia/PCO

(frequently associated with Prolactin levels 26-60 ng/ml)

Medical history/clinical examination• Blood biochemistry (including pregnancy and renal

and thyroid function tests TSH) • Magnetic resonance imaging (MRI) of pituitary and

hypothalamic region

Importance & prevalence of hyperprolactinaemia

Etiology of Anovulation in Infertile patients N= 1000

Hyperandro-

genemia

Hypothalamic

Hyperprolactinemia

Primary

45 %

34 %

12 %

9 %

Hyperprolactinaemia is a common endocrine disorder

• The prevalence of hyperprolactinaemia is difficult to establish:– Not all sufferers are symptomatic or undergo

diagnosis

• Estimates of prevalence1 in different populations:– Unselected normal population: ~0.4% – Family planning clinic population: 5% – Women with reproductive disorders: up to 17%

1Biller et al. J Reprod Med 1999; 44:1075–1084.

Therapy of Hyperprolactinemia Pharmacotherapy:Dopamine Agonists

Bromocriptine Quinagolide Cabergoline

First-line therapies for the treatment of hyperprolactinaemia

Non-ergot derived selective D2-type DA

receptor agonist

Ergot derived, non-specific DA receptor agonist/antagonist

Ergot derived selective D2-type

DA receptor agonist

Oldest; least well tolerated

2nd generation; better tolerated and more effective than bromocriptine

Lisuride

Ergot derived, non-specific DA receptor

activity

Better tolerated than Bromocriptine

Licensed Indications

• NORPROLAC Hyperprolactinaemia (idiopathic or due to prolactinoma)

• Dostinex Hyperprolactinaemia (idiopathic or due to prolactinoma), related disorders

• Parlodel Hyperprolactinaemia, acromegaly

Parkinson’s disease• Dopergin: Hyperprolactinemia,

Parkinsons`disease

Pharmacotherapy – potential complications

• Treatment intolerance

• Treatment resistance

• Recurrence following treatment withdrawal

• Pregnancy

• Compliance

• Severe Side effects

Side effects of antidopaminergic drugs for

treatment of Hyperprolactinemia • Minor side effects(Frequency similar, but severity different for all dopaminergic drugs)

NauseaVomitingConstipationLow blood pressureFatigueInsomnia

Minor side effects are dose dependent,

Resistance to treatment

• Defined as no normalization of Prolactin levels within 6-8 Weeks (functional hyperprolactinemia or Adenoma)

• Occurs in 10 – 20 % of patients.

• Our own data in 850 Patients treated since 1980 show: 15 % primary resistance to Bromocriptine (n=400)

10 % primary resistance to cabergoline (n= 150)

15 % primary resistance to lisuride (Dopergin) (n=100)

5 % primary resistance to quinagolide (n= 200)

up to 5 % of patients are resistant to all dopamine-agonistsMattle und Wildt, in prep.

Recurrence rate after discontinuation of Cabergoline therapy

Colao et al 2003

200 Patients

Inclusion criteria: normalized Prolactin, no tumor or Tumorreduction > 50%, Distance Chiasma opt. > 5 mm, no invasion

Recurrence within 2 – 5 years after discontinuation

Functional Hyperprolactinemia: 24 %

Microprolactinoma: 31 %

Macroprolactinoma: 36 %

Treatment during pregnancy I • Bromocriptine:

– Not associated with detrimental effects on pregnancy or foetal development1

– Treatment suspension recommended upon confirmation of pregnancy• Quinagolide:

– Indicated for use until pregnancy confirmed– No tetarogenic effects during early pregnancy reported (limited data)2, 3

• Cabergoline: – Not approved for use during pregnancy (limited data)– Recommended to cease treatment ≥1 month prior to conception– Repeated pregnancy tests are recommended– Not associated with detrimental effects4

1Weil. Curr Med Res Opin 1986; 10(3): 172–195; 2Disarno et al. J Clin Endocrinol & Metab 2001; 86(11): 5256–5261; 3Schultz et al. Pituitary 2000; 3(4): 239–249; 4Robert et al. Reprod Toxicol 1996; 10(4): 333–367.

Treatment during pregnancy II • When pregnancy is confirmed treatment should be discontinued in cases

of functional hyperprolactinemia. However, treatment during early pregnancy may reduce abortion rate

• In case of pituitary adenomas, treatment can be either continued or discontinued. The choice has to be an individualized decision made by the physician and the informed patients.

• In case of macroprolactinomas, we recommend visual field examination each trimester and MRT once or twice.

• We encourage lactation and breastfeeding, even in the case of makroprolaktinomas under controlled conditions (i.e regular visual field examination and MRT)

Side effects of antidopaminergic drugs for

treatment of Hyperprolactinemia • Minor side effects(Frequency similar, but severity different for all dopaminergic drugs)

NauseaVomitingConstipationLow blood pressureFatigueInsomnia

• Major side effects(only with ergot-derivatives, not observed for quinagolide)

Pulmonary FibrosisElevated LiverenzymesMania, psychiatric symtomsVasoconstrictionRaynauds Disease (Vaskular constriction may be observed in ~20% of patients)ThrombocytosisInterstitial pneumonitisgastrointestinal bleeding„Leaky heart“ syndrome

Minor side effects are dose dependent, major side effects appear to be independent on dose

Risk for valvulopathy

moderate or severe grades

Pergolide 23%

Cabergoline 29%

Control 6%

Alternate therapies: Surgery

(Pituitary Adenomas)Pulsatile GnRH

Naltrexone

Surgery1

• For pharmacotherapy-resistant prolactinomas

• Consideration should be made for surgery-associated complications including1:– Pituitary deficiency– Visual disturbance– Mortality

• Recurrence can occur following surgery (30-60 %)

1Serri et al. CMAJ 2003; 169(6): 575–581.

Transsphenoidal Resection of Prolactinoma

• Microadenoma

72 %

17 %

60 %

.27%

.4 %

• Macroadenoma

30 %

20 %

25 %

0.9 %

6.9%

Instant Normalization of Prolactin

Recurrence

Long term normalization

Mortality

Morbidity

Radiotherapy1

• Considered if pharmacotherapy and surgery fail• Conventional radiotherapy can induce

hypopituitarism• In comparison, gamma-knife (GKS) and focal

radiation surgeries:– Deliver higher radiation doses– Reduce radiation exposure outside the target area– Are more effective in a single session

1Tsang et al. Radiother Oncol 1996; 41(1): 45–53.

Summary

• Hyperprolactinemia is a frequent cause of ovarian insufficiency and infertility• It is caused in ~ 50 % by tumors, 50 % are functional.• Treatment is primarily medical • For medical treatment, mainly Bromocriptine, Cabergoline, Lisuride and

Quinagolide are used. • Bromocriptine therapy has been widely abandonned, mainly because of side

effects. • Cabergoline therapy is effective in normalization of Prolactin –levels, but

compliance may give problems when used for long-time treatment. It has to be discontinued 4 weeks befor pregancy is attempted. It may have severe side effects

• The advantages of treatment with quinagolide consist in the excellent effectiveness and good tolerabilty, the daily dosage regime, its licensed use until the dignosis of pregnancy and the lack of ergot-related side effects.

Prolaktinom Therapie

Medikamente

Operation

Bestrahlung