Hyperprolactinemia: N hidshi i MD. Nahid Shirazian MD. Internist, Endocrinologist
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1 Diagnosis and Treatment of Hyperprolactinemia: p N hidshi i MD Nahid Shirazian MD. Internist, Endocrinologist
2 An Endocrine Society Clinical Practice Guideline (J Clin Endocrinol Metab 96: , 2011) Strong recommendations use phrase we recommend & number 1 Weak recommendations use the phrase we suggest & number 2. Cross filled circlesindicate indicate quality of the evidence: denotes very low quality evidence;,, low quality;, moderate quality;, high quality. 2
3 Prolactin synthesis & secretion by pituitary lactotroph cells Prolactin acts to induce & maintain lactation of the primed breast. 3
4 Regulation of PRL Cycle
5 Regulation of hypothalamic pituitary prolactin axis predominant effect of hypothalamus is inhibitory, that mediate principally i by tuberohypophyseal h dopaminergic neuron system & dopamine D2 receptors on lactotrophs. dopamine neurons; stimulated by acetylcholine (ACh) & glutamate inhibited by histamine & opioid peptides.
6 Regulation of hypothalamic pituitary prolactin axis One or more prolactin releasing factors (PRFs) probably mediateacuterelease acute of PRL (e.g., in suckling, during stress). There are several candidate PRFs; thyrotropin releasing hormone (TRH), vasoactive intestinal polypeptide (VIP), oxytocin. PRF neurons are activated by serotonin (5 HT). Estrogen sensitizes pituitary to release PRL.
7 Regulation of hypothalamic pituitary prolactin axis ultra short loop feedback; Prolactin on pituitary regulate its own secretion Prolactinalso also influences gonadotropinsecretion by suppressing release of luteinizing hormone releasing hormone (LHRH). Short loop feedback; mediated indirectly by PRL receptor regulation of hypothalamic dopamine synthesis, secretion, & turnover. CNS, central nervous system; GABA, γ aminobutyric acid.
8
9 prolactin levels in women prolactin levels in men 25 µg/l~ ng/ml 20 µg/l~ ng/ml
10 To establish diagnosis of hyperprolactinemia, we recommend a single measurement of serum prolactin; A level above upper limit of normal confirms diagnosis as long as serum sample was obtained without excessive venipuncture stress. We recommend against dynamic testing of prolactin secretion for diagnosis of hyperprolactinemia p (1 ). 10
11 Dynamic tests t of prolactin secretion using; TRH, L dopa, nomifensine, i Domperidone are not superior to measuring a single serum prolactin sample for diagnosis of hyperprolactinemia. 11
12 Men & non pregnant women will normally have only small amounts of prolactin in their blood. Prolactin levels do, however, need to be evaluated based on the time of day that they are collected. The levels will vary over a 24 hour period, rising during sleep & peaking in morning. Ideally, a person's blood sample should usually be Ideally, a person s blood sample should usually be drawn shortly after waking, preferably after person has been resting quietly for 30 minutes, although a doctor may have his own reasons for doing them at other times.
13 Initial determination of serum prolactin should avoid excessive venipuncture stress & can be drawn at any time of day. When in doubt, sampling can be repeated on a different day at 15 to 20 min intervals to account for possible prolactin pulsatility.
14 Causes of hyperprolactinemia p Serri, O. et al. CMAJ 2003;169: Copyright 2003 Canadian Medical Association or its licensors
15
16
17 Cause of hyperprolactinemia 1. Physiologic hypersecretion Pregnancy Lactation Chest wall stimulation Sleep Stress 2. Pituitary hypersecretion Prolactinoma Acromegaly 3. Systemic disorders Chronicrenal renal failure Hypothyroidism Cirrhosis Epileptic seizures 4. Drug induced hypersecretion 5. Hypothalamic pituitary stalk damage Tumors Craniopharyngioma Suprasellar pituitary mass extension Meningioma Dysgerminoma Metastases Empty sella Lymphocytic hypophysitis Adenoma with stalk compression Granulomas Irradiation Trauma Pituitary stalk section Suprasellar surgery
18 Serum prolactin concentrations increase during pregnancy
19 Serum prolacin & suckling
20 Ranges of serum prolactin concentrations in several causes of hyperprolactinemia p
21 We recommend excluding; medication use, renal failure, hypothyroidism, & parasellar tumors in patients with symptomatic nonphysiological hyperprolactinemia (1 ). 21
22 Prolactin level > 500 g/lit is diagnostic of a macroprolactinoma. Although a prolactin level > 250 g/lit usually indicates presence of prolactinoma, selected drugs, including risperidone id & metoclopramide, may cause prolactin elevations > 200g/lit in patients without evidence of adenoma. Even minimal prolactin elevations may be consistent with presence of a prolactinoma, but a non prolactin secreting mass should first be considered. d 22
23 Partial list of drugs known to cause hyperprolactin emia and/or galactorrhea
24 Symptom of Hyperprolactinemie hypogonadism, low LH, low FSH, low stradiol infertility, oligomenorrhea, amenorrhea less often by galactorrhea. Low BMD
25 Men hypogonadotropic hypogonadism in men, decreased libido, decreased energy & libido, decreased muscle mass, body hair, osteoporosis. impotence, infertility, gynecomastia, rarely galactorrhea Erectile dysfunction
26 Case 1 female, 26y amenorrhea. LMP; 3 months ago, 3 home pregnancy tests ; negative. Takes no medications. Menarche ; age 12 years, menstrual cycles regular until 3 months ago. Weekly headaches, Occasional induced galactorrhea. Physical examination; normal. Serum prolactin level; 1665 ng/ml(1665 mg/l) Which of the following is the most likely cause of this patient's hyperprolactinemia? A P A. Pregnancy B. Cirrhosis C. Primary hypothyroid D. Prolactin producing pituitary tumor
27
28 Tumor size correlates positively with serum PRL levels PRL level > 100 ng/ml is strongly indicative of a PRL-secreting pituitary tumor
29
30 Adenomas <1 cm Adenomas1 2 cm Adenomas>2 cm below 200 ng/ml ng/ml above 1000 ng/ml
31 A "giant" prolactinoma
32 Case 2 Female 45y, Headache Lab: prolactin 56 ng/ml, E2 < 10 pg/ml, FSH 8.3 miu/ml, LH 2.8 miu/ml, T4 5.54, TSH 2.57 uiu/ml, Cortisol 8 AM 7.49 ug/dl next step?
33 CT scan of brain: Sphenoid sinus mass (2 cm) R/o pituitary i tumor with ihintra sinus i extension
34 Diagnosis of Prolactinomas Prolactin is secreted episodically Nonsecreting tumor causing modest prolactin elevations (usually < 150 ng/ml) Prolactin secreting macroadenoma (prolactin levels l usually > 250 ng/ml) MRI with gadolinium enhancement
35 If tumor size not correlation with serum PRL levels : 1. Hook effect 2. Necrosis or cystic of tumor 3. Mass effect (other adenoma) 4. IGF-1
36 two site immunoradiometric assay
37 Hook Effect In immunometric assays, it is also important that a large excess of capture antibody be used. As the antigen concentration approaches the effective binding capacity of the capture antibody system, the signal no longer increases. If the antigen concentration exceeds binding capacity of capture antibody, the signal may actually decrease.
38 second (signaling) antibody binds directly to excess prolactin remaining in solution &, therefore, is less available to prolactin already bound to first (coupling) antibody. the assay should be repeated after a 1:100 serum sample dilution to overcome a potential hook effect. We recommend that this artifact be excluded in patients who have pituitary macroadenomas & apparently normal or mildly elevated prolactin levels. 38
39 Hook Effecct;
40 Hook Effect This is a potentially dangerous phenomenon, because the same values might be measured with very high & lower concentrations. 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 ). (1 ). If measured value for diluted specimen is higher than original result, a high dose hook effect probably is present.
41 Hook Effect Mostmanufacturers are aware of thispotential problem & configure assays with relatively large amounts of capture antibody; however, some patients produce high concentrations of hormones or antigens that may exceed assay limits. Laboratories can detect this phenomenon by analyzing specimens at 2 dilutions, but this practice generally is not cost effective. Therefore, feedback to laboratory about results that are inconsistent with clinical findings is essential.
42 Goals of therapy The goals of therapy are : to normalize prolactin, to restore fertility, to reduce tumor size, to ameliorate the symptoms of hypogonadism. All patients with macroadenomas & most patients with microprolactinoma require treatment.
43 Prolactinoma prolactinomas are more amenable to pharmacologic treatment than any other kind of pituitary adenoma because of availability of dopamine agonists, decrease both secretion & size of these tumors.
44 Shrinkage of prolactinoma after bromocriptine
45
46
47 Pharmacological options: Dopamine agonist 1. Bromocriptine 2. Cabergoline 3. Pergolide 4. Quinoglide l l l l Normalize prolactin levels. Reduce the volume of the tumor.
48 In all cases, treatment with any dopamine agonist should use lowest dose & shortest duration possible.
49 Big & Big Big Prolactin: 85% of circulating prolactin is monomeric (23.5 kda), serum also contains a covalently bound dimer (polimerization), big prolactin, a much larger polymeric form(tetramer), big big prolactin. Antiprolactin autoantibodies may also be associated with macroprolactinemia. 49
50
51 Big & Big Big Prolactin: macroprolactinemia denotes situation in which a preponderance of the circulating prolactin consists of these larger molecules. These polymers have a lower bioactivity & slower clearance than monomeric form.
52 In patients with asymptomatic hyperprolactinemia, we suggest assessing for macroprolactin (2 ). 52
53 Big & Big Big Prolactin: Retrospective analyses of patients with hyperprolactinemia ; ~ 40% have macroprolactinemia. a smaller proportion of patients with ihmacroprolactinemia i has signs & symptoms of hyperprolactinemia, galactorrhea is present in 20%, oligo/amenorrhea in 45%, & pituitary i adenomas in 20%. 53
54 Big & Big Big Prolactin: Polyethylene y gy glycol precipitation p is an inexpensive way to detect presence of macroprolactin in serum. 54
55 macroprolactin High concentrations of polyethylene glycol (PEG) precipitate macroprolactin fromserum serum. Mean recovery of PRL from serum containing only monomeric PRL was 86% (range, %). 106%) Macroprolactin can be detected by low PRL recovery after precipitation with PEG, & recovery allows an estimate of monomeric PRL. A cutoff of 50% has been used and validated with the Delfia assay to identify presence of macroprolactin.
56 Thanks For Your Attentionti
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