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Hyperprolactinemia

Prolactin ( PRL ) is a polypeptide hormone-containing 198 amino acids and with a molecular weight of 22kDa. Hyperprolactinemia is elevated serum PRL.

Women → 500 milliunits/ L or < 25 micrograms /L
Men → 400 milliunits / L or 20 micrograms / L

Prolactin levels of over 3000 mII/L suggest the presence of a Prolactinoma.

PRL is synthesized and secreted by lactotroph cells in the anterior pituitary Also secreted by various extra pituitary tissues including several brain regions, lymphocytes, mammary epithelial cells, tumours, decidua, myometrium, lacrimal glands, thymus and the spleen Secretion is pulsatile → levels fluctuate throughout the day and the menstrual cycle Unique hormone – predominantly negative mode of regulation by the hypothalamus
○ no hypothalamus derived releasing hormone
○ controlled by the inhibitory effect of DOPAMINE released from the hypothalamus Acts to induce and maintain lactation of the primed breast ( Mammogenic & lactogenic ) Nonpeurperal hyperprolactinemia is caused by lactotroph adenomas → PROLACTINOMA. Prolactinomas account for 40 % of all pituitary tumours

Causes- physiological Coitus Exercise Lactation Pregnancy Sleep Stress. Pathological- Granulomas Infiltration Irradiation Rathke’s cyst Trauma
○ pituitary stalk section
○ suprasellar surgery Tumours
○ craniopharyngioma
○ germinoma
○ hypothalamic metasteses
○ meningioma
○ suprasellar pituitary mass Acromegaly Idiopathic Lymphocytic hypophysitis of parasellar mass Macroadenoma Macroprolactinemia Plurihormonal adenoma Prolactinoma Surgery Trauma Chest- neurogenic wall trauma , surgery , herpes zoster Chronic renal failure Cirrhosis Primary hypothyroidism Cranial radiation Epileptic seizures PCOS Multiple endocrine neoplasia. drug related- Antipsychotics 
○ phenothiazines
○ thioxanthenes
○ butyrophenones
○ atypical antipsychotics

Usually < 100 mcgm/L
Dose dependent
At the start of treatment
Highest with amisulpride and risperidone
 Drugs that block dopamine receptors
○ metoclopramide
○ domperidone
○ risperidone
○ tricylcic antidepressants
○ cimetidine
 Interfere with synthesis and storage of Dopamine
○ methyldopa
○ MAOIs
 Anti-depressants- SSRIs , nefazodone , bupropion , venlafaxine
 Opiates , opiate antagonists and cocaine
 Antihypertensives
○ verapamil
○ methyldopa
 Estrogen – Oral contraceptives
Oral contraceptive withdrawal
 Prolactinomas are the
 commonest functioning
 pituitary tumour. Vast majority 
are less than 10 mm – Microprolactinoma

Presentation- Females ↑ PRL can cause disorders of gonadotrophin sex steroid function – result
○ menstrual cycle derangement ( oligomenorrhoea and amenorrhoea , anovulation )
○ sexual dysfunction
○ inappropriate lactation or glactorrhoea
○ ↓↓ libido , hirsuitism 

Post-menopausal women –> Galactorrhoea less common due to lack of oestrogen 
Osteopenia and Osteoporosis , hirsuitism and acne
 Males ↑ PRL causes secondary hypogonadism and infertility by suppression of GnRH pulses and a ↓↓ in LH and FSH levels
○ patients may have low or normal testosterone levels
○ abnormal sperm counts and morphology
○ diminished libido and impotence
○ galactorrhoea , gynaecomastia , ↓↓ bone density Macroadenoma -Headache and visual field defect
○ only when macroadenomas with suprasellar extension impinge on optic chiasm
○ bitemporal hemianopia or upper temporal quadrantanopia Hypopituitarism Cranial nerve palsy ( invasion of cavernous sinus ) Rarely CSF leak or secondary meningitis Serum PRL > 4000 U/L is diagnostic of a macroprolactinoma Drug related -Usually only mild to moderate elevation in PRL Risperidone and metoclopramide can cause more than mild elevations Neuroleptics / Antipsychotic medications are the commonest cause If possible discontinue or substitute the medication and recheck in 3 Days Discuss first with Psychiatry team/Prescribing consultant – before considering changing/ discontinuing medications

History and Physical examination Medications incl excess alcohol Family history Further testing
○ LFT and PT 
○ U/E
○ TFT
 Pregnancy test
Consider testosterone , FSH, LH ( in men as well )
 Macroprolactin – usually excluded by all labs considering asking if not done routinely

Macroprolactins are biologically inactive prolactin aggregates that accumulate in blood to a high level- contribute to analytical difficulties
 DEXA scan

Treatment-Dopamine agonists as bromocriptine , cabergoline

For tumors of any size

Referral –Absence of secondary causes Prolactin conc persistently > 3000 mIU/L Signs of mass effect Signs of hypogonadism Neuroimaging MRI findings suggestive of prloactinoma / other abnormal findings

LINKS AND RESOURCES

PATIENT RESOURCES

A very useful page from the website Yourhormones.info on Prolactin https://www.yourhormones.info/hormones/prolactin/

Pituitary Org is a very useful resource and you can use this link to explain patients about Prolactinoma https://www.pituitary.org.uk/information/pituitary-conditions/prolactinoma/

Prolactinoma from NIH http://www.bartsendocrinology.co.uk/resources/prolactinoma+patient+information.pdf

Labtestsonline has a comprehensive section for patients on Prolactin https://labtestsonline.org.uk/tests/prolactin

WebMD for patients in the US https://www.webmd.com/a-to-z-guides/prolactin-test#1

RESOURCES FOR CLINICIANS

A plain-language summary for clinicians from NPS Medicinewise, very concise and easy to understand decluttering this complex topic https://www.nps.org.au/australian-prescriber/articles/hyperprolactinaemia

A guide to Prolactin testing National Laboratory Handbook https://www.hse.ie/eng/about/who/cspd/ncps/pathology/resources/lab-testing-for-hyperprolactinaemia.pdf

Prolactin and antipsychotic therapy– a guide for clinicians from Kent https://www.ekhuft.nhs.uk/EasySiteWeb/GatewayLink.aspx?alId=446006

References

  1. Serri, Omar et al. “Diagnosis and management of hyperprolactinemia.” CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne vol. 169,6 (2003): 575-81. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC191295/
  2. Hyperprolactinemia E medicine Donald Shenerberger et al May 2017 https://emedicine.medscape.com/article/121784-overview
  3. Hyperprolactenemia , Galacatorrhoea , and Pituitary Adenomas : Etiology , Differential Diagnosis , Natural History , Management Roger A. Lobo Comprehensive Gynecology , 39 , 853-864.e1
  4. Hyperprolactinemia Ming Li MD , PhD et al Conn’s Current Therapy 2018
  5. Interpreting raised serum prolactin results BMJ 2014 ;348:g3207
  6. Shlomo Melmed, Felipe F. Casanueva, Andrew R. Hoffman, David L. Kleinberg, Victor M. Montori, Janet A. Schlechte, John A. H. Wass, Diagnosis and Treatment of Hyperprolactinemia: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 96, Issue 2, 1 February 2011, Pages 273–288, https://doi.org/10.1210/jc.2010-1692
  7. Prolocatinomas -Oxford Handbook of Endocrinology and Diabetes
  8. The epidemiology of hyperprolactinaemia over 20 years in the Tayside region of Scotland : the Prolactin Epidemiology , Audit and Research Study ( PROLEARS ) Clin Endocrinol ( Oxf ) Jan ; 86 (1) : 60-67 ( Abstract )

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