36

Prolactin (PRL)

36

Prolactin (PRL)

36

Prolactin (PRL)

36

Prolactin (PRL)

  36 Prolactin (PRL)

Lothar Thomas

The primary source of PRL (also called lactogenic hormone) production is the lactotrophs of the anterior pituitary gland. However, there are a number of other organs, cells, and tissues in which PRL is expressed and secreted (extrapituitary PRL).

PRL is very versantile, with many biological functions in different species that fall into the following general categories: reproduction, pregnancy and lactation, growth and development, metabolism, immune modulation, electrolyte transport, regulation of the integument, behavior, and carcinogenesis. The main role, of pituitary PRL is to stimulate the production of milk in women after childbirth. The specific function of pituitary PRL in men is not well known, however, it is most commonly measured in individuals with reproductive disorders. The regulation of extrapituitary PRL is dissimilar to that of pituitary PRL and is typically cell- or tissue specifc. The biologically active form of PRL is the monomeric 23 kDa peptide /1/.

Circulating prolactin exists in a number of post-translational modifications of active and inactivated forms, which are measured in varying quantities depending on the PRL immunoassay used /2/:

  • Big PRL, with a molecular mass of 48–56 kDa, which is a covalently bound dimer of 23 kDa PRL.
  • Big-big PRL (macro PRL), with a molecular mass of 150–205 kDa, which consists of antigen-antibody complexes of 23 kDa PRL with IgG, IgM and IgA or with other proteins, or is a hyperglycosylated form of PRL.

Big PRL and macro PRL are clinically irrelevant as they do not bind to the PRL receptors. They can, however, cause apparent hyperprolactinemia (pseudo-hyperprolactinemia), which can lead to misdiagnosis and mismanagement of patients. Therefore, in cases of elevated serum PRL levels, laboratories are advised to remove the big PRL and macro PRL components by precipitation with polyethylene glycol (PEG), and to report the results for total PRL and the hormonally active 23 kDa PRL. The clinical evaluation should be based on the concentration of 23 kDa PRL. Only increased PRL secretion (i.e., hyperprolactinemia) is of clinical significance.

Pituitary PRL and extrapituitary PRL proteins are identical in terms of their primary, secondary, or tertiary structure, and both bind to the same receptor.

36.1 Indication

Both sexes

  • Suspected pituitary adenoma and pituitary insufficiency
  • Treatment with anti-psychotics.

Females

  • Amenorrhea, oligomenorrhea, anovulatory cycles, corpus luteum insufficiency
  • Galactorrhea, mastodynia, mastopathy, osteopenia
  • Acne, virilization symptoms
  • Workup of infertility.

Males

  • Hypogonadism, sometimes combined with headache and impaired vision (macro prolactinoma)
  • Reduced libido
  • Erectile dysfunction
  • Gynecomastia, in rare cases with galactorrhea.

36.2 Method of determination

Enzyme immunoassay, immunometric assay. Assays are calibrated against the WHO’s Third International Standard IS 84/500. Prolactin units can be converted from mIU/L to μg/L by dividing by 21.2.

Determination of 23 kDa prolactin

250 μL of serum is mixed with an equal volume of polyethylene glycol (250 g/L, dissolved in 137 mmol/L of NaCl, 10 mmol/L of sodium phosphate) and incubated at room temperature for 10 minutes. The clear supernatant is removed from the suspension by centrifugation at 1,800 × g for 30 minutes. PRL is measured in the serum and in the clear supernatant. The serum contains the total PRL, the clear supernatant the post-PEG PRL (23 kDa prolactin) /3/.

The reference method of separation 23 kDa prolactin from macro prolactin is gel filtration chromatography.

36.3 Specimen

Serum (blood collection 8–10 a.m.): 1 mL

36.4 Reference interval

Reference intervals vary between diagnostics manufacturers and are age- and sex dependent /45/. Refer to:

36.5 Clinical assessment

In normal sera, monomeric (23 kDa) PRL accounts for 85–95%, big PRL for less than 10%, and macro PRL (big-big PRL) for less than 5% of the serum PRL. Depending on the study, macro PRL is identified as the sole cause of hyperprolactinemia in 4% of cases /7/, while other studies report a prevalence of macro prolactinemia of about 10% in patients with hyperprolactinemia /8/. It is therefore recommended to perform PEG precipitation on all hyperprolactinemic sera and to report the concentrations of total PRL and post-PEG PRL (bioactive PRL) /5/.

36.5.1 Macro prolactin

Macro PRL is a large antigen-antibody complex of molecular weight greater than 100 kDa and constitutes less than 1% of circulating PRL. The antigen-antibody complex consists of monomeric PRL and anti-PRL autoantibodies, these being IgG antibodies with low receptor affinity. Macro-PRL is cleared more slowly than monomeric (23 kDa) PRL /9/.

Many laboratories perform the determination of post-PEG PRL if prolactin levels are at or above 600 mIU/L (30 ug/L) in females or above 400 mIU/L (20 ug/L) in males. The findings should be commented as follows /5/:

  • Elevated post-PEG PRL: all sera with elevated total PRL concentrations are routinely screened for the presence of macro PRL. This abnormal form of PRL cross reacts with the biologically active PRL in the immunoassay but is biologically inactive. When corrected for macro PRL, the bioactive PRL concentration in this serum is increased.
  • Normal post-PEG PRL: all sera with elevated total PRL concentrations are routinely screened for the presence of macro PRL. This abnormal form of PRL cross reacts with the biologically active PRL in the immunoassay but is biologically inactive. When corrected for macro PRL, the bioactive PRL concentration in this serum is normal.

The prevalence of hyperprolactinemia ranges from 0.4%, as found in Japanese factory workers, to as high as 9% and 17% in women with infertility or polycystic ovarian syndrome /9/. There is a clear gender predilection for hyperprolactinemia, with women being affected six times more often than men /9/. If hyperprolactinemia is present, confirmatory testing of a second blood sample must be carried out. Prior to this, pregnancy should be ruled out in women of reproductive age.

If PRL levels are only mildly elevated or within the upper reference interval and a consistent clinical picture is observed, it is recommended to measure the basal prolactin concentration with an intravenous cannula in situ three times at 20 minute intervals to rule out stress induced hyperprolactinemia, or to take a blood sample in the morning on two different days.

Hyperprolactinemia can have physiological, pathological or pharmacological causes (Tab. 36-3 – Causes of hyperprolactinemia). The most common causes of pathological hyperprolactinemia are prolactinomas, which account for 25–30% of clinically diagnosed pituitary tumors. Prolactinomas are treated with dopamine agonists or surgically.

36.5.2 Clinical symptoms

Hyperprolactinemia presents predominantly with hypogonadism, galactorrhea, and symptoms of the mass effect of the pituitary tumor on the surrounding structures (Tab. 36-4 – Clinical symptoms of hyperprolactinemia/10/.

36.5.3 Evaluation of PRL levels

Hyperprolactinemia can be diagnosed based on the test results from two blood samples. While PRL levels above 250 μg/L (5,000 mIU/L) are virtually always diagnostic of a prolactinoma, less elevated levels may also be due to a prolactinoma /9/. Causes of hyperprolactinemia are listed in Tab. 36-5 – Conditions and diseases with hyperprolactinemia.

Other possible causes are pregnancy, drugs, and central hypothyroidism. Once these causes have been ruled out by anamnesis, determination of TSH levels, and pregnancy testing, the next step is to image the base of the skull /10/.

The behavior of PRL in the presence of different conditions and diseases is outlined in Tab. 36-3 – Causes of hyperprolactinemia.

36.5.3.1 Hyperprolactinemia in females

Hyperprolactinemia is the reported cause of amenorrhea in 10–40% of patients. Approximately 70% of women with hyperprolactinemia have galactorrhea, which in most cases is expressible rather than spontaneous. The most common form of hyperprolactinemia in women are micro prolactinomas with normal sella turcica /10/.

Pituitary adenoma comprises 10–15% of all diagnosed intracranial tumors. Prolactinoma is the most common type of functional pituitary adenoma, with a prevalence of 100 per 1 million people. According to the 2016 WHO classification of tumors, prolactinomas are grade I/II, which are considered to be benign tumors. In addition, prolactinoma is one of the functional pituitary tumors, which are classified into adrenocoticotropic hormone-secreting pituitary adenoma, growth hormone-secreting pituitary adenoma and prolactinoma /11/. In approximately 20% of hyperprolactinemic women, a large pituitary tumor (macroprolactinoma) is found with diagnostic imaging. If no adenoma is diagnosed and other possible causes of hyperprolactinemia, such as drugs and hypothyroidism, have been excluded, the hyperprolactinemia is of functional origin.

36.5.3.2 Hyperprolactinemia in males

Men with hyperprolactinemia often present with large (> 2 cm) pituitary adenomas with markedly elevated PRL levels. The clinical picture is characterized by loss of libido, impotence, symptoms of hypogonadism with gynecomastia, and occasionally galactorrhea. Since the adenoma mass often leads to compression of the anterior pituitary, further symptoms resulting from anterior pituitary insufficiency are not uncommon. In addition, visual field defects (chiasm syndrome) with suprasellar expansion may develop. Very large pituitary adenomas, in particular in young men, are usually prolactinomas, and the endocrine axes are inactive, and prolactin levels are high.

36.6 Comments and problems

Blood sampling

Blood sampling should not be performed after a gynecological examination (stress) or test for galactorrhea. It is important to note that stress alone (e.g., anxiety over blood drawing) can cause mildly elevated PRL levels and that manipulation of the nipple (e.g., provocation of galactorrhea) can cause PRL to rise to hyperprolactinemic levels /12/. The blood draw should be performed 3 to 4 hours later i.e., between 8 a.m. and 10 a.m. /12/.

Method of determination

The determination of monomeric endocrinologically active PRL (post-PEG PRL) is still a rarely performed procedure. One drawback of PEG precipitation is that it is not quantitative and up to 25% of the monomeric PRL may be co precipitated with the macro PRL. However, PEG precipitation has the advantage that, if monomeric PRL levels after PEG treatment are higher than the reference interval, biologically active hyperprolactinemia is confirmed /4/. One of the main causes of the co precipitation are matrix effects of the sample /3/.

Reference interval

PRL levels follow a circadian rhythm. During the course of the day, they fall to approximately half the morning levels, then rise continuously during sleep to reach a peak in the early morning hours. Parametric total and monomeric gender-specific reference intervals were determined for six immunoassay methods using female and male sera /13/.

Half life

The half life in plasma is 40–50 minutes.

Stability in serum

Stable for 1 day at 20° and 4 °C; for long term storage samples should be frozen.

36.7 Pathophysiology

The lactotroph cells account for 20–50% of pituitary cells. They are located in the inner region of the organ and respond to dopamine. The PRL produced by these cells belongs to the same family as GH and human placental lactogen. PRL is a single chain peptide with 199 amino acids which contains six cysteine residues and three disulfide bonds and has a molecular mass of 23 kDa. PRL binds to a receptor of the class 1 cytokine family and is also expressed in organs such as the liver, pancreas, prostate and uterus.

Refer to Section 20.1 – Definition, classification, structure and function of cytokines.

PRL is released by the anterior pituitary by pulsatile secretion with approximately 10 pulsations per day in young people. PRL levels follow a circadian rhythm, with the highest levels occurring during sleep and the lowest between 8 a.m. and 10 a.m.

PRL secretion is controlled and inhibited by dopamine. Dopamine is released by hypothalamic, dopaminergic neurons and transported to the anterior pituitary via the hypophysial portal vessels. The lactotroph cells have a high basal PRL secretion which is adapted to the relevant situation through appropriate inhibition by dopamine. The released PRL in turn regulates the release of dopamine via feedback inhibition.

While PRL secretion is mainly regulated by dopamine, it is also influenced by other hormones such as TSH or vasoactive polypeptide. In contrast to the inhibitory effect of dopamine, these hormones stimulate PRL secretion.

PRL stimulates lactogenesis and galactopoiesis (i.e., the onset and maintenance of milk secretion after delivery). Furthermore, suckling induced PRL secretion maintains postpartum anovulation. Approximately 50% of women with non physiological galactorrhea have hyperprolactinemia.

In hyperprolactinemia, dopamine and opiate concentrations are increased in the basal hypothalamic regions without having any significant influence on the autonomous pituitary PRL secretion. However, the pulsatility of the GNRH producing neurons is inhibited, leading to suppression of the pulsatile LH secretion. Since proper gonadal function relies on pulsatile LH secretion, functional hypothalamic normogonadotropic hypogonadism develops. Approximately 25% of women with secondary amenorrhea have hyperprolactinemia. Absence of ovarian cyclicity leads to a lack of estrogen with atrophy of the vaginal mucosa, and to osteoporosis. Replacement therapy with pulsatile application of GnRH leads to normalization of gonadal function despite persistently elevated PRL /14/.

Dopamine and L-dopa, the direct precursor of dopamine which crosses the blood-brain barrier, inhibit PRL secretion. This is also the case with dopaminergic agonists (bromocriptine, cabergoline, lisuride, metergoline, quinagolide) /14/. They are used in the treatment of hyperprolactinemia. Following medication with these drugs, PRL falls within 2.5 to 5 hours and remains low for a good day. Dopamine agonists not only inhibit PRL secretion but in prolactinomas also lead to shrinkage of the tumor in up to 85% of cases /15/. This can be achieved even more effectively with second generation dopamine agonists such as cabergoline or the non-ergot preparation quinagolide /16/. After normalization of PRL secretion, hypogonadism is reversible and fertility can be restored.

The dopamin agonists are the best medical treatment of prolactinoma and can reduce the secretion of PRL. Approximately 70–90% of patients with microadenomas have normalized prolactin concentrations after dopamin agonist treatment, with menstruation resuming, lactation ceasing, fertility restored and shrinkage of the tumor. However 20% of patients are resistant to medications and below 4% of properly regulated patients with prolactinoma can develop acromegaly. Although prolactinomas can be removed by a frontal or a butterfly pathway, it is often difficult to completely excise and postoperative PRL levels are difficult to recover. Approximately 40–80% of surgeries will result in temporary improvement and half of them will relapse /17/.

Prolactinoma expression of specific ErbB receptors is associated with tumor invasion, symptoms, and response to doamin agonists /18/.

References

1. Marano RJ, Ben-Jonathan N. Minireview: extrapituitary prolactin: an update on the distribution, regulation, and functions. Mol Endocrinol 2014; 28 (5): 622–33.

2. Smith TP, Suliman AW, Fahie-Wilson MN, McKenna TJ. Gross variability in the detection of big big prolactin (macroprolactin) by commercial immunoassays. J Clin endocrinol Metab 2002; 87: 5410–5.

3. Suliman AM, Smith TP, Gibney J, McKenna TJ. Frequent misdiagnosis and mismanagement of hyperprolactinemic patients before the introduction of macroprolactin screening: application of a new strict laboratory definition of macroprolactinemia. Clin Chem 2003; 49: 1504–9.

4. Beltran L, Fahie-Wilson MN, McKenna TJ, Kavanagh L, Smith TP. Serum total prolactin and monomeric prolactin reference intervals determined by precipitation with polyethylene glycol: evaluation and validation on common immunoassay platforms. Clin Chem 2008; 54: 1673–81.

5. Smith TP, Fahie-Wilson MN. Reporting of post-PEG prolactin concentrations: time to change. Clin Chem 2010; 56: 484–5.

6. Aitkenhead H, Heales SJ. Establishment of paedriatric age-related reference intervals for serum prolactin to aid in the diagnosis of neurometabolic conditions affecting dopamine metabolism. Ann Clin Chem 2013; 50: 156–8.

7. Jassam NF, Paterson A, Lippiatt C, Barth JH. Macroprolactin on the Advia Centaur: experience with 409 patients over a three-year peroid. Ann Clin Biochem 2009; 46: 501–4.

8. Vallette-Kasic, S, Morange-Ramos I, Selin A, et al. Macroprolactinemia revisited: a study of 106 patients. J Clin Endocrinol Metab 2002; 87: 581–8.

9. Sadideen H, Swaminathan S. Macroprolactin: what is it and what is its importande? Int J Clin Pract 2006; 60 (4): 457–61.

10. Molitch ME. Disorders of prolactin secretion. Endocrinol Metab Clin North Am 2001; 30: 585–610.

11. Zhong S, Wu B, Wang X, Sun D, Liu D. Jiang S, et al. Identification of driver genes and key pathways of prolactinoma predicts the therapeutic effect of genipin. Molecular Medicine Reports 2019; 20: 2712-24.

12. Torner L. Actions of prolactin in the brain: from physiological adaptations to stress and neurogenesis to psychopathology. Frontiers in Endocrinology 2016; vol 7, article 25. https://doi.org/10.3389/fendo.2016.00025.

13. Overgaard M, Pedersen SM. Serum prolactin revisited: parametric reference intervals and cross platform evaluation of polyethylene glycol precipitation-based methods for discrimination between hyperprolactinemia and macroprolactinemia. Clin Chem Lab Med 2017; 55 (11): 1744–53.

14. Von Werder K. Prolactin. In Thomas L, ed. Labor und Diagnose. Frankfurt; TH-Books 2008: 1472–7.

15. Bevan JS, Webster J, Burke CW, Scanlon MF. Dopamine agonists and pituitary tumor shrinkage. Endocr Rev 1992; 13: 220–40.

16. Chahal J, Schlechte J. Hyperprolactinemia. Pituitary 2008; 11 (2): 141–6.

17. Nakhleh A, Shehadeh N, Hochberg I, Zloczower M, Zolotov S, Taher R, et al. Management of cystic prolactinomas: a review. Pituitary 2018; 21: 425–30.

18. Cooper O, Mamelek A, Bannykh S, Carmichael J, Bonert V, Lim S, et al. Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors. Endocrine 2014; 46 (2): 318–27.

19. Chen DK, So YT, Fisher RS. Use of serum prolactin in diagnosing epileptic seizures. Neurology 2005; 65: 668–75.

20. Bushe CJ, Bradley A, Pendlebury J. A review of hyperprolactinaemia and severe mental illness: are there implications for clinical biochemistry? Ann Clin Biochem 2010; 47: 292–300.

21. Bushe C, Shaw M. Prevalence of hyperprolactinemia in a naturalistic cohort of schizophrenia and bipolar outpatients during treatment with typical and atypical psychotics. J Psychopharmacol 2007; 21: 768–73.

22. Peveler RC, Branford D, Citrome L, et al. Antipsychotics and hyperprolactinemia: clinical recommendations. J Psychopharmacol 2008; 22, suppl: S98–S103.

23. Serri O, Chik CL, Ur E, Ezzat S. Diagnosis and management of hyperprolactinemia. Can Med Ass J 2003; 169: 575–81.

24. Howard L, Kirkwood G, Leese M. Risk of hip fracture in patients with a history of schizophrenia. Br J Psych 2007; 190: 129–34.

25. Kurian MA, Gissen P, Smith M, Heales SJR, Clayton PT. The monoamine neurotransmitter disorders: an expanding range of neurological syndromes. Lancet Neurology 2011; 10: 721–33.

26. Manegold C, Hoffmann GF, Degen I, Ikonomidou H, Knust A, Laaß MW, et al. Aromatic L-aminoacid decarboxylase deficiency: clinical features, drug therapy and follow-up. J Inherit Metab Dis 2009; 32: 371–80.

27. Klibanski A. Prolactinomas. N Engl J Med 2010; 362: 1219–26.

28. Kaltsas GA, Grossman AB. Malignant pituitary tumors. Pituitary 1998; 1: 69–81.

29 Raverot G, Wierinckx A, Dantony E, Auger C, Chapas G, Villeneuve L, et al. Prognostic factors in prolactin pituitary tumors: clinical, histological, and molecular data from a series of 94 patients with a long postoperative followup. J Clin Endocrinol Metab 2010; 95: 1708–16.

Table 36-1 Reference intervals of total Prolactin (PRL) und 23kDa-PRL after precipitation with PEG (Post-PEG-PRL) /45/

Assay

Total
PRL (F)

Total
PRL (M)

Post-PEG
PRL (F)

Post-PEG
PRL (M)

Centaur
(Siemens)

61–404

51–298

58–314

56–214

Access
(Beckman)

66–527

51–303

66–422

60–228

Immulite
(Siemens)

68–479

55–305

64–437

54–279

Centaur
(Siemens)

66–278

61–196

Elecsys
(Roche)

72–577

62–391

74–448

60–246

Architekt
(Abbott)

86–527

70–322

73–462

65–262

AIA
(Tosoh)

89–604

75–393

79–533

61–347

Olympus

61–330

56–208

Data in mIU/l; 21.2 mIU/l correspond to 1 μg/l; F, females; M, males

Table 36-2 Reference intervals for total prolactin in children /6/

Age

Female

Male

0–30 days

667–5,034

667–5,034

31–60 days

510–3,136

510–3,136

61–90 days

108–2,100

108–2,100

3–5 months

80–2,095

80–2,095

6–8 months

86–1,647

86–1,647

9–12 months

106– 820

106– 820

1 year

67–865

65–789

2–4 years

56–640

57–717

5–8 years

45–466

47–438

9–11 years

44–548

40–555

12–16 years

58–602

44–479

Data are expressed in mIU/L. Values are the 2.5th and 97.5th percentiles for the assay from Siemens Health Care Diagnostics

Table 36-3 Causes of hyperprolactinemia /7/

Physiological

  • Pregnancy
  • Postpartum lactation
  • Sexual intercourse, physical exercise
  • Stress (e.g., hypoglycemia, surgery, heart attack)

Pathological

PRL-secreting pituitary adenoma (prolactinoma)

  • Macroprolactinoma; generalized enlargement of the sella turcica
  • Microprolactinoma; normal sella turcica or discrete changes in the contour of the sella

Impaired transport of PIH to the adenohypophysis or impaired production of PIH

  • Compression by an endocrine-inactive or non-PRL-producing tumor
  • Pituitary stalk transection
  • Granulomatous inflammation of the basal meninges, e.g. sarcoidosis
  • Suprasellar tumors, e.g. craniopharyngioma, dermoid cysts, Hodgkin’s lymphoma, lymphomas

Pharmacological

  • Dopamine antagonists
  • Catecholamine depletors

Hypothalamic stimulation in hypothyroidism (endogenous TRH)

Renal insufficiency

Other rare causes

  • Herpes zoster encephalitis
  • Chest wall trauma
  • Ectopic PRL production (very rare)

Table 36-4 Clinical symptoms of hyperprolactinemia /10/

Females

Males

Amenorrhea

Oligomenorrhea

Corpus luteum insufficiency

Anovulation

Galactorrhea

Impaired libido

Hirsutism

Seborrhea

Impaired libido

Erectile dysfunction

Hypogonadism with and without gynecomastia

Galactorrhea (rare)

Symptoms of a pituitary tumor

Anterior pituitary insufficiency

Visual field defect

Eye muscle paralysis

Headache

Cerebral dysfunction, inclusive coma (foramen of Monro obstruction)

Table 36-5 Disorders and diseases with hyperprolactinemia (values represent total prolactin)

Clinical and laboratory findings

Physiological condition

Physiological hyperprolactinemia is mild: below 2,000 mIU/L (100 ug/L)

Puberty, menopause

In females, PRL levels rise by about 50% during puberty, then decrease by the same percentage at the end of the reproductive years, in menopause. During the menstrual cycle, there are no significant changes in PRL levels except for a mild elevation mid-cycle. In males, there are no known significant variations in PRL levels in the different phases of life.

Pregnancy

At the end of a normal pregnancy, concentrations of 200–500 μg/L (4,000–10,000 mIU/L) are measured, which result from estrogen-induced hyperplasia of the anterior pituitary lactotroph cells. Hyperprolactinemia is also present during lactation, where it is maintained by the suckling stimulus. In non lactating women, PRL levels remain elevated for several weeks postpartum, in lactating women for six months and longer.

Stress exposure

Stressors like physical exercise, anxiety over blood withdrawal, sexual intercourse, hypoglycemia, heart attack or surgery can lead to hyperprolactinemia, which usually lasts for several hours since PRL has a half life of 45 to 50 minutes. Stress exposure activates the hypothalamic-pituitary-adrenal axis, triggering the release of corticotrophin releasing hormone (CRH), which promotes the secretion of ACTH from the pituitary. In turn, ACTH triggers the release of glucocorticoids from the adrenal glands. PRL is also secreted in response to a number of stressors /19/.

PRL alters neural circuits to help the individual to cope with the stress. Reduced activation of neural inputs, activation of ionic channels, or the modulation of signalling pathways are some of the putative mechanisms of action underlying the effects of PRL on brain circuits.

Epileptic seizure

Stress causes plasma levels of PRL, hGH, ACTH and TSH to rise. The rise in PRL levels is likely to be caused by a PRL releasing factor, possibly vasoactive intestinal polypeptide (VIP), rather than by suppression of the dopaminergic inhibitory effect. An increase to 2 times the upper reference interval 10 to 20 min. after a suspected event in adults and older children is considered by some clinicians as a criterion for differentiating between generalized tonic-clonic seizure (GTC) or complex partial seizure (CPS) and psychogenic non epileptic seizure (NES).

The report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology states as follows in this regard /19/:

  • Elevated serum PRL level, when measured in the appropriate clinical setting at 10–20 min. after a suspected event, is a useful adjunct for the differentiation of GTC and CPS from NES
  • Serum PRL levels should be representative of the baseline PRL level when measured 6 h after an event
  • Serum PRL assay is not useful in distinguishing seizure from syncope
  • The use of serum PRL level has not been established in the evaluation of status epilepticus, repetitive seizures, and neonatal seizures.

Medication

Drugs that interact with the hypothalamic dopamine system and/or the pituitary dopamine receptors can cause hyperprolactinemia. These are essentially dopamine receptor antagonists, dopamine-depleting drugs, antidepressants, and hormones. Important PRL secretion stimulating drugs include chlorpromazine, butyrophenones (haloperidol), perphenazine, α-methyldopa, sulpiride, reserpine, metoclopramide, cimetidine, domperidone, estrogens, pimozide, antiandrogens, tricyclic antidepressants.

Laboratory findings: PRL concentrations are generally below 2,000 mIU/L (100 μg/l).

Psychiatric patients

All psychiatric patients receiving antipsychotic treatment experience mild to moderate elevations in PRL /20/. In particular anti psychotics with slow dissociation rates occupy the central D2 receptors for an extended period of time, leading to increased secretion of PRL. In a study /21/ of patients receiving anti psychotics for schizophrenia or bipolar disorder, 21% had PRL concentrations above 1,000 mIU/L, women twice as often as men.

PRL levels should therefore be measured as follows in patients receiving antipsychotic treatment /22/:

  • Prior to treatment, regardless of the type of antipsychotic prescribed
  • Three months after stable dose treatment
  • If relevant clinical symptoms develop.

If PRL is already elevated at the beginning of treatment, the following procedure should be adhered to:

  • If PRL levels are < 1,000 mIU/L (50 μg/L) , they should be monitored and controlled to ensure they do not remain elevated for an extended period of time
  • If PRL levels are ≥ 1,000 mIU/L (50 μg/L), consideration should be given to switching medication or changing dosage
  • If PRL levels are ≥ 3,000 mIU/L (150 μg/L), the patient should be referred to an endocrinologist to be tested for prolactinoma.

Reasons for this recommendation for patients who receive long term treatment with antipsychotic medication and have mild to moderate hyperprolactinemia:

  • Dysregulation of sex hormones /23/ (elevated but < 1,000 mIU/L (50 μg/L), reduced libido and infertility, 1,000–1,600 mIU/L (50–80 (50 μg/L) oligomenorrhea, > 2,000 mIU/L (100 μg/L), amenorrhea and hypogonadism)
  • Long term, but also relatively short term antipsychotic induced hyperprolactinemia compromises bone density. The odds ratio for hip fractures in these patients is 2.6 /24/.

Organic disease

Approximately 40% of patients with primary hypothyroidism, approximately 30% of patients with chronic renal insufficiency, and 80% of hemodialysis patients have hyperprolactinemia.

Dopamine deficiency

Elevated PRL levels are seen in dopamine deficiency and medication with dopamine receptor antagonists. The hypothalamic dopamine is the main inhibitor of the release of PRL by the anterior pituitary.

Monoamine neurotransmitter disorder

Primary monoamine neurotransmitter disorders with deficiencies of the neurotransmitters serotonin and dopamine are due to (for further information refer to review Ref. /25/):

  • A cofactor deficiency (vitamin B6 deficiency, tetrahydrobiopterin (BH4) deficiency
  • An enzyme deficiency (tyrosine hydroxylase deficiency, aromatic L-amino acid decarboxylase deficiency)
  • Defective monoamine transport.

Neurological symptoms occur in the first 6 months of life and include mental retardation, truncal hypotension, hypokinesis, reduced facial expression, dystonic movement, and occulogyric crisis. In recessive hereditary deficiency of aromatic L-amino acid decarboxylase (OMIM 608643), the production of serotonin and the catecholamines dopamine and noradrenaline is compromised.

Laboratory findings /26/: in cerebrospinal fluid markedly decreased are:

  • Breakdown products of homo vanillic acid; they represent the dopamine pathway
  • Breakdown products of 5-hydroxy indoleacetic acid; they represent the serotonin pathway.

Serum PRL levels were elevated in 2 of 6 cases.

Prolactinoma

Pituitary micro adenomas are found in 10.9% of autopsies, and 44% of these micro adenomas are prolactinomas /27/. Micro adenomas are less, macro adenomas larger than 1 cm in diameter. Serum levels of PRL in patients with prolactinomas usually increase to the tumor mass, but PRL levels and clinical symptoms are only loosely correlated. Since PRL secretion is under the tonic inhibitory control of PRL inhibiting hormone (PIH, dopamine), any disorders which interfere with this control can also lead to hyperprolactinemia.

This is the case with:

  • Inflammatory diseases such as lymphocytic hypophysitis
  • Disruption of the pituitary stalk as a result of an accident
  • Use of anti-psychotics (risperidone) and other dopaminergic blockers such as metoclopramide, or opiates and H2 blockers.
  • Radiologically significantly enlarged sella turcica. In this case the PRL does not need to be produced in the tumor itself. In the case of suprasellar expansion of the adenoma and compression of the pituitary stalk, dopamine is unable to reach the rest of the pituitary gland, allowing the latter to secrete PRL at an increased rate due to the loss of dopaminergic inhibitory control (disinhibition). In suprasellar processes, hyperprolactinemia can be due to destruction of the dopamine-secreting hypothalamic neurons or impaired transport of PIH to the lactotroph cells of the anterior pituitary. Pituitary carcinomas are very rare. If they occur, they are usually associated with high PRL levels which cannot be suppressed with dopamine agonists. These carcinomas can produce metastases, even outside the CNS /28/.

With macro adenomas, post surgery recurrence of the tumor and its progression depend on:

  • The pathological classification of the tumor as non invasive, invasive, and aggressive invasive. Latter classification, determined by at least two of the three proliferative markers (Ki-67 index above 1%, number of mitoses greater than 2 per 10 high power fields with 400-fold magnification, p53 nuclear detection). Adenomas of this type are called atypical adenomas, as defined by the WHO.
  • The presence of seven genes evaluated by molecular genetic tests. Thus, the genes ADAMTS6, CRMP1, PTTG, ASK, CCNB1, AURKB and CENPE are associated with recurrence or progression of the tumor, and five of these (ADAMTS6, CRMP1, ASK, CCNB1 and CENPE) with an atypical adenoma /29/.

Laboratory findings: PRL levels above 2,000 mIU/L (100 μg/L) almost never occur in non-functioning adenomas,concentrations of 3,000–5,000 mIU/L (150–250 μg/L) measured at least twice, are generally indicative of a macro prolactinoma. Levels can exceed 20,000 mIU/L (1,000 μg/L).

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