Prolactin

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Prolactin

PDB rendering based on 1n9d.
Available structures
PDBOrtholog search: PDBe, RCSB
Identifiers
SymbolPRL
External IDsOMIM176760 MGI97762 HomoloGene732 GeneCards: PRL Gene
Orthologs
SpeciesHumanMouse
Entrez561719109
EnsemblENSG00000172179ENSMUSG00000021342
UniProtP01236P06879
RefSeq (mRNA)NM_000948NM_001163530
RefSeq (protein)NP_000939NP_001157002
Location (UCSC)Chr 6:
22.29 – 22.3 Mb
Chr 13:
27.06 – 27.07 Mb
PubMed search[1][2]
 
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Prolactin

PDB rendering based on 1n9d.
Available structures
PDBOrtholog search: PDBe, RCSB
Identifiers
SymbolPRL
External IDsOMIM176760 MGI97762 HomoloGene732 GeneCards: PRL Gene
Orthologs
SpeciesHumanMouse
Entrez561719109
EnsemblENSG00000172179ENSMUSG00000021342
UniProtP01236P06879
RefSeq (mRNA)NM_000948NM_001163530
RefSeq (protein)NP_000939NP_001157002
Location (UCSC)Chr 6:
22.29 – 22.3 Mb
Chr 13:
27.06 – 27.07 Mb
PubMed search[1][2]

Prolactin (PRL), also known as lactotrope, is a protein that in humans is probably best known for its role in enabling female mammals to produce milk however it is influential over a large number of functions with over 300 separate actions of PRL having been reported in various vertebrates.[1]

Discovered in non-human animals around 1930 by Oscar Riddle, and confirmed in humans in 1970 by Henry Friesen [2] prolactin is a peptide hormone, encoded by the PRL gene. [3]

Although often associated with human milk production, prolactin plays a wide range of other roles in both humans and other vertebrates. (For example, in fish—the oldest known vertebrates—an important function is probably related to control of water and salt balance.) Prolactin also acts in a cytokine-like manner and as an important regulator of the immune system. It has important cell cycle related functions as a growth-, differentiating- and anti-apoptotic factor. As a growth factor, binding to cytokine like receptors, it also has profound influence on hematopoiesis, angiogenesis and is involved in the regulation of blood clotting through several pathways. The hormone acts in endocrine, autocrine, and paracrine manner through the prolactin receptor and a large number of cytokine receptors.[1]

Pituitary prolactin secretion is regulated by endocrine neurons in the hypothalamus, the most important ones being the neurosecretory tuberoinfundibulum (TIDA) neurons of the arcuate nucleus, which secrete dopamine (aka Prolactin Inhibitory Hormone) to act on the D2 receptors of lactotrophs, causing inhibition of prolactin secretion. Thyrotropin-releasing factor (thyrotropin-releasing hormone) has a stimulatory effect on prolactin release.[not verified in body]

Several variants and forms are known per species. Many fish have variants prolactin A and prolactin B. Most vertebrates including humans also have the closely related somatolactin. In humans, three smaller (4, 16, and 22 kDa) and several larger (so called big and big-big) variants exist.[not verified in body]

Effects[edit]

Prolactin has a wide range of effects. It stimulates the mammary glands to produce milk (lactation): increased serum concentrations of prolactin during pregnancy cause enlargement of the mammary glands of the breasts and prepare for the production of milk. Milk production normally starts when the levels of progesterone fall by the end of pregnancy and a suckling stimulus is present. Sometimes, newborn babies (males as well as females) secrete a milky substance from their nipples known as witch's milk. This is in part caused by maternal prolactin and other hormones.

Prolactin provides the body with sexual gratification after sexual acts: The hormone counteracts the effect of dopamine, which is responsible for sexual arousal. This is thought to cause the sexual refractory period. The amount of prolactin can be an indicator for the amount of sexual satisfaction and relaxation. Unusually high amounts are suspected to be responsible for impotence and loss of libido (see hyperprolactinemia symptoms).

Highly elevated levels of prolactin decrease the levels of sex hormones — estrogen in women and testosterone in men.[4] The effects of mildly elevated levels of prolactin are much more variable, in women both substantial increase or decrease of estrogen levels may result.

Prolactin is sometimes classified as a gonadotropin[5] although in humans it has only a weak luteotropic effect while the effect of suppressing classical gonadotropic hormones is more important.[6] Prolactin within the normal reference ranges can act as a weak gonadotropin but at the same time suppresses GnRH secretion. The exact mechanism by which it inhibits GnRH is poorly understood although expression of prolactin receptors (PRL-R) have been demonstrated in rat's hypothalmus, the same has not been observed in GnRH neurons.[7] Physiologic levels of prolactin in males enhance luteinizing hormone-receptors in Leydig cells, resulting in testosterone secretion, which leads to spermatogenesis.[8]

Prolactin also stimulates proliferation of oligodendrocyte precursor cells. These cells differentiate into oligodendrocytes, the cells responsible for the formation of myelin coatings on axons in the central nervous system.[9]

Prolactin also has a number of other effects including contributing to surfactant synthesis of the fetal lungs at the end of the pregnancy and immune tolerance of the fetus by the maternal organism during pregnancy.

Prolactin delays hair regrowth in mice.[10]

Prolactin promotes neurogenesis in maternal and fetal brains.[11][12]

Production and regulation[edit]

In humans, prolactin is produced at least in the pituitary, decidua, myometrium, breast, lymphocytes, leukocytes and prostate.[13][14]

Pituitary PRL is controlled by the Pit-1 transcription factor and ultimately dopamine, extrapituitary PRL is controlled by a superdistal promoter and apparently unaffected by dopamine.[14]

In decidual cells and in lymphocytes the distal promoter and thus prolactin expression is stimulated by cAMP. Responsivness to cAMP is mediated by an imperfect cAMP–responsive element and two CAAT/enhancer binding proteins (C/EBP).[14] Progesterone has been observed to upregulate prolactin synthesis in the endometrium but decreases it in myometrium and breast glandular tissue.[15] However breast and other tissues may also express the Pit-1 promoter in addition to the distal promoter.

Extrapituitary production of prolactin is thought to be special to humans and primates and may serve mostly tissue specific paracrine and autocrine purposes. It has been hypothesized that in other vertebrates such as mice a similar tissue specific effect is achieved by a large family of prolactin like proteins controlled by at least 26 paralogous PRL genes not present in primates.[14]

Vasoactive intestinal peptide and peptide histidine isoleucine help to regulate prolactin secretion in humans, but the functions of these hormones in birds can be quite different.[16]

Variance in levels[edit]

There is a diurnal as well as an ovulatory cycle in prolactin secretion. In many mammals, there is also a seasonal change in prolactin release.

During pregnancy, high circulating concentrations of estrogen increase prolactin levels by 10- to 20-fold. However, at the same time, estrogen, as well as progesterone, inhibit the stimulatory effects of prolactin on milk production. It is the abrupt drop of estrogen and progesterone levels following delivery that allows prolactin — which temporarily remains high — to induce lactation.

After childbirth, prolactin levels fall as the internal stimulus for them is removed. Sucking by the baby on the nipple then promotes further prolactin release, maintaining the ability to lactate. The sucking activates mechanoreceptors in and around the nipple. These signals are carried by nerve fibers through the spinal cord to the hypothalamus, where changes in the electrical activity of neurons that regulate the pituitary gland cause increased prolactin secretion. The suckling stimulus also triggers the release of oxytocin from the posterior pituitary gland, which triggers milk let-down: Prolactin controls milk production (lactogenesis) but not the milk-ejection reflex; the rise in prolactin fills the breast with milk in preparation for the next feed.

In usual circumstances, in the absence of galactorrhea, lactation will cease within one or two weeks of the end of demand breastfeeding.

It has also been found that compared to un-mated males, fathers and expectant fathers have increased prolactin concentrations.[17]

High prolactin levels can also contribute to mental health issues.

Prolactin levels peak during REM sleep, and in the early morning. Levels can rise after exercise, meals, sexual intercourse, minor surgical procedures,[18] or following epileptic seizures.[19]

Hypersecretion of prolactin is more common than hyposecretion. Hyperprolactinemia is the most frequent abnormality of the anterior pituitary tumors, termed prolactinomas. Prolactinomas may disrupt the hypothalamic-pituitary-gonadal axis as prolactin tends to suppress the secretion of GnRH from the hypothalamus and in turn decreases the section of FSH and LH from the anterior pituitary, therefore disrupting the ovulatory cycle in females.[20] Such hormonal changes may manifest as amenorrhea and infertility in females as well as impotence in males. Inappropriate lactation is another important clinical sign of prolactinomas.

Structure and isoforms[edit]

The structure of prolactin is similar to that of growth hormone and placental lactogen. The molecule is folded due to the activity of three disulfide bonds. Significant heterogeneity of the molecule has been described, thus bioassays and immunoassays can give different results due to differing glycosylation, phosphorylation, sulfation, as well as degradation. The non-glycosylated form of prolactin is the dominant form of prolactin that is secreted by the pituitary gland.

There are mainly three different forms of prolactin in regard to size:

The levels of larger ones are somewhat higher during the early postpartum period.[24]

Pit-1 is a transcription factor that binds to the prolactin gene at several sites to allow for the production of prolactin in the pituitary gland. A key regulator of prolactin production is estrogens that enhance growth of prolactin-producing cells and stimulate prolactin production directly, as well as suppressing dopamine.

Human prolactin receptors are insensitive to mouse prolactin.[25]

Prolactin receptor[edit]

Prolactin receptors are present in the mamillary glands, ovaries, pituitary glands, heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal gland, uterus, skeletal muscle, skin, and areas of the central nervous system.[26] When prolactin binds to the receptor, it causes it to dimerize with another prolactin receptor. This results in the activation of Janus kinase 2, a tyrosine kinase that initiates the JAK-STAT pathway. The activation of the prolactin receptor also results in the activation of mitogen-activated protein kinases and Src kinase.[26]

Diagnostic use[edit]

Prolactin levels may be checked as part of a sex hormone workup, as elevated prolactin secretion can suppress the secretion of FSH and GnRH, leading to hypogonadism, and sometimes causing erectile dysfunction in men.

Prolactin levels may be of some use in distinguishing epileptic seizures from psychogenic non-epileptic seizures. The serum prolactin level usually rises following an epileptic seizure.[27]

Units and unit conversions[edit]

The serum concentration of prolactin can be given in mass concentration (µg/L or ng/mL), molar concentration (nmol/L or pmol/L) or in international units (typically mIU/L). The current IU is calibrated against the third International Standard for Prolactin, IS 84/500.[28][29] Reference ampoules of IS 84/500 contain 2.5 µg of lyophilized human prolactin,[30] and have been assigned an activity of .053 International Units of prolactin.[28][29] Measurements that are calibrated against the current international standard can be converted into mass units using this ratio of grams to IUs;[31] prolactin concentrations expressed in mIU/L can be converted to µg/L by dividing by 21.2. Previous standards use other ratios.[32][33][34][35]

The first International Reference Preparation (or IRP) of human Prolactin for Immunoassay was established in 1978 (75/504 1st IRP for human Prolactin) at a time when purified human prolactin was in short supply.[31][32] Previous standards relied on prolactin from animal sources.[35] Purified human prolactin was scarce, heterogeneous, unstable, and difficult to characterize. A preparation labelled 81/541 was distributed by the WHO Expert Committee on Biological Standardization without official status and given the assigned value of 50 mIU/ampoule based on an earlier collaborative study.[31][33] It was determined that this preparation behaved anomalously in certain immunoassays and was not suitable as an IS.[31] However, in the absence of an alternative, it was used. Three different human pituitary extracts containing prolactin were subsequently obtained as candidates for an IS. These were distributed into ampoules coded 83/562, 83/573, and 84/500.[28][29][31][34] On the basis of collaborative studies involving 20 different laboratories, it was concluded that there was little difference between these three preparations. 83/562 appeared to be the most stable. This preparation was largely free of dimers and polymers of prolactin. On the basis of these investigations 83/562 was established as the Second IS for human Prolactin.[34] Once stocks of these ampoules were depleted, 84/500 was established as the Third IS for human Prolactin.[28][31]

Reference ranges[edit]

General guidelines for diagnosing prolactin excess (hyperprolactinemia) define the upper threshold of normal prolactin at 25 µg/L for women, and 20 µg/L for men.[26] Similarly, guidelines for diagnosing prolactin deficiency (hypoprolactinemia) are defined as prolatin levels below 3 µg/L in women,[36][37] and 5 µg/L in men.[38][39][40] However, different assays and methods for measuring prolactin are employed by different laboratories, and as such the serum reference range for prolactin is often determined by the laboratory performing the measurement.[26][41] Furthermore, prolactin levels also vary with, for example, age,[42] sex,[42] menstrual cycle stage,[42] and pregnancy.[42] The circumstances surrounding a given prolactin measurement (assay, patient condition, etc.) must therefore be considered before the measurement can be accurately interpreted.[26]

The following chart illustrates the variations seen in normal prolactin measurements across different populations. Prolactin values were obtained from specific control groups of varying sizes using the IMMULITE assay.[42]

Typical prolactin values
ProbandProlactin, µg/L
women, follicular phase (n = 803)
12.1
women, luteal phase (n = 699)
13.9
women, mid-cycle (n = 53)
17
women, whole cycle (n = 1555)
13.0
women, pregnant, 1st trimester (n = 39)
16
women, pregnant, 2nd trimester (n = 52)
49
women, pregnant, 3rd trimester (n = 54)
113
Men, 21–30 (n = 50)
9.2
Men, 31–40 (n = 50)
7.1
Men, 41–50 (n = 50)
7.0
Men, 51–60 (n = 50)
6.2
Men, 61–70 (n = 50)
6.9

Inter-method variability[edit]

The following table illustrates variability in reference ranges of prolactin between some commonly used assay methods (as of 2008), using a control group of healthy health care professionals (53 males, age 20–64 years, median 28 years; 97 females, age 19–59 years, median 29 years) in Essex, England:[41]

Assay methodMean
Prolactin
Lower limit
2.5th percentile
Upper limit
97.5th percentile
µg/LmIU/Lµg/LmIU/Lµg/LmIU/L
Females
Centaur7.921683.357116.4348
Immulite9.251963.547518.7396
Access9.061923.637719.3408
AIA9.52[43]257[43]3.89[43]105[43]20.3[43]548[43]
Elecsys10.52224.158823.2492
Architect10.62254.629821.1447
Males
Access6.891462.745813.1277
Centaur7.881672.976312.4262
Immulite7.451583.307013.3281
AIA7.81[43]211[43]3.30[43]89[43]13.5[43]365[43]
Elecsys8.491803.407215.6331
Architect8.871884.018514.6310

An example usage of table above is, if using the Centaur assay to estimate prolactin values in µg/L for females, the mean is 7.92 µg/L, and the reference range is 3.35–16.4 µg/L.

Conditions associated with elevated levels[edit]

Hyperprolactinaemia, or excess serum prolactin, is associated with hypoestrogenism, anovulatory infertility, oligomenorrhoea, amenorrhoea, unexpected lactation, and loss of libido in women, and erectile dysfunction and loss of libido in men.[44]

1. Physiological

    • Coitus
    • Exercise
    • Lactation
    • Pregnancy
    • Sleep
    • Stress

2. Pharmacological

    • Anesthetics
    • Anticonvulsant
    • Antihistamines (H2)
    • Antihypertensives
    • Cholinergic agonist
    • Drug-induced hypersecretion
    • Catecholamine depletor
    • Dopamine receptor blockers
    • Dopamine synthesis inhibitor
    • Estrogens
      • Oral contraceptives
      • Oral contraceptive withdrawal
    • Neuroleptics
    • Antipsychotics
    • Neuropeptides
    • Opiates and opiate antagonists

3. Pathological

    • Hypothalamic-pituitary stalk damage
      • Granulomas
      • Infiltrations
      • Irradiation
      • Rathke's cyst
    • Trauma
      • Pituitary stalk resection
      • Suprasellar surgery
    • Tumors
      • Craniopharyngioma
      • Germinoma
      • Hypothalamic metastases
      • Meningioma
      • Suprasellar pituitary mass extension
    • Pituitary
      • Acromegaly
      • Idiopathic
      • Lymphocytic hypophysitis or parasellar mass
      • Macroadenoma (compressive)
      • Macroprolactinemia
      • Plurihumoral adenoma
      • Prolactinoma
    • Surgery
    • Systemic disorders
      • Chest-neurologic chest wall trauma
      • Herpes Zoster
      • Chronic renal failure
      • Cirrhosis
      • Cranial radiation
      • Epileptic seizures
      • Polycystic ovarian disease
      • Pseudocyesis

Conditions associated with decreased levels[edit]

Hypoprolactinaemia, or serum prolactin deficiency, is associated with ovarian dysfunction in women,[36][37] and metabolic syndrome, anxiety, arteriogenic erectile dysfunction, premature ejaculation,[38] oligozoospermia, asthenospermia, hypofunction of seminal vesicles, and hypoandrogenism[39] in men. In one study, normal sperm characteristics were restored when prolactin levels were brought up to normal values in hypoprolactinemic men.[40]

Hypoprolactinemia can result from:

See also[edit]

References[edit]

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  24. ^ Kamel MA, Neulen J, Sayed GH, Salem HT, Breckwoldt M (September 1993). "Heterogeneity of human prolactin levels in serum during the early postpartum period". Gynecol. Endocrinol. 7 (3): 173–7. PMID 8291454. 
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  26. ^ a b c d e Mancini, T.; Casanueva, FF; Giustina, A (2008). "Hyperprolactinemia and Prolactinomas". Endocrinology & Metabolism Clinics of North America 37 (1): 67–99, viii. doi:10.1016/j.ecl.2007.10.013. PMID 18226731. 
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  29. ^ a b c "WHO Expert Committee on Biological Standardization". Thirty-ninth Report, WHO Technical Report Series. World Health Organization. 1989. Retrieved 2009-06-03. "86.1520, WHO/BS documents: 86.1520 Add 1, 88.1596" 
  30. ^ "WHO International Standard, Prolactin, Human. NIBSC code: 84/500, Instructions for use". WHO International Standard, Prolactin, Human. NIBSC code: 84/500, Instructions for use. NIBSC / Health Protection Agency. 1989. Retrieved 2011-03-21. 
  31. ^ a b c d e f Canadian Society of Clinical Chemists (Dec 1992). "Canadian Society of Clinical Chemists position paper: standardization of selected polypeptide hormone measurements". Clin Biochem. 25 (6): 415–24. doi:10.1016/0009-9120(92)90030-V. PMID 1477965. 
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  33. ^ a b "WHO Expert Committee on Biological Standardization". Thirty-fifth Report, WHO Technical Report Series. World Health Organization. 1985. Retrieved 2011-03-21. 
  34. ^ a b c "WHO Expert Committee on Biological Standardization". Thirty-seventh Report, WHO Technical Report Series. World Health Organization. 1987. Retrieved 2011-03-21. 
  35. ^ a b Bangham DR, Mussett MV, Stack-Dunne MP (1963). "The second International Standard for Prolactin". Bull World Health Organ. 29 (6): 721–8. PMC 2555104. PMID 14107744. 
  36. ^ a b Kauppila A, Martikainen H, Puistola U, Reinilä M, Rönnberg L (Mar 1988). "Hypoprolactinemia and ovarian function". Fertil Steril. 49 (3): 437–41. PMID 3342895. 
  37. ^ a b Schwärzler P, Untergasser G, Hermann M, Dirnhofer S, Abendstein B, Berger P (Oct 1997). "Prolactin gene expression and prolactin protein in premenopausal and postmenopausal human ovaries". Fertil Steril. 68 (4): 696–701. doi:10.1016/S0015-0282(97)00320-8. PMID 9341613. 
  38. ^ a b Corona G, Mannucci E, Jannini EA, Lotti F, Ricca V, Monami M, Boddi V, Bandini E, Balercia G, Forti G, Maggi M (May 2009). "Hypoprolactinemia: a new clinical syndrome in patients with sexual dysfunction". J Sex Med. 6 (5): 1457–66. doi:10.1111/j.1743-6109.2008.01206.x. PMID 19210705. 
  39. ^ a b Gonzales GF, Velasquez G, Garcia-Hjarles M (1989). "Hypoprolactinemia as related to seminal quality and serum testosterone". Arch Androl. 23 (3): 259–65. doi:10.3109/01485018908986849. PMID 2619414. 
  40. ^ a b Ufearo CS, Orisakwe OE (September 1995). "Restoration of normal sperm characteristics in hypoprolactinemic infertile men treated with metoclopramide and exogenous human prolactin". Clin Pharmacol Ther. 58 (3): 354–9. doi:10.1016/0009-9236(95)90253-8. PMID 7554710. 
  41. ^ a b Table 2 in Beltran L, Fahie-Wilson MN, McKenna TJ, Kavanagh L, Smith TP (October 2008). "Serum total prolactin and monomeric prolactin reference intervals determined by precipitation with polyethylene glycol: evaluation and validation on common immunoassay platforms". Clin. Chem. 54 (10): 1673–81. doi:10.1373/clinchem.2008.105312. PMID 18719199. 
  42. ^ a b c d e Prolaktin at medical.siemens.com—reference ranges as determined from the IMMULITE assay method
  43. ^ a b c d e f g h i j k l The AIA essay values are also from Table 2 in Beltran 2008, like the other values, but it uses a different conversion factor of 27.0 mIU/L per µg/L, taken from the second international standard, IS 83/562).
  44. ^ Melmed S, Kleinberg D 2008 Anterior pituitary. 1n: Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, eds. Willams textbook of endocrinology. 11th ed. Philadelphia: Saunders Elsevier; 185-261

External links[edit]