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Prolactin


Author:Elabscience
views:1428

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

Discovered innon-human animals around 1930 by Oscar Riddle, and confirmed in humans in 1970by Henry Friesenprolactin is apeptide hormone, encoded by the PRL gene.

Although oftenassociated with human milk production, prolactin plays a wide range of otherroles in both humans and other vertebrates. (For example, in fish—the oldestknown vertebrates—an important function is probably related to control of waterand salt balance.) Prolactin also acts in a cytokine-like manner and as animportant regulator of the immune system. It has important cell cycle relatedfunctions as a growth-, differentiating- and anti-apoptotic factor. As a growthfactor, binding to cytokine like receptors, it also has profound influence onhematopoiesis,angiogenesis and is involved in the regulation of blood clottingthrough several pathways. The hormone acts in endocrine, autocrine, andparacrine manner through the prolactin receptorand a large number of cytokinereceptors.

Pituitaryprolactin secretion is regulated by endocrine neurons in the hypothalamus, themost important ones being the neurosecretory tuberoinfundibulum (TIDA) neuronsof the arcuate nucleus, which secrete dopamine (aka Prolactin InhibitoryHormone) to act on the D2 receptors of lactotrophs, causinginhibition ofprolactin secretion. Thyrotropin-releasing factor(thyrotropin-releasinghormone) has a stimulatory effect on prolactin release.

Several variantsand forms are known per species. Many fish have variants prolactin A and prolactinB. Most vertebrates including humans also have the closely relatedsomatolactin. In humans, three smaller (4, 16, and 22kDa) and several larger (so called big andbig-big) variants exist.

Effects

Prolactin has awide range of effects. It stimulates the mammary glands to produce milk(lactation): increased serum concentrations of prolactin during pregnancy causeenlargement of the mammary glands of the breasts and prepare for the productionof milk. Milk production normally starts when the levels of progesterone fallby the end of pregnancy and a suckling stimulus is present. Sometimes, newbornbabies (males as well as females) secrete a milky substance from their nipplesknown as witch's milk. This is in part caused by maternal prolactin and otherhormones.

Prolactinprovides the body with sexual gratification after sexual acts: The hormonecounteracts the effect ofdopamine, which is responsible for sexual arousal.This is thought to cause the sexual refractory period. The amount of prolactincan be an indicator for the amount of sexual satisfaction and relaxation.Unusually high amounts are suspected to be responsible for impotence and lossof libido (see hyperprolactinemia symptoms).

Highly elevatedlevels of prolactin decrease the levels of sex hormones — estrogen in women andtestosteronein men. The effects of mildly elevated levels of prolactin are muchmore variable, in women both substantial increase or decrease of estrogenlevels may result.

Prolactin issometimes classified as a gonadotropin although in humans it has only a weakluteotropic effect while the effect of suppressing classical gonadotropichormones is more important. Prolactin within the normal reference ranges canact as a weak gonadotropin but at the same time suppresses GnRH secretion. Theexact mechanism by which it inhibits GnRH is poorly understood althoughexpression of prolactin receptors (PRL-R) have been demonstrated in rat'shypothalmus, the same has not been observed in GnRH neurons. Physiologic levelsof prolactin in males enhance luteinizing hormone-receptors in Leydig cells,resulting in testosterone secretion, which leads to spermatogenesis.

Prolactin alsostimulates proliferation of oligodendrocyte precursor cells. These cellsdifferentiate intooligodendrocytes, the cells responsible for the formation ofmyelin coatings on axons in the central nervous system.

Prolactin alsohas a number of other effects including contributing to surfactant synthesis ofthe fetal lungsat the end of the pregnancy and immune tolerance of the fetus bythe maternal organism during pregnancy.

Prolactin delayshair regrowth in mice.

Prolactinpromotes neurogenesis in maternal and fetal brains.

Production and regulation

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

Pituitary PRL iscontrolled by the Pit-1 transcription factor and ultimately dopamine,extrapituitary PRL is controlled by a superdistal promoter and apparentlyunaffected by dopamine.

In decidualcells and in lymphocytes the distal promoter and thus prolactin expression isstimulated by cAMP. Responsivness to cAMP is mediated by an imperfectcAMP–responsive element and two CAAT/enhancer binding proteins (C/EBP).Progesterone has been observed to upregulate prolactin synthesis in theendometrium but decreases it in myometrium and breast glandular tissue. Howeverbreast and other tissues may also express the Pit-1 promoter in addition to thedistal promoter.

Extrapituitaryproduction of prolactin is thought to be special to humans and primates and mayserve mostly tissue specific paracrine and autocrine purposes. It has beenhypothesized that in other vertebrates such as mice a similar tissue specificeffect is achieved by a large family of prolactin like proteins controlled byat least 26 paralogous PRL genes not present in primates.

Vasoactiveintestinal peptide and peptide histidine isoleucine help to regulate prolactinsecretion in humans, but the functions of these hormones in birds can be quitedifferent.

Variance in levels

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

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

Afterchildbirth, 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 inand around the nipple. These signals are carried by nerve fibers through thespinal cord to the hypothalamus, where changes in the electrical activity ofneurons that regulate the pituitary gland cause increased prolactin secretion.The suckling stimulus also triggers the release of oxytocin from the posteriorpituitary gland, which triggers milk let-down: Prolactin controls milkproduction (lactogenesis) but not the milk-ejection reflex; the rise inprolactin fills the breast with milk in preparation for the next feed.

In usualcircumstances, in the absence of galactorrhea, lactation will cease within oneor two weeks of the end of demand breastfeeding.

It has also beenfound that compared to un-mated males, fathers and expectant fathers haveincreased prolactin concentrations.

High prolactinlevels can also contribute to mental health issues.

Prolactin levelspeak during REM sleep, and in the early morning. Levels can rise afterexercise, meals, sexual intercourse, minor surgical procedures, or followingepileptic seizures.

Hypersecretionof prolactin is more common than hyposecretion. Hyperprolactinemia is the mostfrequent abnormality of the anterior pituitary tumors, termed prolactinomas.Prolactinomas may disrupt the hypothalamic-pituitary-gonadal axis as prolactintends to suppress the secretion of GnRH from the hypothalamus and in turndecreases the section of FSH and LH from the anterior pituitary, thereforedisrupting the ovulatory cycle in females. Such hormonal changes may manifestas amenorrhea and infertility in females as well as impotence in males.Inappropriate lactation is another important clinical sign of prolactinomas.

Structure and isoforms

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

There are mainlythree different forms of prolactin in regard to size:

Little prolactinis the predominant form. It has a molecular weight of appxoximately 22-kDa. Itis a single-chain polypeptide of 198 amino acids, and is apparently the resultof removal of some amino acids.

Big prolactin ofapproximately 48 kDa. It may be the product of interaction of several prolactinmolecules. It appears to have little, if any, biological activity.

Big bigprolactin of approximately 150 kDa. It appears to have a low biologicalactivity.

The levels oflarger ones are somewhat higher during the early postpartum period.

Pit-1 is atranscription factor that binds to the prolactin gene at several sites to allowfor the production of prolactin in the pituitary gland. A key regulator ofprolactin production is estrogens that enhance growth of prolactin-producingcells and stimulate prolactin production directly, as well as suppressingdopamine.

Human prolactinreceptors are insensitive to mouse prolactin.

Prolactin receptor

Main article:Prolactin receptor

Prolactinreceptors 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. When prolactinbinds to the receptor, it causes it to dimerize with another prolactinreceptor. This results in the activation of Janus kinase 2, a tyrosine kinasethat initiates the JAK-STAT pathway. The activation of the prolactin receptor alsoresults in the activation of mitogen-activated protein kinases andSrc kinase.

Diagnostic use

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

Prolactin levelsmay be of some use in distinguishing epileptic seizures from psychogenicnon-epileptic seizures. The serum prolactin level usually rises following anepileptic seizure.

Units and unit conversions

The serumconcentration of prolactin can be given in mass concentration (µg/L or ng/mL),molar concentration(nmol/L or pmol/L) or in international units (typicallymIU/L). The current IU is calibrated against the third International Standardfor Prolactin, IS 84/500. Reference ampoules of IS 84/500 contain 2.5 µgoflyophilized human prolactin, and have been assigned an activity of .053International Units of prolactin. Measurements that are calibrated against thecurrent international standard can be converted into mass units using thisratio of grams to IUs; prolactin concentrations expressed in mIU/L can beconverted to µg/L by dividing by 21.2. Previous standards use other ratios.

The firstInternational Reference Preparation (or IRP) of human Prolactin for Immunoassaywas established in 1978 (75/504 1st IRP for human Prolactin) at a time whenpurified human prolactin was in short supply.Previous standards relied onprolactin from animal sources. Purified human prolactin was scarce, heterogeneous,unstable, and difficult to characterize. A preparation labelled 81/541 wasdistributed by theWHO Expert Committee on Biological Standardization withoutofficial status and given the assigned value of 50 mIU/ampoule based on anearlier collaborative study. It was determined that this preparation behavedanomalously in certain immunoassays and was not suitable as an IS. However, inthe absence of an alternative, it was used. Three different human pituitaryextracts containing prolactin were subsequently obtained as candidates for anIS. These were distributed into ampoules coded 83/562, 83/573, and 84/500. Onthe basis of collaborative studies involving 20 different laboratories, it wasconcluded that there was little difference between these three preparations.83/562 appeared to be the most stable. This preparation was largely free ofdimers and polymers of prolactin. On the basis of these investigations 83/562was established as the Second IS for human Prolactin. Once stocks of theseampoules were depleted, 84/500 was established as the Third IS for humanProlactin.

Reference ranges

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

The followingchart illustrates the variations seen in normal prolactin measurements acrossdifferent populations. Prolactin values were obtained from specific controlgroups of varying sizes using the IMMULITE assay.

Typical prolactin values

Proband Prolactin

µg/L

women,  follicular phase (n = 803)

12.1

women, luteal  phase (n = 699)

13.9

women, luteal  phase (n = 699)

13.9

women,  mid-cycle (n = 53)

17

women, whole  cycle (n = 1555)

13

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

Men, 51–60 (n  = 50)

6.2

Men, 61–70 (n  = 50)

6.9


Inter-method variability

The followingtable illustrates variability in reference ranges of prolactin between somecommonly used assay methods (as of 2008), using a control group of healthyhealth care professionals (53 males, age 20–64 years, median 28 years; 97females, age 19–59 years, median 29 years) in Essex, England:

Assay method

Mean
 Prolactin

Lower limit
2.5th percentile

Upper limit
97.5th  percentile

µg/L

mIU/L

µg/L

mIU/L

µg/L

mIU/L

Females

Centaur

7.92

168

3.35

71

16.4

348

Immulite

9.25

196

3.54

75

18.7

396

Access

9.06

192

3.63

77

19.3

408

AIA

9.52

257

3.89

105

20.3

548

Elecsys

10.5

222

4.15

88

23.2

492

Architect

10.6

225

4.62

98

21.1

447

Males

Access

6.89

146

2.74

58

13.1

277

Centaur

7.88

167

2.97

63

12.4

262

Immulite

7.45

158

3.30

70

13.3

281

AIA

7.81

211

3.30

89

13.5

365

Elecsys

8.49

180

3.40

72

15.6

331

Architect

8.87

188

4.01

85

14.6

310


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



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