Prolactin (PRL), also known aslactotropin andmammotropin, is aprotein best known for its role in enabling mammals toproduce milk. It is influential in over 300 separate processes in various vertebrates, including humans.[5] Prolactin is secreted from thepituitary gland in response to eating, mating, estrogen treatment, ovulation and nursing. It is secreted heavily in pulses in between these events. Prolactin plays an essential role in metabolism, regulation of theimmune system and pancreatic development.[6][7]
In mammals, prolactin is associated with milk production; in fish it is thought to be related to the control of water and salt balance. Prolactin also acts in acytokine-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 influenceshematopoiesis andangiogenesis and is involved in the regulation of blood clotting through several pathways. The hormone acts inendocrine,autocrine, andparacrine manners through theprolactin receptor and numerouscytokine receptors.[5]
Several variants and forms are known per species. Many fish have variantsprolactin A andprolactin B. Most vertebrates, including humans, also have the closely related somatolactin. In humans, 14, 16, and 22 kDa variants exist.[11]
Prolactin has a wide variety of effects. It stimulates themammary glands to produce milk (lactation): increased serum concentrations of prolactin duringpregnancy cause enlargement of the mammary glands and prepare for milk production, which normally starts when levels ofprogesterone fall by the end of pregnancy and a suckling stimulus is present. Prolactin plays an important role inmaternal behavior.[12]
It has been shown in rats and sheep that prolactin affects lipid synthesis differentially in mammary and adipose cells. Prolactin deficiency induced by bromocriptine increased lipogenesis and insulin responsiveness in adipocytes while decreasing them in the mammary gland.[13]
In general,dopamine inhibits prolactin[14] but this process has feedback mechanisms.[15]
Elevated levels of prolactin decrease the levels of sex hormones—estrogen in women andtestosterone in men.[16] The effects of mildly elevated levels of prolactin are much more variable, in women, substantially increasing or decreasing estrogen levels.
Prolactin is sometimes classified as agonadotropin[17] although in humans it has only a weak luteotropic effect while the effect of suppressing classical gonadotropic hormones is more important.[18] Prolactin within the normal reference ranges can act as a weak gonadotropin, but at the same time suppressesgonadotropin-releasing hormone secretion. The exact mechanism by which it inhibits gonadotropin-releasing hormone is poorly understood. Although expression of prolactin receptors have been demonstrated in rat hypothalamus, the same has not been observed in gonadotropin-releasing hormone neurons.[19] Physiologic levels of prolactin in males enhanceluteinizing hormone-receptors inLeydig cells, resulting in testosterone secretion, which leads tospermatogenesis.[20]
Inmusic psychology, it is conjectured that prolactin may play a role in the pleasurable perception of sad music, as the levels of the hormone increase when a person feels sad, producing a consoling psychological effect.[24]
The primary function of prolactin infish isosmoregulation,[25] i.e., controlling the movement of water and salts between the tissues of the fish and the surrounding water. Like mammals, however, prolactin in fish also has reproductive functions, including promoting sexual maturation and inducing breeding cycles, as well as brooding and parental care.[26] In the South Americandiscus, prolactin may also regulate the production of a skin secretion that provides food for larvalfry.[27] An increase in brooding behaviour caused by prolactin has been reported inhens.[28]
Prolactin andits receptor are expressed in the skin, specifically in the hair follicles, where they regulate hair growth and moulting in anautocrine fashion.[29][30] Elevated levels of prolactin can inhibit hair growth,[31] and knock-outmutations in the prolactin gene cause increased hair length in cattle[32] and mice.[30] Conversely, mutations in the prolactin receptor can cause reduced hair growth, resulting in the "slick" phenotype in cattle.[32][33] Additionally, prolactin delays hair regrowth in mice.[34]
Analogous to its effects on hair growth and shedding in mammals, prolactin in birds controls themoulting of feathers,[35] as well as the age at onset of feathering in both turkeys and chickens.[36]Pigeons,flamingos and maleemperor penguins feed their young a cheese-like secretion from the upper digestive tract calledcrop milk, whose production is regulated by prolactin.[37][38]
In rodents,pseudopregnancy can occur when a female is mated with a sterile male. This mating can cause bi-daily surges of prolactin which would normally occur in rodent pregnancy.[39] Prolactin surges initiate the secretion of progesterone which maintains pregnancy and hence can initiate pseudopregnancy. The false maintenance of pregnancy exhibits the outward physical symptoms of pregnancy, in the absence of a foetus.[40]
Prolactin receptor activation is essential for normalmammary gland development duringpuberty in mice.[41] Adult virgin female prolactin receptorknockout mice have much smaller and less developed mammary glands than theirwild-type counterparts.[41] Prolactin and prolactin receptor signaling are also essential for maturation of the mammary glands during pregnancy in mice.[41]
Pituitary prolactin is controlled by thePit-1transcription factor, which binds to the gene at several sites including a proximal promoter.[43] This promoter is inhibited by dopamine and stimulated by estrogens, neuropeptides, and growth factors.[44] Estrogens can also suppress dopamine.
Interaction with neuropeptides is still a matter of active research: no specificprolactin-releasing hormone has been identified. It is known that mice react to bothVIP andTRH, but humans seem to only react to TRH. There areprolactin-releasing peptides that workin vitro, but whether they deserve their name has been questioned.Oxytocin does not play a large role. Mice without a posterior pituitary do not raise their prolactin levels even with suckling and oxytocin injection, but scientists have yet to identify which specific hormone produced by this region is responsible.[45]
Extrapituitary prolactin is controlled by a superdistal promoter, located 5.8 kb upstream of the pituitary start site. The promoter does not react to dopamine, estrogens, or TRH. Instead, it is stimulated bycAMP. Responsiveness to cAMP is mediated by an imperfect cAMP–responsive element and two CAAT/enhancer binding proteins (C/EBP).[43]Progesterone upregulates prolactin synthesis in theendometrium but decreases it inmyometrium and breast glandular tissue.[47]
Breast and other tissues may express the Pit-1 promoter in addition to the distal promoter.Oct-1 appears able to substitute for Pit-1 in activating the promoter in breast cancer cells.[45]
Extrapituitary production of prolactin is thought to be special to humans and primates and may serve mostly tissue-specificparacrine andautocrine purposes. It has been hypothesized that in vertebrates such as mice a similar tissue-specific effect is achieved by a large family of prolactin-like proteins controlled by at least 26 paralogousPRL genes not present in primates.[43]
Prolactin followsdiurnal andovulatory cycles. Prolactin levels peak during REM sleep and in the early morning. Many mammals experience a seasonal cycle.[38]
Duringpregnancy, high circulating concentrations of estrogen and progesterone increase prolactin levels by 10- to 20-fold. Estrogen and progesterone inhibit the stimulatory effects of prolactin on milk production. The abrupt drop of estrogen and progesterone levels following delivery allow prolactin—which temporarily remains high—to induce lactation.[48]
Sucking on the nipple offsets the fall in prolactin as the internal stimulus for them is removed. The sucking activates mechanoreceptors in and around the nipple. These signals are carried by nerve fibers through the spinal cord to thehypothalamus, where changes in the electrical activity of neurons that regulate thepituitary gland increase prolactin secretion. The suckling stimulus also triggers the release ofoxytocin from theposterior 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. The posterior pituitary produces a yet-unidentified hormone that causes prolactin production.[45]
In usual circumstances, in the absence ofgalactorrhea, lactation ceases within one or two weeks following the end ofbreastfeeding.
Levels can rise after exercise, high-protein meals, minor surgical procedures,[49] followingepileptic seizures[50] or due to physical or emotionalstress.[51][52] In a study on female volunteers under hypnosis, prolactin surges resulted from the evocation, with rage, of humiliating experiences, but not from the fantasy of nursing.[52] Stress-induced PRL changes are not linked to the posterior pituitary in rodents.[45]
Hypersecretion is more common than hyposecretion. Hyperprolactinemia is the most frequent abnormality of the anterior pituitary tumors, termedprolactinomas. Prolactinomas may disrupt thehypothalamic-pituitary-gonadal axis as prolactin tends to suppress the secretion of gonadotropin-releasing hormone from the hypothalamus and in turn decreases the secretion offollicle-stimulating hormone andluteinizing hormone from the anterior pituitary, therefore disrupting theovulatory cycle.[53] Such hormonal changes may manifest asamenorrhea and infertility in females as well aserectile dysfunction in males.[54][7] Inappropriate lactation (galactorrhoea) is another important clinical sign of prolactinomas.
Little prolactin—the predominant form.[55] It has amolecular weight of approximately 23-kDa.[55] It is a single-chainpolypeptide of 199amino acids and is apparently the result of removal of some amino acids.
Big prolactin—approximately 48 kDa.[55] It may be the product of interaction of several prolactin molecules. It appears to have little, if any, biological activity.[56]
Macroprolactin—approximately 150 kDa.[55] It appears to have a low biological activity.[57]
Other variants with the molecular masses of 14, 16, and 22 kDa.[11]
The levels of larger ones are somewhat higher during the earlypostpartum period.[58]
Prolactin levels may be checked as part of asex hormone workup, as elevated prolactin secretion can suppress the secretion of follicle stimulating hormone and gonadotropin-releasing hormone, leading tohypogonadism and sometimes causingerectile dysfunction.[61]
The serum concentration of prolactin can be given inmass concentration (μg/L orng/mL),molar concentration (nmol/L orpmol/L), orinternational units (typically mIU/L). The current IU is calibrated against the third International Standard for Prolactin, IS 84/500.[63][64] Reference ampoules of IS 84/500 contain "approximately" 2.5 μg oflyophilized human prolactin[65] and have been assigned an activity of 0.053 International Units by calibrating against the previous standard.[63][64] Measurements can be converted into mass units using this ratio of grams to IUs to obtain an equivalent in relationship to the contents of IS 84/500;[66] prolactin concentrations expressed in mIU/L can be converted to μg/L of IS 84/500 equivalent by dividing by 21.2. Previous standards had other ratios in relation to their potency on the assay measurement. For example, the previous IS (83/562) had a potency of 27.0 mIU per μg.[67][68][69][70]
The firstInternational 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.[66][67] Previous standards relied on prolactin from animal sources.[70] Purified human prolactin was scarce, heterogeneous, unstable, and difficult to characterize. A preparation labeled 81/541 was distributed by theWHO Expert Committee on Biological Standardization without official status and given the assigned value of 50 mIU/ampoule based on an earlier collaborative study.[66][68] It was determined that this preparation behaved anomalously in certainimmunoassays and was not suitable as an IS.[66]
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.[63][64][66][69] Collaborative studies involving 20 different laboratories found little difference between these three preparations. 83/562 appeared to be the most stable. This preparation was largely free of dimers andpolymers of prolactin. On the basis of these investigations, 83/562 was established as the Second IS for human prolactin.[69] Once stocks of these ampoules were depleted, 84/500 was established as the Third IS for human prolactin.[63][66]
84/500 has nearly run out and in 2016 replacement was proposed. The new 83/573 contains 67.2 mIU per ampoule when calibrated against the third IS and contains 1.002 g of human pituitary extract each (which is then lyophilized). Each ampoule contains approximately 3.2 μg of prolactin. Theassigned value will be 67 mIU per ampoule. If a fifth IS is needed, it will likely be based onrecombinant protein, as WHO has not received any further donations of human pituitary extracts.[71]
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.[59] Similarly, guidelines for diagnosing prolactin deficiency (hypoprolactinemia) are defined as prolactin levels below 3 μg/L in women[72][73] and 5 μg/L in men.[74][75][76] However, different assays and methods for measuring prolactin are employed by different laboratories and as such theserum reference range for prolactin is often determined by the laboratory performing the measurement.[59][77] Furthermore, prolactin levels vary according to factors as age,[78] sex,[78]menstrual cycle stage[78] and pregnancy.[78] The circumstances surrounding a given prolactin measurement (assay, patient condition, etc.) must therefore be considered before the measurement can be accurately interpreted.[59]
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 IMMULITEassay.[78]
The following table illustrates variability in reference ranges of serum 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) inEssex, England:[77]
An example of the use of the above table is, if using the Centaur assay to estimate prolactin values in μg/L for females, the mean is 168 mIU/L (7.92 μg/L) and the reference range is 71–348 mIU/L (3.35–16.4 μg/L).
Prolactin is available commercially for use in other animals, but not in humans.[81] It is used to stimulate lactation in animals.[81] Thebiological half-life of prolactin in humans is around 15–20 minutes.[82] The D2 receptor is involved in the regulation of prolactin secretion, and agonists of the receptor such asbromocriptine andcabergoline decrease prolactin levels while antagonists of the receptor such asdomperidone,metoclopramide,haloperidol,risperidone, andsulpiride increase prolactin levels.[83] D2 receptor antagonists like domperidone, metoclopramide, and sulpiride are used asgalactogogues to increase prolactin secretion in the pituitary gland and induce lactation in humans.[84]
^abBeltran 2008Table 2Archived 9 November 2011 at theWayback Machine reports measurements in mIU/L. AIA machines are calibrated to read the correct amount of μg/L against the second international standard IS 83/562, which has a potency of 27.0 mIU per μg.[79] By converting these measurements to mIU/L, Beltran makes measurements from machines calibrated against the second and third IS comparable, because the third IS is calibrated against the second to maintain the magnitude of the IU. However, the raw readout of the machine will still be in μg/L of IS-83/562-equivalent, unlike the other machines which report in μg/L of IS-84/500-equivalent.
^Ben-Jonathan N, Hugo ER, Brandebourg TD, LaPensee CR (April 2006). "Focus on prolactin as a metabolic hormone".Trends in Endocrinology and Metabolism.17 (3):110–116.doi:10.1016/j.tem.2006.02.005.PMID16517173.S2CID37979194.
^Evans AM, Petersen JW, Sekhon GS, DeMars R (May 1989). "Mapping of prolactin and tumor necrosis factor-beta genes on human chromosome 6p using lymphoblastoid cell deletion mutants".Somatic Cell and Molecular Genetics.15 (3):203–13.doi:10.1007/BF01534871.PMID2567059.S2CID36302971.
^Ros M, Lobato MF, García-Ruíz JP, Moreno FJ (March 1990). "Integration of lipid metabolism in the mammary gland and adipose tissue by prolactin during lactation".Molecular and Cellular Biochemistry.93 (2):185–94.doi:10.1007/BF00226191.PMID2345543.S2CID19824793.
^Freeman ME, Kanyicska B, Lerant A, Nagy G (October 2000). "Prolactin: structure, function, and regulation of secretion".Physiological Reviews.80 (4):1523–631.doi:10.1152/physrev.2000.80.4.1523.PMID11015620.
^Sakamoto T, McCormick SD (May 2006). "Prolactin and growth hormone in fish osmoregulation".General and Comparative Endocrinology.147 (1):24–30.doi:10.1016/j.ygcen.2005.10.008.PMID16406056.
^Khong HK, Kuah MK, Jaya-Ram A, Shu-Chien AC (May 2009). "Prolactin receptor mRNA is upregulated in discus fish (Symphysodon aequifasciata) skin during parental phase".Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology.153 (1):18–28.doi:10.1016/j.cbpb.2009.01.005.PMID19272315.
^Dawson A (July 2006). "Control of molt in birds: association with prolactin and gonadal regression in starlings".General and Comparative Endocrinology.147 (3):314–22.doi:10.1016/j.ygcen.2006.02.001.PMID16530194.
^Kulick RS, Chaiseha Y, Kang SW, Rozenboim I, El Halawani ME (July 2005). "The relative importance of vasoactive intestinal peptide and peptide histidine isoleucine as physiological regulators of prolactin in the domestic turkey".General and Comparative Endocrinology.142 (3):267–73.doi:10.1016/j.ygcen.2004.12.024.PMID15935152.
^Garnier PE, Aubert ML, Kaplan SL, Grumbach MM (December 1978). "Heterogeneity of pituitary and plasma prolactin in man: decreased affinity of "Big" prolactin in a radioreceptor assay and evidence for its secretion".The Journal of Clinical Endocrinology and Metabolism.47 (6):1273–81.doi:10.1210/jcem-47-6-1273.PMID263349.
^Leite V, Cosby H, Sobrinho LG, Fresnoza MA, Santos MA, Friesen HG (October 1992). "Characterization of big, big prolactin in patients with hyperprolactinaemia".Clinical Endocrinology.37 (4):365–72.doi:10.1111/j.1365-2265.1992.tb02340.x.PMID1483294.S2CID42796831.
^Kamel MA, Neulen J, Sayed GH, Salem HT, Breckwoldt M (September 1993). "Heterogeneity of human prolactin levels in serum during the early postpartum period".Gynecological Endocrinology.7 (3):173–7.doi:10.3109/09513599309152499.PMID8291454.
^abcdeMancini T, Casanueva FF, Giustina A (March 2008). "Hyperprolactinemia and prolactinomas".Endocrinology and Metabolism Clinics of North America.37 (1):67–99, viii.doi:10.1016/j.ecl.2007.10.013.PMID18226731.
^Al-Chalabi M, Bass AN, Alsalman I (2023),"Physiology, Prolactin",StatPearls, Treasure Island (FL): StatPearls Publishing,PMID29939606, retrieved10 January 2024
^Banerjee S, Paul P, Talib VJ (August 2004). "Serum prolactin in seizure disorders".Indian Pediatrics.41 (8):827–31.PMID15347871.
^abcdSchulster D, Gaines Das RE, Jeffcoate SL (April 1989). "International Standards for human prolactin: calibration by international collaborative study".The Journal of Endocrinology.121 (1):157–66.doi:10.1677/joe.0.1210157.PMID2715755.
^abcdefCanadian Society of Clinical Chemists (December 1992). "Canadian Society of Clinical Chemists position paper: standardization of selected polypeptide hormone measurements".Clinical Biochemistry.25 (6):415–24.doi:10.1016/0009-9120(92)90030-V.PMID1477965.
^abGaines Das RE, Cotes PM (January 1979). "International Reference Preparation of human prolactin for immunoassay: definition of the International Unit, report of a collaborative study and comparison of estimates of human prolactin made in various laboratories".The Journal of Endocrinology.80 (1):157–68.doi:10.1677/joe.0.0800157.PMID429949.
^abKauppila A, Martikainen H, Puistola U, Reinilä M, Rönnberg L (March 1988). "Hypoprolactinemia and ovarian function".Fertility and Sterility.49 (3):437–41.doi:10.1016/s0015-0282(16)59769-6.PMID3342895.
^abCorona 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".The Journal of Sexual Medicine.6 (5):1457–66.doi:10.1111/j.1743-6109.2008.01206.x.PMID19210705.
^abGonzales GF, Velasquez G, Garcia-Hjarles M (1989). "Hypoprolactinemia as related to seminal quality and serum testosterone".Archives of Andrology.23 (3):259–65.doi:10.3109/01485018908986849.PMID2619414.
^abUfearo CS, Orisakwe OE (September 1995). "Restoration of normal sperm characteristics in hypoprolactinemic infertile men treated with metoclopramide and exogenous human prolactin".Clinical Pharmacology and Therapeutics.58 (3):354–9.doi:10.1016/0009-9236(95)90253-8.PMID7554710.S2CID1735908.
