prolactin

Prolactin has a wide variety of effects. It stimulates the mammary glands to produce milk (lactation): increased serum concentrations of prolactin during pregnancy cause enlargement of the mammary glands and prepare for milk production, which normally starts when levels of progesterone fall by the end of pregnancy and a suckling stimulus is present. Prolactin plays an important role in maternal behavior.{{cite journal | vauthors = Lucas BK, Ormandy CJ, Binart N, Bridges RS, Kelly PA | title = Null mutation of the prolactin receptor gene produces a defect in maternal behavior | journal = Endocrinology | volume = 139 | issue = 10 | pages = 4102–7 | date = Oct 1998 | pmid = 9751488 | doi = 10.1210/endo.139.10.6243 | doi-access = free }}

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.{{cite journal|vauthors=Ros M, Lobato MF, García-Ruíz JP, Moreno FJ|title=Integration of lipid metabolism in the mammary gland and adipose tissue by prolactin during lactation|journal=Molecular and Cellular Biochemistry|volume=93|issue=2|pages=185–94|date=March 1990|pmid=2345543|doi=10.1007/BF00226191 |s2cid=19824793 }}

In general, dopamine inhibits prolactin{{cite journal | vauthors = Ben-Jonathan N | title = Dopamine: a prolactin-inhibiting hormone | journal = Endocrine Reviews | volume = 6 | issue = 4 | pages = 564–89 | date = 1985 | pmid = 2866952 | doi = 10.1210/edrv-6-4-564 }} but this process has feedback mechanisms.{{cite journal | vauthors = Freeman ME, Kanyicska B, Lerant A, Nagy G | title = Prolactin: structure, function, and regulation of secretion | journal = Physiological Reviews | volume = 80 | issue = 4 | pages = 1523–631 | date = October 2000 | pmid = 11015620 | doi = 10.1152/physrev.2000.80.4.1523 }}

Elevated levels of prolactin decrease the levels of sex hormones—estrogen in women and testosterone in men.[http://www.mayoclinic.com/health/prolactinoma/DS00532 Prolactinoma]—Mayo Clinic 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 a gonadotropin{{cite book |vauthors=Hoehn K, Marieb EN | title = Human Anatomy & Physiology |url=https://archive.org/details/humananatomyphys0000mari_r3o8 |url-access=registration | publisher = Pearson Benjamin Cummings | location = San Francisco | year = 2007 | isbn = 978-0-8053-5909-1 | page = 605 }} although in humans it has only a weak luteotropic effect while the effect of suppressing classical gonadotropic hormones is more important.{{MeSH name|Gonadotropins}} Prolactin within the normal reference ranges can act as a weak gonadotropin, but at the same time suppresses gonadotropin-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.{{cite journal | vauthors = Grattan DR, Jasoni CL, Liu X, Anderson GM, Herbison AE | title = Prolactin regulation of gonadotropin-releasing hormone neurons to suppress luteinizing hormone secretion in mice | journal = Endocrinology | volume = 148 | issue = 9 | pages = 4344–51 | date = Sep 2007 | pmid = 17569755 | doi = 10.1210/en.2007-0403 | doi-access = free }} Physiologic levels of prolactin in males enhance luteinizing hormone-receptors in Leydig cells, resulting in testosterone secretion, which leads to spermatogenesis.{{cite journal | vauthors = Hair WM, Gubbay O, Jabbour HN, Lincoln GA | title = Prolactin receptor expression in human testis and accessory tissues: localization and function | journal = Molecular Human Reproduction | volume = 8 | issue = 7 | pages = 606–11 | date = Jul 2002 | pmid = 12087074 | doi = 10.1093/molehr/8.7.606 | doi-access = free }}

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.{{cite journal | vauthors = Gregg C, Shikar V, Larsen P, Mak G, Chojnacki A, Yong VW, Weiss S | title = White matter plasticity and enhanced remyelination in the maternal CNS | journal = The Journal of Neuroscience | volume = 27 | issue = 8 | pages = 1812–23 | date = Feb 2007 | pmid = 17314279 | pmc = 6673564 | doi = 10.1523/JNEUROSCI.4441-06.2007 }}

Other actions include contributing to pulmonary 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 promotes neurogenesis in maternal and fetal brains.{{cite journal | vauthors = Shingo T, Gregg C, Enwere E, Fujikawa H, Hassam R, Geary C, Cross JC, Weiss S | title = Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin | journal = Science | volume = 299 | issue = 5603 | pages = 117–20 | date = Jan 2003 | pmid = 12511652 | doi = 10.1126/science.1076647 | bibcode = 2003Sci...299..117S | s2cid = 38577726 }}{{cite journal | vauthors = Larsen CM, Grattan DR | title = Prolactin, neurogenesis, and maternal behaviors | journal = Brain, Behavior, and Immunity | volume = 26 | issue = 2 | pages = 201–9 | date = Feb 2012 | pmid = 21820505 | doi = 10.1016/j.bbi.2011.07.233 | s2cid = 27182670 }}

In music 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.{{Cite journal |last=Huron |first=David |date=2011-07-13 |title=Why is sad music pleasurable? A possible role for prolactin |url=https://journals.sagepub.com/doi/abs/10.1177/1029864911401171 |journal= Musicae Scientiae|volume=15 |issue=2|pages=146–158 |doi=10.1177/1029864911401171 |s2cid=45981792 }}

The primary function of prolactin in fish is osmoregulation,{{cite journal | vauthors = Sakamoto T, McCormick SD | title = Prolactin and growth hormone in fish osmoregulation | journal = General and Comparative Endocrinology | volume = 147 | issue = 1 | pages = 24–30 | date = May 2006 | pmid = 16406056 | doi = 10.1016/j.ygcen.2005.10.008 }} 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.{{cite journal | vauthors = Whittington CM, Wilson AB | title = The role of prolactin in fish reproduction | journal = General and Comparative Endocrinology | volume = 191 | pages = 123–36 | date = September 2013 | pmid = 23791758 | doi = 10.1016/j.ygcen.2013.05.027 | url = https://ses.library.usyd.edu.au/bitstream/2123/9291/2/GCE_PRL_in_fish_reproduction_postprint.pdf }} In the South American discus, prolactin may also regulate the production of a skin secretion that provides food for larval fry.{{cite journal | vauthors = Khong HK, Kuah MK, Jaya-Ram A, Shu-Chien AC | title = Prolactin receptor mRNA is upregulated in discus fish (Symphysodon aequifasciata) skin during parental phase | journal = Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology | volume = 153 | issue = 1 | pages = 18–28 | date = May 2009 | pmid = 19272315 | doi = 10.1016/j.cbpb.2009.01.005 }} An increase in brooding behaviour caused by prolactin has been reported in hens.{{cite journal | vauthors = Jiang RS, Xu GY, Zhang XQ, Yang N | title = Association of polymorphisms for prolactin and prolactin receptor genes with broody traits in chickens | journal = Poultry Science | volume = 84 | issue = 6 | pages = 839–845 | date = June 2005 | pmid = 15971519 | doi = 10.1093/ps/84.6.839 | doi-access = free }}

Prolactin and its receptor are expressed in the skin, specifically in the hair follicles, where they regulate hair growth and moulting in an autocrine fashion.{{cite journal | vauthors = Foitzik K, Krause K, Nixon AJ, Ford CA, Ohnemus U, Pearson AJ, Paus R | title = Prolactin and Its Receptor Are Expressed in Murine Hair Follicle Epithelium, Show Hair Cycle-Dependent Expression, and Induce Catagen | journal = The American Journal of Pathology | volume = 162 | issue = 5 | pages = 1611–21 | date = May 2003 | pmid = 12707045 | pmc = 1851183 | doi = 10.1016/S0002-9440(10)64295-2 }}{{cite journal | vauthors = Craven AJ, Ormandy CJ, Robertson FG, Wilkins RJ, Kelly PA, Nixon AJ, Pearson AJ | title = Prolactin Signaling Influences the Timing Mechanism of the Hair Follicle: Analysis of Hair Growth Cycles in Prolactin Receptor Knockout Mice | journal = Endocrinology | volume = 142 | issue = 6 | pages = 2533–9 | date = June 2001 | pmid = 11356702 | doi = 10.1210/endo.142.6.8179 | doi-access = free }} Elevated levels of prolactin can inhibit hair growth,{{cite journal | vauthors = Foitzik K, Krause K, Conrad F, Nakamura M, Funk W, Paus R | title = Human scalp hair follicles are both a target and a source of prolactin, which serves as an autocrine and/or paracrine promoter of apoptosis-driven hair follicle regression | journal = The American Journal of Pathology | volume = 168 | issue = 3 | pages = 748–56 | date = March 2006 | pmid = 16507890 | pmc = 1606541 | doi = 10.2353/ajpath.2006.050468 }} and knock-out mutations in the prolactin gene cause increased hair length in cattle{{cite journal | vauthors = Littlejohn MD, Henty KM, Tiplady K, Johnson T, Harland C, Lopdell T, Sherlock RG, Li W, Lukefahr SD, Shanks BC, Garrick DJ, Snell RG, Spelman RJ, Davis SR | title = Functionally reciprocal mutations of the prolactin signalling pathway define hairy and slick cattle | journal = Nature Communications | volume = 5 | pages = 5861 | date = December 2014 | pmid = 25519203 | pmc = 4284646 | doi = 10.1038/ncomms6861 | bibcode = 2014NatCo...5.5861L }} and mice. Conversely, mutations in the prolactin receptor can cause reduced hair growth, resulting in the "slick" phenotype in cattle.{{cite journal | vauthors = Porto-Neto LR, Bickhart DM, Landaeta-Hernandez AJ, Utsunomiya YT, Pagan M, Jimenez E, Hansen PJ, Dikmen S, Schroeder SG, Kim ES, Sun J, Crespo E, Amati N, Cole JB, Null DJ, Garcia JF, Reverter A, Barendse W, Sonstegard TS | title = Convergent Evolution of Slick Coat in Cattle through Truncation Mutations in the Prolactin Receptor | journal = Frontiers in Genetics | volume = 9 | pages = 57 | date = February 2018 | pmid = 29527221 | pmc = 5829098 | doi = 10.3389/fgene.2018.00057 | doi-access = free }} Additionally, prolactin delays hair regrowth in mice.{{cite journal | vauthors = Craven AJ, Nixon AJ, Ashby MG, Ormandy CJ, Blazek K, Wilkins RJ, Pearson AJ | title = Prolactin delays hair regrowth in mice | journal = The Journal of Endocrinology | volume = 191 | issue = 2 | pages = 415–25 | date = Nov 2006 | pmid = 17088411 | doi = 10.1677/joe.1.06685 | doi-access = free | hdl = 10289/1353 | hdl-access = free }}

Analogous to its effects on hair growth and shedding in mammals, prolactin in birds controls the moulting of feathers,{{cite journal | vauthors = Dawson A | title = Control of molt in birds: association with prolactin and gonadal regression in starlings | journal = General and Comparative Endocrinology | volume = 147 | issue = 3 | pages = 314–22 | date = July 2006 | pmid = 16530194 | doi = 10.1016/j.ygcen.2006.02.001 }} as well as the age at onset of feathering in both turkeys and chickens.{{cite journal | vauthors = Derks MF, Herrero-Medrano JM, Crooijmans RP, Vereijken A, Long JA, Megens HJ, Groenen MA | title = Early and late feathering in turkey and chicken: same gene but different mutations | journal = Genetics Selection Evolution | volume = 50 | issue = 1 | pages = 7 | date = February 2018 | pmid = 29566646 | pmc = 5863816 | doi = 10.1186/s12711-018-0380-3 | doi-access = free }} Pigeons, flamingos and male emperor penguins feed their young a cheese-like secretion from the upper digestive tract called crop milk, whose production is regulated by prolactin.{{Cite journal |date=2023-06-08 |title=Spatio-temporal transcriptome dynamics coordinate rapid transition of core crop functions in 'lactating' pigeon |journal=PLOS Genetics |language=en |volume=19 |issue=6 |pages=e1010746 |doi=10.1371/journal.pgen.1010746 |doi-access=free |issn=1553-7404 |last1=Wang |first1=Yujie |last2=Wang |first2=Xun |last3=Luo |first3=Yi |last4=Zhang |first4=Jiaman |last5=Lin |first5=Yu |last6=Wu |first6=Jie |last7=Zeng |first7=Bo |last8=Liu |first8=Lei |last9=Yan |first9=Peiqi |last10=Liang |first10=Jiyuan |last11=Guo |first11=Hongrui |last12=Jin |first12=Long |last13=Tang |first13=Qianzi |last14=Long |first14=Keren |last15=Li |first15=Mingzhou |pmid=37289658 |pmc=10249823 }}{{Cite journal |last1=Stewart |first1=Calum |last2=Marshall |first2=Christopher J. |date=2022 |title=Seasonality of prolactin in birds and mammals |journal=Journal of Experimental Zoology Part A: Ecological and Integrative Physiology |language=en |volume=337 |issue=9–10 |pages=919–938 |doi=10.1002/jez.2634 |issn=2471-5638 |pmc=9796654 |pmid=35686456|bibcode=2022JEZA..337..919S }}

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.{{cite journal | vauthors = Ladyman SR, Hackwell EC, Brown RS | title = The role of prolactin in co-ordinating fertility and metabolic adaptations during reproduction | journal = Neuropharmacology | volume = 167 | pages = 107911 | date = May 2020 | pmid = 32058177 | doi = 10.1016/j.neuropharm.2019.107911 | s2cid = 208985116 }} 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.{{Cite journal | vauthors = Demirel MA, Suntar I, Ceribaşı S, Zengin G, Ceribaşı AO |date=2018-08-01 |title=Evaluation of the therapeutic effects of Artemisia absinthium L. on pseudopregnancy model in rats |journal=Phytochemistry Reviews |language=en |volume=17 |issue=4 |pages=937–946 |doi=10.1007/s11101-018-9571-3 |bibcode=2018PChRv..17..937D |s2cid=4953983 |issn=1572-980X}}

Prolactin receptor activation is essential for normal mammary gland development during puberty in mice.{{cite journal | vauthors = Ormandy CJ, Binart N, Kelly PA | title = Mammary gland development in prolactin receptor knockout mice | journal = J Mammary Gland Biol Neoplasia | volume = 2 | issue = 4 | pages = 355–64 | date = October 1997 | pmid = 10935023 | doi = 10.1023/a:1026395229025 | s2cid = 24217896 | url = }} Adult virgin female prolactin receptor knockout mice have much smaller and less developed mammary glands than their wild-type counterparts. Prolactin and prolactin receptor signaling are also essential for maturation of the mammary glands during pregnancy in mice.

In humans, prolactin is produced at least in the anterior pituitary, decidua, myometrium, breast, lymphocytes, leukocytes and prostate.{{cite journal | vauthors = Ben-Jonathan N, Mershon JL, Allen DL, Steinmetz RW | title = Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects | journal = Endocrine Reviews | volume = 17 | issue = 6 | pages = 639–69 | date = Dec 1996 | pmid = 8969972 | doi = 10.1210/edrv-17-6-639 | doi-access = free }}{{cite journal | vauthors = Gerlo S, Davis JR, Mager DL, Kooijman R | title = Prolactin in man: a tale of two promoters | journal = BioEssays | volume = 28 | issue = 10| pages = 1051–5 | date = Oct 2006 | pmid = 16998840 | pmc = 1891148 | doi = 10.1002/bies.20468 }}

Pituitary prolactin is controlled by the Pit-1 transcription factor, which binds to the gene at several sites including a proximal promoter. This promoter is inhibited by dopamine and stimulated by estrogens, neuropeptides, and growth factors.Ben-Jonathan N. (2001) Hypothalamic control of prolactin synthesis and secretion . In: Horseman ND, ed. Prolactin. Boston: Kluwer; 1 –24 Estrogens can also suppress dopamine.

Interaction with neuropeptides is still a matter of active research: no specific prolactin-releasing hormone has been identified. It is known that mice react to both VIP and TRH, but humans seem to only react to TRH. There are prolactin-releasing peptides that work in 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.{{cite journal |last1=Ben-Jonathan |first1=Nira |last2=LaPensee |first2=Christopher R. |last3=LaPensee |first3=Elizabeth W. |title=What can we learn from rodents about prolactin in humans? |url=18057139 |journal=Endocrine Reviews |pages=1–41 |doi=10.1210/er.2007-0017 |date=February 2008|volume=29 |issue=1 |pmid=18057139 |pmc=2244934 }}

In birds (turkeys), VIP is a powerful prolactin-releasing factor, while peptide histidine isoleucine has almost no effect.{{cite journal | vauthors = Kulick RS, Chaiseha Y, Kang SW, Rozenboim I, El Halawani ME | title = The relative importance of vasoactive intestinal peptide and peptide histidine isoleucine as physiological regulators of prolactin in the domestic turkey | journal = General and Comparative Endocrinology | volume = 142 | issue = 3 | pages = 267–73 | date = Jul 2005 | pmid = 15935152 | doi = 10.1016/j.ygcen.2004.12.024 }}

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 by cAMP. Responsiveness to cAMP is mediated by an imperfect cAMP–responsive element and two CAAT/enhancer binding proteins (C/EBP). Progesterone upregulates prolactin synthesis in the endometrium but decreases it in myometrium and breast glandular tissue.{{cite journal | vauthors = Zinger M, McFarland M, Ben-Jonathan N | title = Prolactin expression and secretion by human breast glandular and adipose tissue explants | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 2 | pages = 689–96 | date = Feb 2003 | pmid = 12574200 | doi = 10.1210/jc.2002-021255 | doi-access = free }}

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.

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 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.

=== Stimuli ===

Prolactin follows diurnal and ovulatory cycles. Prolactin levels peak during REM sleep and in the early morning. Many mammals experience a seasonal cycle.

During pregnancy, 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.{{Cite journal |last1=Calik-Ksepka |first1=Anna |last2=Stradczuk |first2=Monika |last3=Czarnecka |first3=Karolina |last4=Grymowicz |first4=Monika |last5=Smolarczyk |first5=Roman |date=2022-01-31 |title=Lactational Amenorrhea: Neuroendocrine Pathways Controlling Fertility and Bone Turnover |journal=International Journal of Molecular Sciences |volume=23 |issue=3 |pages=1633 |doi=10.3390/ijms23031633 |doi-access=free |issn=1422-0067 |pmc=8835773 |pmid=35163554}}

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 the hypothalamus, where changes in the electrical activity of neurons that regulate the pituitary gland increase 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. The posterior pituitary produces a yet-unidentified hormone that causes prolactin production.

In usual circumstances, in the absence of galactorrhea, lactation ceases within one or two weeks following the end of breastfeeding.

Levels can rise after exercise, high-protein meals, minor surgical procedures,{{cite book |vauthors=Melmed S, Jameson JL |chapter=333 Disorders of the Anterior Pituitary and Hypothalamus |veditors=Jameson JN, Kasper DL, Harrison TR, Braunwald E, Fauci AS, Hauser SL, Longo DL |title=Harrison's principles of internal medicine |publisher=McGraw-Hill Medical Publishing Division |location=New York |year=2005 |edition=16th |isbn=978-0-07-140235-4 |chapter-url=http://highered.mcgraw-hill.com/sites/0071402357/information_center_view0/}} following epileptic seizures{{cite journal | vauthors = Mellers JD | title = The approach to patients with "non-epileptic seizures" | journal = Postgraduate Medical Journal | volume = 81 | issue = 958 | pages = 498–504 | date = Aug 2005 | pmid = 16085740 | pmc = 1743326 | doi = 10.1136/pgmj.2004.029785 }} or due to physical or emotional stress.{{cite news|url=https://www.nlm.nih.gov/medlineplus/ency/article/003718.htm|title=Prolactin|publisher=MedLine plus|access-date=2014-10-24}}{{cite journal | vauthors = Sobrinho LG | title = Prolactin, psychological stress and environment in humans: adaptation and maladaptation | journal = Pituitary | volume = 6 | issue = 1 | pages = 35–9 | year = 2003 | pmid = 14674722 | doi = 10.1023/A:1026229810876 | s2cid = 1335211 }} 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. Stress-induced PRL changes are not linked to the posterior pituitary in rodents.

Hypersecretion 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 gonadotropin-releasing hormone from the hypothalamus and in turn decreases the secretion of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary, therefore disrupting the ovulatory cycle.{{cite web | vauthors = Welt CK, Barbieri RL, Geffner ME | location = Waltham, MA | work = UpToDate | date = 2020 |title=Etiology, diagnosis, and treatment of secondary amenorrhea |url= http://www.uptodate.com/contents/etiology-diagnosis-and-treatment-of-secondary-amenorrhea?detectedLanguage=en&source=search_result&search=etiology+of+secondary+amenorrhea&selectedTitle=1%7E30&provider=noProvider |access-date=7 November 2013}} Such hormonal changes may manifest as amenorrhea and infertility in females as well as erectile dysfunction in males.{{cite journal | vauthors = Saleem M, Martin H, Coates P | title = Prolactin Biology and Laboratory Measurement: An Update on Physiology and Current Analytical Issues | journal = The Clinical Biochemist. Reviews | volume = 39 | issue = 1 | pages = 3–16 | date = February 2018 | pmid = 30072818 | pmc = 6069739 }} Inappropriate lactation (galactorrhoea) is another important clinical sign of prolactinomas.

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 and sulfation, as well as degradation. The non-glycosylated form of prolactin is the dominant form that is secreted by the pituitary gland.

The three different sizes of prolactin are:

• Little prolactin—the predominant form.{{cite journal | vauthors = Sabharwal P, Glaser R, Lafuse W, Varma S, Liu Q, Arkins S, Kooijman R, Kutz L, Kelley KW, Malarkey WB | title = Prolactin synthesized and secreted by human peripheral blood mononuclear cells: an autocrine growth factor for lymphoproliferation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 16 | pages = 7713–6 | date = Aug 1992 | pmid = 1502189 | pmc = 49781 | doi = 10.1073/pnas.89.16.7713 | bibcode = 1992PNAS...89.7713S | doi-access = free }}, in turn citing: {{cite journal | vauthors = Kiefer KA, Malarkey WB | title = Size heterogeneity of human prolactin in CSF and serum: experimental conditions that alter gel filtration patterns | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 46 | issue = 1 | pages = 119–24 | date = Jan 1978 | pmid = 752015 | doi = 10.1210/jcem-46-1-119 }} It has a molecular weight of approximately 23-kDa. It is a single-chain polypeptide of 199 amino acids and is apparently the result of removal of some amino acids.
• Big prolactin—approximately 48 kDa. It may be the product of interaction of several prolactin molecules. It appears to have little, if any, biological activity.{{cite journal | vauthors = Garnier PE, Aubert ML, Kaplan SL, Grumbach MM | title = Heterogeneity of pituitary and plasma prolactin in man: decreased affinity of "Big" prolactin in a radioreceptor assay and evidence for its secretion | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 47 | issue = 6 | pages = 1273–81 | date = Dec 1978 | pmid = 263349 | doi = 10.1210/jcem-47-6-1273 }}
• Macroprolactin—approximately 150 kDa. It appears to have a low biological activity.{{cite journal | vauthors = Leite V, Cosby H, Sobrinho LG, Fresnoza MA, Santos MA, Friesen HG | title = Characterization of big, big prolactin in patients with hyperprolactinaemia | journal = Clinical Endocrinology | volume = 37 | issue = 4 | pages = 365–72 | date = Oct 1992 | pmid = 1483294 | doi = 10.1111/j.1365-2265.1992.tb02340.x | s2cid = 42796831 }}
• Other variants with the molecular masses of 14, 16, and 22 kDa.

The levels of larger ones are somewhat higher during the early postpartum period.{{cite journal | vauthors = Kamel MA, Neulen J, Sayed GH, Salem HT, Breckwoldt M | title = Heterogeneity of human prolactin levels in serum during the early postpartum period | journal = Gynecological Endocrinology | volume = 7 | issue = 3 | pages = 173–7 | date = Sep 1993 | pmid = 8291454 | doi = 10.3109/09513599309152499 }}

{{Main|Prolactin receptor}}

Prolactin receptors are present in the mammillary glands, ovaries, pituitary glands, heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal gland, uterus, skeletal muscle, skin and areas of the central nervous system.{{cite journal | vauthors = Mancini T, Casanueva FF, Giustina A | title = Hyperprolactinemia and prolactinomas | journal = Endocrinology and Metabolism Clinics of North America | volume = 37 | issue = 1 | pages = 67–99, viii | date = Mar 2008 | pmid = 18226731 | doi = 10.1016/j.ecl.2007.10.013 }} 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. Activation also results in the activation of mitogen-activated protein kinases and Src kinase.

Human prolactin receptors are insensitive to mouse prolactin.{{cite journal | vauthors = Utama FE, LeBaron MJ, Neilson LM, Sultan AS, Parlow AF, Wagner KU, Rui H | title = Human prolactin receptors are insensitive to mouse prolactin: implications for xenotransplant modeling of human breast cancer in mice | journal = The Journal of Endocrinology | volume = 188 | issue = 3 | pages = 589–601 | date = Mar 2006 | pmid = 16522738 | doi = 10.1677/joe.1.06560 | doi-access = free }}

Prolactin levels may be checked as part of a sex hormone workup, as elevated prolactin secretion can suppress the secretion of follicle stimulating hormone and gonadotropin-releasing hormone, leading to hypogonadism and sometimes causing erectile dysfunction.{{Citation |last1=Al-Chalabi |first1=Mustafa |title=Physiology, Prolactin |date=2023 |url=http://www.ncbi.nlm.nih.gov/books/NBK507829/ |work=StatPearls |access-date=2024-01-10 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29939606 |last2=Bass |first2=Autumn N. |last3=Alsalman |first3=Ihsan}}

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.{{cite journal | vauthors = Banerjee S, Paul P, Talib VJ | title = Serum prolactin in seizure disorders | journal = Indian Pediatrics | volume = 41 | issue = 8 | pages = 827–31 | date = Aug 2004 | pmid = 15347871 }}

The serum concentration of prolactin can be given in mass concentration (μg/L or ng/mL), molar concentration (nmol/L or pmol/L), or international units (typically mIU/L). The current IU is calibrated against the third International Standard for Prolactin, IS 84/500.{{cite journal | vauthors = Schulster D, Gaines Das RE, Jeffcoate SL | title = International Standards for human prolactin: calibration by international collaborative study | journal = The Journal of Endocrinology | volume = 121 | issue = 1 | pages = 157–66 | date = Apr 1989 | pmid = 2715755 | doi = 10.1677/joe.0.1210157 }}{{cite web | url = http://whqlibdoc.who.int/trs/WHO_TRS_786.pdf | title = WHO Expert Committee on Biological Standardization | year = 1989 | work = Thirty-ninth Report, WHO Technical Report Series | publisher = World Health Organization | quote = 86.1520, WHO/BS documents: 86.1520 Add 1, 88.1596 | access-date = 2009-06-03}} Reference ampoules of IS 84/500 contain "approximately" 2.5 μg of lyophilized human prolactin{{cite web | url = http://www.nibsc.ac.uk/documents/ifu/84-500.pdf | title = WHO International Standard, Prolactin, Human. NIBSC code: 84/500, Instructions for use | year = 1989 | publisher = NIBSC / Health Protection Agency | archive-url =https://web.archive.org/web/20111003214114/http://www.nibsc.ac.uk/documents/ifu/84-500.pdf| archive-date =2011-10-03| url-status = dead | access-date = 2011-03-21}} and have been assigned an activity of 0.053 International Units by calibrating against the previous standard. 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;{{cite journal | author = Canadian Society of Clinical Chemists | title = Canadian Society of Clinical Chemists position paper: standardization of selected polypeptide hormone measurements | journal = Clinical Biochemistry | volume = 25 | issue = 6 | pages = 415–24 | date = Dec 1992 | pmid = 1477965 | doi = 10.1016/0009-9120(92)90030-V }} 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.{{cite journal | vauthors = Gaines Das RE, Cotes PM | title = 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 | journal = The Journal of Endocrinology | volume = 80 | issue = 1 | pages = 157–68 | date = Jan 1979 | pmid = 429949 | doi = 10.1677/joe.0.0800157 }}{{cite web | url = http://whqlibdoc.who.int/trs/WHO_TRS_725.pdf | title = WHO Expert Committee on Biological Standardization | year = 1985 | work = Thirty-fifth Report, WHO Technical Report Series | publisher = World Health Organization | access-date = 2011-03-21}}{{cite web | url = http://whqlibdoc.who.int/trs/WHO_TRS_760.pdf | title = WHO Expert Committee on Biological Standardization | year = 1987 | work = Thirty-seventh Report, WHO Technical Report Series | publisher = World Health Organization | access-date = 2011-03-21}}{{dead link|date=December 2021|bot=medic}}{{cbignore|bot=medic}}{{cite journal | vauthors = Bangham DR, Mussett MV, Stack-Dunne MP | journal = Bulletin of the World Health Organization | volume = 29 | issue = 6 | pages = 721–8 | year = 1963 | pmid = 14107744 | pmc = 2555104 | title = The Second International Standard for Prolactin }}

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. Previous standards relied on prolactin from animal sources. Purified human prolactin was scarce, heterogeneous, unstable, and difficult to characterize. A preparation labeled 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. It was determined that this preparation behaved anomalously in certain immunoassays and was not suitable as an IS.

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. 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 and polymers of prolactin. On the basis of these investigations, 83/562 was established as the Second IS for human prolactin. Once stocks of these ampoules were depleted, 84/500 was established as the Third IS for human prolactin.

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. The assigned value will be 67 mIU per ampoule. If a fifth IS is needed, it will likely be based on recombinant protein, as WHO has not received any further donations of human pituitary extracts.{{cite web |last1=Ferguson |first1=Jackie |title=WHO International Collaborative Study of the Proposed 4th International Standard for Prolactin, Human |date=2016 |url=https://www.who.int/publications/m/item/WHO-BS-2016.2292}}

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. Similarly, guidelines for diagnosing prolactin deficiency (hypoprolactinemia) are defined as prolactin levels below 3 μg/L in women{{cite journal | vauthors = Kauppila A, Martikainen H, Puistola U, Reinilä M, Rönnberg L | title = Hypoprolactinemia and ovarian function | journal = Fertility and Sterility | volume = 49 | issue = 3 | pages = 437–41 | date = Mar 1988 | pmid = 3342895 | doi=10.1016/s0015-0282(16)59769-6| doi-access = }}{{cite journal | vauthors = Schwärzler P, Untergasser G, Hermann M, Dirnhofer S, Abendstein B, Berger P | title = Prolactin gene expression and prolactin protein in premenopausal and postmenopausal human ovaries | journal = Fertility and Sterility | volume = 68 | issue = 4 | pages = 696–701 | date = Oct 1997 | pmid = 9341613 | doi = 10.1016/S0015-0282(97)00320-8 | doi-access = free }} and 5 μg/L in men.{{cite journal |author3-link=Emmanuele A. Jannini | vauthors = Corona G, Mannucci E, Jannini EA, Lotti F, Ricca V, Monami M, Boddi V, Bandini E, Balercia G, Forti G, Maggi M | title = Hypoprolactinemia: a new clinical syndrome in patients with sexual dysfunction | journal = The Journal of Sexual Medicine | volume = 6 | issue = 5 | pages = 1457–66 | date = May 2009 | pmid = 19210705 | doi = 10.1111/j.1743-6109.2008.01206.x }}{{cite journal | vauthors = Gonzales GF, Velasquez G, Garcia-Hjarles M | title = Hypoprolactinemia as related to seminal quality and serum testosterone | journal = Archives of Andrology | volume = 23 | issue = 3 | pages = 259–65 | year = 1989 | pmid = 2619414 | doi = 10.3109/01485018908986849 }}{{cite journal | vauthors = Ufearo CS, Orisakwe OE | title = Restoration of normal sperm characteristics in hypoprolactinemic infertile men treated with metoclopramide and exogenous human prolactin | journal = Clinical Pharmacology and Therapeutics | volume = 58 | issue = 3 | pages = 354–9 | date = Sep 1995 | pmid = 7554710 | doi = 10.1016/0009-9236(95)90253-8 | s2cid = 1735908 }} 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. Furthermore, prolactin levels vary according to factors as age, sex, menstrual cycle stage and pregnancy.[http://www.medical.siemens.com/siemens/en_GLOBAL/gg_diag_FBAs/files/referenzwerte_pdf/IMMULITE_Systeme/prolaktin.pdf Prolaktin] {{webarchive|url=https://web.archive.org/web/20110728085232/http://www.medical.siemens.com/siemens/en_GLOBAL/gg_diag_FBAs/files/referenzwerte_pdf/IMMULITE_Systeme/prolaktin.pdf |date=28 July 2011 }} at medical.siemens.com—reference ranges as determined from the IMMULITE assay method The circumstances surrounding a given prolactin measurement (assay, patient condition, etc.) must therefore be considered before the measurement can be accurately interpreted.

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.

{{Bar graph

| title = Typical prolactin values

| label_type = Proband

| data_type = Prolactin, μg/L (ng/mL)

| bar_width = 35

| width_units = em

| data_max = 113

| label1 = women, follicular phase (n = 803)

| data1 = 12.1

| label2 = women, luteal phase (n = 699)

| data2 = 13.9

| label3 = women, mid-cycle (n = 53)

| data3 = 17

| label4 = women, whole cycle (n = 1555)

| data4 = 13.0

| label5 = women, pregnant, 1st trimester (n = 39)

| data5 = 16

| label6 = women, pregnant, 2nd trimester (n = 52)

| data6 = 49

| label7 = women, pregnant, 3rd trimester (n = 54)

| data7 = 113

| label8 = Men, 21–30 (n = 50)

| data8 = 9.2

| label9 = Men, 31–40 (n = 50)

| data9 = 7.1

| label10 = Men, 41–50 (n = 50)

| data10 = 7.0

| label11 = Men, 51–60 (n = 50)

| data11 = 6.2

| label12 = Men, 61–70 (n = 50)

| data12 = 6.9

}}

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) in Essex, England:[http://www.clinchem.org/cgi/content/full/54/10/1673/T2 Table 2] {{Webarchive|url=https://web.archive.org/web/20111109064854/http://www.clinchem.org/cgi/content/full/54/10/1673/T2 |date=9 November 2011 }} in {{cite journal | vauthors = Beltran L, Fahie-Wilson MN, McKenna TJ, Kavanagh L, Smith TP | title = Serum total prolactin and monomeric prolactin reference intervals determined by precipitation with polyethylene glycol: evaluation and validation on common immunoassay platforms | journal = Clinical Chemistry | volume = 54 | issue = 10 | pages = 1673–81 | date = Oct 2008 | pmid = 18719199 | doi = 10.1373/clinchem.2008.105312 | doi-access = free }}

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).

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.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

Causes of Elevated Prolactin Levels

{{Col-begin}}

{{Col-break}}

Physiological

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

{{Col-break}}

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
• Antipsychotics
• Neuropeptides
• Opioids and opioid receptor antagonists

{{Col-break}}

Pathological

• Hypothalamic-pituitary stalk damage
• Granulomas
• Infiltrations
• Radiation
• Rathke's cyst
• Trauma
• Pituitary stalk resection
• Suprasellar surgery
• Tumors
• Craniopharyngioma
• Germinoma
• Hypothalamic metastases
• Meningioma
• Suprasellar pituitary mass extension
• Surgery

{{Col-break}}

: 

• Pituitary
• Acromegaly
• Idiopathic
• Lymphocytic hypophysitis or parasellar mass
• Macroadenoma (compressive)
• Macroprolactinemia
• Plurihumoral adenoma
• Prolactinoma
• Systemic disorders
• Chest-neurologic chest wall trauma
• Herpes Zoster
• Chronic renal failure
• Cirrhosis
• Cranial radiation
• Epileptic seizures
• Polycystic ovarian disease
• Pseudocyesis
• Chronic low levels of thyroid hormone

{{col-end}}

{{Main|Hypoprolactinemia}}

Hypoprolactinemia, or serum prolactin deficiency, is associated with ovarian dysfunction in women, and arteriogenic erectile dysfunction, premature ejaculation, oligozoospermia, asthenospermia, hypofunction of seminal vesicles and hypoandrogenism in men. In one study, normal sperm characteristics were restored when prolactin levels were raised to normal values in hypoprolactinemic men.

Hypoprolactinemia can result from hypopituitarism, excessive dopaminergic action in the tuberoinfundibular pathway and ingestion of D₂ receptor agonists such as bromocriptine.{{cn|date=September 2023}}

Prolactin is available commercially for use in other animals, but not in humans.{{cite book| vauthors = Coutts RT, Smail GA | title = Polysaccharides Peptides and Proteins: Pharmaceutical Monographs|url=https://books.google.com/books?id=ojGRBQAAQBAJ&pg=PA153|date=12 May 2014|publisher=Elsevier|isbn=978-1-4831-9612-1|pages=153–}} It is used to stimulate lactation in animals. The biological half-life of prolactin in humans is around 15–20 minutes.{{cite book|author=D.F. Horrobin|title=Prolactin: Physiology and Clinical Significance|url=https://books.google.com/books?id=h_Q-BAAAQBAJ&pg=PA13|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-010-9695-9|pages=13–}} The D₂ receptor is involved in the regulation of prolactin secretion, and agonists of the receptor such as bromocriptine and cabergoline decrease prolactin levels while antagonists of the receptor such as domperidone, metoclopramide, haloperidol, risperidone, and sulpiride increase prolactin levels.{{cite book|author=Martin H. Johnson|title=Essential Reproduction|url=https://books.google.com/books?id=qXpBst5hJs0C&pg=PT40|date=14 December 2012|publisher=John Wiley & Sons|isbn=978-1-118-42388-2|pages=40–}} D₂ receptor antagonists like domperidone, metoclopramide, and sulpiride are used as galactogogues to increase prolactin secretion in the pituitary gland and induce lactation in humans.{{cite book|author=Jan Riordan|title=Breastfeeding and Human Lactation|url=https://books.google.com/books?id=aiVesab_2bwC&pg=PA468|date=January 2005|publisher=Jones & Bartlett Learning|isbn=978-0-7637-4585-1|pages=468–}}

• Breast-feeding
• Breastfeeding and fertility
• Epileptic seizure
• Hyperprolactinaemia
• Hypothalamic–pituitary–prolactin axis
• Male lactation
• Prolactin modulator
• Prolactin receptor
• Prolactin-releasing hormone
• Prolactinoma
• Weaning

{{notelist}}

{{Reflist}}

• {{MedlinePlusEncyclopedia|003718|Prolactin}}
• {{PDBe-KB2|P01236|Prolactin}}

{{Hormones}}

{{Amyloidosis}}

{{Galactagogues}}

{{Prolactin receptor modulators}}

{{Authority control}}

Category:Anterior pituitary hormones

Category:Breastfeeding

Category:Galactagogues

Category:Hormones of the hypothalamic-pituitary-prolactin axis

Category:Hormones of the pregnant female

Category:Human hormones

Category:Human female endocrine system

Category:Peptide hormones