Prolactin
Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans.[5] Prolactin is secreted from the pituitary 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 the immune system and pancreatic development.[6][7]
Discovered in non-human animals around 1930 by Oscar Riddle[8] and confirmed in humans in 1970 by Henry Friesen,[9] prolactin is a peptide hormone, encoded by the PRL gene.[10]
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 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 influences hematopoiesis and angiogenesis and is involved in the regulation of blood clotting through several pathways. The hormone acts in endocrine, autocrine, and paracrine manners through the prolactin receptor and numerous cytokine receptors.[5]
Pituitary prolactin secretion is regulated by endocrine neurons in the hypothalamus. The most important of these are the neurosecretory tuberoinfundibulum (TIDA) neurons of the arcuate nucleus that secrete dopamine (a.k.a. Prolactin Inhibitory Hormone) to act on the D2 receptors of lactotrophs, causing inhibition of prolactin secretion. Thyrotropin-releasing hormone has a stimulatory effect on prolactin release, although prolactin is the only anterior pituitary hormone whose principal control is inhibitory.
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, 14, 16, and 22 kDa variants exist.[11]
Function[edit]
In humans[edit]
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.[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 and testosterone 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 a gonadotropin[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 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.[19] Physiologic levels of prolactin in males enhance luteinizing hormone-receptors in Leydig cells, resulting in testosterone secretion, which leads to spermatogenesis.[20]
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.[21]
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.[22][23]
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.[24]
In other vertebrates[edit]
The primary function of prolactin in fish is osmoregulation,[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 American discus, prolactin may also regulate the production of a skin secretion that provides food for larval fry.[27] An increase in brooding behaviour caused by prolactin has been reported in hens.[28]
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.[29][30] Elevated levels of prolactin can inhibit hair growth,[31] and knock-out mutations 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 the moulting of feathers,[35] as well as the age at onset of feathering in both turkeys and chickens.[36] 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.[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 normal mammary gland development during puberty in mice.[41] Adult virgin female prolactin receptor knockout mice have much smaller and less developed mammary glands than their wild-type counterparts.[41] Prolactin and prolactin receptor signaling are also essential for maturation of the mammary glands during pregnancy in mice.[41]
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.[11]
The three different sizes of prolactin are:
The levels of larger ones are somewhat higher during the early postpartum period.[58]
Diagnostic use[edit]
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.[61]
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.[62]
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 international 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 2.5 µg of lyophilized human prolactin[65] and have been assigned an activity of .053 International Units.[63][64] Measurements that are calibrated against the current international standard can be converted into mass units using this ratio of grams to IUs;[66] prolactin concentrations expressed in mIU/L can be converted to µg/L by dividing by 21.2. Previous standards use other ratios.[67][68][69][70]
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.[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 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.[66][68] It was determined that this preparation behaved anomalously in certain immunoassays 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 and polymers 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]
Conditions[edit]
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.[79]
Causes of Elevated Prolactin Levels
In medicine[edit]
Prolactin is available commercially for use in other animals, but not in humans.[80] It is used to stimulate lactation in animals.[80] The biological half-life of prolactin in humans is around 15–20 minutes.[81] 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.[82] 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.[83]