Prolactin (PRL), also known as luteotropic hormone or luteotropin, is a protein best known for its role in enabling mammals, usually females, to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pituitary gland in response to eating, mating, estrogen treatment, ovulation and nursing. It is secreted in pulses in between these events. Prolactin plays an essential role in metabolism, regulation of the immune system and pancreatic development.
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 manner through the prolactin receptor and numerous cytokine receptors.
Several variants and forms are known per species. Many fish have variants prolactin A and prolactin B. Most vertebrates including humans also have the closely related somatolactin. In humans, three smaller (4, 16 and 22 kDa) and several larger (so called big and big-big) variants exist.[not verified in body]
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.
In general, dopamine inhibits prolactin but this process has feedback mechanisms.
Elevated levels of prolactin decrease the levels of sex hormones — estrogen in women and testosterone in men. 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 although in humans it has only a weak luteotropic effect while the effect of suppressing classical gonadotropic hormones is more important. Prolactin within the normal reference ranges can act as a weak gonadotropin, but at the same time suppresses GnRH secretion. The exact mechanism by which it inhibits GnRH is poorly understood. Although expression of prolactin receptors (PRL-R) have been demonstrated in rat hypothalamus, the same has not been observed in GnRH neurons. Physiologic levels of prolactin in males enhance luteinizing hormone-receptors in Leydig cells, resulting in testosterone secretion, which leads to spermatogenesis.
The primary function of prolactin in fish is osmoregulation, 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. In the South American discus, prolactin may also regulate the production of a skin secretion that provides food for larval fry. An increase in brooding behaviour caused by prolactin has been reported in hens.
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. Elevated levels of prolactin can inhibit hair growth, and knock-out mutations in the prolactin gene cause increased hair length in cattle and mice. Conversely, mutations in the prolactin receptor can cause reduced hair growth, resulting in the "slick" phenotype in cattle. Additionally, prolactin delays hair regrowth in mice.
Analogous to its effects on hair growth and shedding in mammals, prolactin in birds controls the moulting of feathers, as well as the age at onset of feathering in both turkeys and chickens.
Pituitary PRL is controlled by the Pit-1transcription factor that binds to the prolactin gene at several sites. Ultimately dopamine, extrapituitary PRL is controlled by a superdistal promoter and apparently unaffected by dopamine. The thyrotropin-releasing hormone and the vasoactive intestinal peptide stimulate the secretion of prolactin in experimental settings, however their physiological influence is unclear. The main stimulus for prolactin secretion is suckling, the effect of which is neuronally mediated. A key regulator of prolactin production is estrogens that enhance growth of prolactin-producing cells and stimulate prolactin production directly, as well as suppressing dopamine.
In decidual cells and in lymphocytes the distal promoter and thus prolactin expression is stimulated by cAMP. Responsivness to cAMP is mediated by an imperfect cAMP–responsive element and two CAAT/enhancer binding proteins (C/EBP).Progesterone upregulates prolactin synthesis in the endometrium and decreases it in myometrium and breast glandular tissue. Breast and other tissues may express the Pit-1 promoter in addition to the distal promoter.
Extrapituitary production of prolactin is thought to be special to humans and primates and may serve mostly tissue-specific paracrine and autocrine purposes. It has been hypothesized that in 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.
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.[verification needed]
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.
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, following epileptic seizures or due to physical or emotional stress. 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.
The serum concentration of prolactin can be given in mass concentration (µg/L or ng/mL), molar concentration (nmol/L or pmol/L) or in international units (typically mIU/L). The current IU is calibrated against the third International Standard for Prolactin, IS 84/500. Reference ampoules of IS 84/500 contain 2.5 µg of lyophilized human prolactin and have been assigned an activity of .053 International Units. Measurements that are calibrated against the current international standard can be converted into mass units using this ratio of grams to IUs; prolactin concentrations expressed in mIU/L can be converted to µg/L by dividing by 21.2. Previous standards use other ratios.
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 labelled 81/541 was distributed by the WHOExpert 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.
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 and 5 µg/L in men. 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 also vary factors including age, sex,menstrual cycle stage and pregnancy. 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.
Typical prolactin values
women, follicular phase (n = 803)
women, luteal phase (n = 699)
women, mid-cycle (n = 53)
women, whole cycle (n = 1555)
women, pregnant, 1st trimester (n = 39)
women, pregnant, 2nd trimester (n = 52)
women, pregnant, 3rd trimester (n = 54)
Men, 21–30 (n = 50)
Men, 31–40 (n = 50)
Men, 41–50 (n = 50)
Men, 51–60 (n = 50)
Men, 61–70 (n = 50)
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:
While there is evidence that women who smoke tend to breast feed for shorter periods, there is a wide variation of breast-feeding rates in women who do smoke. This suggest that psychosocial factors rather than physiological mechanisms (e.g., nicotine suppressing prolactin levels) are responsible for the lower rates of breast feeding in women who do smoke.
Prolactin is available commercially for use in animals, but not in humans. It is used to stimulate lactation in animals. The biological half-life of prolactin in humans is around 15–20 minutes. 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. D2 receptor antagonists like domperidone, metoclopramide, and sulpiride are used as galactogogues to increase prolactin secretion in pituitary gland and induce lactation in humans.
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^ abcdefghijklThe AIA essay values are also from Table 2 in Beltran 2008, like the other values, but it uses a different conversion factor of 27.0 mIU/L per µg/L, taken from the second international standard, IS 83/562).