Prolactin
Encyclopedia
Prolactin also known as luteotropic hormone (LTH) is a protein
that in humans is encoded by the PRL gene
.
Prolactin is a peptide hormone
discovered by Henry Friesen
. Although it is perhaps best known for its role in lactation
, prolactin already existed in the oldest known vertebrate
s—fishes—where its most important functions were probably related to control of water and salt balance.
Prolactin also acts in a cytokine
-like manner and as an important regulator of the immune system
. Prolactin has important cell cycle related functions as a growth-, differentiating- and anti-apoptotic factor. As a growth factor binding to cytokine like receptors it has also profound influence on hematopoiesis, angiogenesis
and is involved in the regulation of blood clotting through several pathways. In summary, "more than 300 separate actions of PRL have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection". Prolactin acts in endocrine, autocrine, and paracrine manner through the prolactin receptor
and a large number of cytokine receptor
s..
In breastfeeding, the act of an infant
suckling the nipple
stimulates the production of oxytocin
, which stimulates the "milk let-down" reflex, which fills the breast
with milk
via a process called lactogenesis, in preparation for the next feed.
Pituitary prolactin secretion is regulated by endocrine neurons in the hypothalamus
, the most important ones being the neurosecretory tuberoinfundibulum
(TIDA) neurons of the arcuate nucleus
, which secrete dopamine
to act on the dopamine-2 receptors of lactotrophs, causing inhibition of prolactin secretion. Thyrotropin-releasing factor (thyrotropin-releasing hormone) has a stimulatory
effect on prolactin release.
Vasoactive intestinal peptide
and peptide histidine isoleucine help to regulate prolactin secretion in humans, but the functions of these hormones in birds can be quite different.
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.
and stimulating proliferation of oligodendrocyte precursor cell
s.
It stimulates the mammary gland
s to produce milk (lactation
): Increased serum concentrations of prolactin during pregnancy
cause enlargement of the mammary gland
s of the breasts and prepare for the production of milk. However, the high levels of progesterone
during pregnancy suppress the production of milk. Milk production normally starts when the levels of progesterone fall by the end of pregnancy and a suckling stimulus is present. Sometimes, newborn babies (males as well as females) secrete a milky substance from their nipple
s known as witch's milk. This is in part caused by maternal prolactin and other hormones.
Prolactin provides the body with sexual gratification
after sexual acts
: The hormone
counteracts the effect of dopamine
, which is responsible for sexual arousal
. This is thought to cause the sexual refractory period
. The amount of prolactin can be an indicator for the amount of sexual satisfaction and relaxation. Unusually high amounts are suspected to be responsible for impotence
and loss of libido
(see hyperprolactinemia symptoms).
Prolactin also stimulates proliferation of oligodendrocyte precursor cell
s. These cells differentiate into oligodendrocyte
s, the cells responsible for the formation of myelin
coatings on axon
s in the central nervous system
.
Prolactin also has a number of other effects including contributing to surfactant
synthesis of the fetal lung
s at the end of the pregnancy and immune tolerance
of the fetus by the maternal organism during pregnancy; it also decreases normal levels of sex hormones — estrogen
in women and testosterone
in men. It is this inhibition of sex steroids that is responsible for loss of the menstrual cycle in lactating women as well as lactation-associated osteoporosis. Prolactin also enhances luteinizing hormone
-receptors in Leydig cells, resulting in testosterone secretion, which leads to spermatogenesis. Prolactin delays hair regrowth in mice.
It has been shown that Prolactin promotes neurogenesis
.
, myometrium
, breast, lymphocytes, leukocytes and prostate
.
Pituitary PRL is controlled by the Pit-1 transcription factor and ultimately dopamine, extrapituitary PRL is controlled by a superdistal promoter and apparently unaffected by 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
has been observed to upregulate prolactin synthesis in the endometrium
but decreases it myometrium
and breast glandular tissue. However breast and other tissues may also 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 other vetrabrates 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.
as well as an ovulatory
cycle in prolactin secretion. In many mammals, there is also a seasonal change in prolactin release.
During pregnancy
, high circulating concentrations of estrogen
and progesterone inhibit the action of prolactin on milk production. Following delivery, reduced estrogen and progesterone production allows prolactin to induce lactation.
After childbirth
, 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 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 cause increased 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 will cease within one or two weeks of the end of demand breastfeeding
.
It has also been found that compared to un-mated males, fathers and expectant fathers have increased prolactin concentrations.
High prolactin levels also tend to suppress the ovulatory cycle by inhibiting the secretion of both follicle-stimulating hormone (FSH
) and gonadotropic-releasing hormone (GnRH). High prolactin levels can also contribute to mental health issues.
Prolactin levels peak during REM sleep, and in the early morning. Levels can rise after exercise, meals, sexual intercourse, minor surgical procedures, or following epileptic seizures.
Hypersecretion of prolactin is more common than hyposecretion. Hyperprolactinemia is the most frequent abnormality of the anterior pituitary tumors. Clinical signs include inappropriate lactation, lack of menses, infertility in females, and impotence in males.
and placental lactogen
. The molecule is folded due to the activity of three disulfide bond
s. Significant heterogeneity of the molecule has been described, thus bioassay
s and immunoassay
s can give different results due to differing glycosylation
, phosphorylation
, sulfation
, as well as degradation. The non-glycosylated form of prolactin is the dominant form of prolactin that is secreted by the pituitary gland
.
There are mainly three different forms of prolactin in regard to size:
The levels of larger ones are somewhat higher during the early postpartum period.
Pit-1 is a transcription factor
that binds to the prolactin gene at several sites to allow for the production of prolactin in the pituitary gland. A key regulator of prolactin production is estrogen
s that enhance growth of prolactin-producing cells and stimulate prolactin production directly, as well as suppressing dopamine
.
Human prolactin receptors are insensitive to mouse prolactin.
, a tyrosine kinase that initiates the JAK-STAT pathway. The activation of the prolactin receptor also results in the activation of mitogen-activated protein kinases and Src kinase.
, and sometimes causing erectile dysfunction
in men.
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.
(µg
/L
or ng/mL), molar concentration (nmol/L or pmol/L) or in international unit
s (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 of prolactin. 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 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. However, in the absence of an alternative, it was used. 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. On the basis of collaborative studies involving 20 different laboratories, it was concluded that there was 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.
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.
, England:
An example usage of table above is, if using the Centaur assay to estimate prolactin values in µg/L for females, the mean is 7.92 µg/L, and the reference range is 3.35–16.4 µg/L.
, 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.
Hyperprolactinemia can result from:
, anxiety
, 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 brought up to normal values in hypoprolactinemic men.
Hypoprolactinemia can result from:
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the PRL gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Prolactin is a peptide hormone
Peptide hormone
Peptide hormones are a class of peptides that are secreted into the blood stream and have endocrine functions in living animals.Like other proteins, peptide hormones are synthesized in cells from amino acids according to an mRNA template, which is itself synthesized from a DNA template inside the...
discovered by Henry Friesen
Henry Friesen
Henry George Friesen, is a Canadian endocrinologist, a distinguished professor emeritus of the University of Manitoba and the discoverer of prolactin, a hormone which stimulates lactation in mammary glands....
. Although it is perhaps best known for its role in lactation
Lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...
, prolactin already existed in the oldest known vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
s—fishes—where its most important functions were probably related to control of water and salt balance.
Prolactin also acts in a cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
-like manner and as an important regulator of the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. Prolactin has important cell cycle related functions as a growth-, differentiating- and anti-apoptotic factor. As a growth factor binding to cytokine like receptors it has also profound influence on hematopoiesis, angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
and is involved in the regulation of blood clotting through several pathways. In summary, "more than 300 separate actions of PRL have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection". Prolactin acts in endocrine, autocrine, and paracrine manner through the prolactin receptor
Prolactin receptor
The prolactin receptor—encoded by a gene on Chromosome 5p13-14—interacts with the prolactin molecule as a transmembrane receptor.Thus it contains an extracellular region that binds prolactin, a transmembrane regions, and a cytoplasmatic region....
and a large number of cytokine receptor
Cytokine receptor
Cytokine receptors are receptors that bind cytokines.In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly because a deficiency of cytokine receptors has now been...
s..
In breastfeeding, the act of an infant
Infant
A newborn or baby is the very young offspring of a human or other mammal. A newborn is an infant who is within hours, days, or up to a few weeks from birth. In medical contexts, newborn or neonate refers to an infant in the first 28 days after birth...
suckling the nipple
Nipple
In its most general form, a nipple is a structure from which a fluid emanates. More specifically, it is the projection on the breasts or udder of a mammal by which breast milk is delivered to a mother's young. In this sense, it is often called a teat, especially when referring to non-humans, and...
stimulates the production of oxytocin
Oxytocin
Oxytocin is a mammalian hormone that acts primarily as a neuromodulator in the brain.Oxytocin is best known for its roles in sexual reproduction, in particular during and after childbirth...
, which stimulates the "milk let-down" reflex, which fills the breast
Breast
The breast is the upper ventral region of the torso of a primate, in left and right sides, which in a female contains the mammary gland that secretes milk used to feed infants.Both men and women develop breasts from the same embryological tissues...
with milk
Milk
Milk is a white liquid produced by the mammary glands of mammals. It is the primary source of nutrition for young mammals before they are able to digest other types of food. Early-lactation milk contains colostrum, which carries the mother's antibodies to the baby and can reduce the risk of many...
via a process called lactogenesis, in preparation for the next feed.
Pituitary prolactin secretion is regulated by endocrine neurons in the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
, the most important ones being the neurosecretory tuberoinfundibulum
Tuberoinfundibular pathway
The tuberoinfundibular pathway refers to a population of dopamine neurons in the arcuate nucleus of the mediobasal hypothalamus that project to the median eminence . It is one of the four major dopamine pathways in the brain...
(TIDA) neurons of the arcuate nucleus
Arcuate nucleus
The arcuate nucleus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence...
, which secrete dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
to act on the dopamine-2 receptors of lactotrophs, causing inhibition of prolactin secretion. Thyrotropin-releasing factor (thyrotropin-releasing hormone) has a stimulatory
Stimulation
Stimulation is the action of various agents on nerves, muscles, or a sensory end organ, by which activity is evoked; especially, the nervous impulse produced by various agents on nerves, or a sensory end organ, by which the part connected with the nerve is thrown into a state of activity.The word...
effect on prolactin release.
Vasoactive intestinal peptide
Vasoactive intestinal peptide
Vasoactive intestinal peptide also known as the vasoactive intestinal polypeptide or VIP is a peptide hormone containing 29 amino acid residues that is produced in many tissues of vertebrates including the gut, pancreas and suprachiasmatic nuclei of the hypothalamus in the brain...
and peptide histidine isoleucine help to regulate prolactin secretion in humans, but the functions of these hormones in birds can be quite different.
Prolactin is sometimes classified as a gonadotropin
Gonadotropin
Gonadotropins are protein hormones secreted by gonadotrope cells of the pituitary gland of vertebrates. This is a family of proteins, which include the mammalian hormones follitropin , lutropin , placental chorionic gonadotropins hCG and eCG and chorionic gonadotropin , as well as at least two...
although in humans it has only a weak luteotropic effect while the effect of suppressing classical gonadotropic hormones is more important.
Effects
Prolactin has many effects including regulating lactationLactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...
and stimulating proliferation of oligodendrocyte precursor cell
Oligodendrocyte precursor cell
Oligodendrocyte precursor cells in nervous tissue cells precede oligodendrocytes, and may also be able to generate neurons and astrocytes. The principal function of oligodendrocytes is to provide support to axons and to produce the Myelin sheath, which insulates and lowers the effective...
s.
It stimulates the mammary gland
Mammary gland
A mammary gland is an organ in mammals that produces milk to feed young offspring. Mammals get their name from the word "mammary". In ruminants such as cows, goats, and deer, the mammary glands are contained in their udders...
s to produce milk (lactation
Lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...
): Increased serum concentrations of prolactin during pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
cause enlargement of the mammary gland
Mammary gland
A mammary gland is an organ in mammals that produces milk to feed young offspring. Mammals get their name from the word "mammary". In ruminants such as cows, goats, and deer, the mammary glands are contained in their udders...
s of the breasts and prepare for the production of milk. However, the high levels of progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
during pregnancy suppress the production of milk. Milk production normally starts when the levels of progesterone fall by the end of pregnancy and a suckling stimulus is present. Sometimes, newborn babies (males as well as females) secrete a milky substance from their nipple
Nipple
In its most general form, a nipple is a structure from which a fluid emanates. More specifically, it is the projection on the breasts or udder of a mammal by which breast milk is delivered to a mother's young. In this sense, it is often called a teat, especially when referring to non-humans, and...
s known as witch's milk. This is in part caused by maternal prolactin and other hormones.
Prolactin provides the body with sexual gratification
Orgasm
Orgasm is the peak of the plateau phase of the sexual response cycle, characterized by an intense sensation of pleasure...
after sexual acts
Human sexual behavior
Human sexual activities or human sexual practices or human sexual behavior refers to the manner in which humans experience and express their sexuality. People engage in a variety of sexual acts from time to time, and for a wide variety of reasons...
: The hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
counteracts the effect of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, which is responsible for sexual arousal
Sexual arousal
Sexual arousal, or sexual excitement, is the arousal of sexual desire, during or in anticipation of sexual activity. Things that precipitate human sexual arousal are called erotic stimuli, or colloquially known as turn-ons. There are many potential stimuli, both physical or mental, which can cause...
. This is thought to cause the sexual refractory period
Refractory period (sex)
In sexuality, the refractory period is the recovery phase after orgasm during which it is physiologically impossible for an individual to have additional orgasms. Most men are unable to maintain or achieve an erection during this time, and many perceive a psychological feeling of "satiation" and...
. The amount of prolactin can be an indicator for the amount of sexual satisfaction and relaxation. Unusually high amounts are suspected to be responsible for impotence
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
and loss of libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
(see hyperprolactinemia symptoms).
Prolactin also stimulates proliferation of oligodendrocyte precursor cell
Oligodendrocyte precursor cell
Oligodendrocyte precursor cells in nervous tissue cells precede oligodendrocytes, and may also be able to generate neurons and astrocytes. The principal function of oligodendrocytes is to provide support to axons and to produce the Myelin sheath, which insulates and lowers the effective...
s. These cells differentiate into oligodendrocyte
Oligodendrocyte
Oligodendrocytes , or oligodendroglia , are a type of brain cell. They are a variety of neuroglia. Their main function is the insulation of axons in the central nervous system of some vertebrates...
s, the cells responsible for the formation of myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
coatings on axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
s in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
.
Prolactin also has a number of other effects including contributing to surfactant
Surfactant
Surfactants are compounds that lower the surface tension of a liquid, the interfacial tension between two liquids, or that between a liquid and a solid...
synthesis of the fetal lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s at the end of the pregnancy and immune tolerance
Immune tolerance
Immune tolerance or immunological tolerance is the process by which the immune system does not attack an antigen. It can be either 'natural' or 'self tolerance', in which the body does not mount an immune response to self antigens, or 'induced tolerance', in which tolerance to external antigens can...
of the fetus by the maternal organism during pregnancy; it also decreases normal levels of sex hormones — estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
in women and testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
in men. It is this inhibition of sex steroids that is responsible for loss of the menstrual cycle in lactating women as well as lactation-associated osteoporosis. Prolactin also enhances luteinizing hormone
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
-receptors in Leydig cells, resulting in testosterone secretion, which leads to spermatogenesis. Prolactin delays hair regrowth in mice.
It has been shown that Prolactin promotes neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
.
Production and regulation
In humans, prolactin is produced at least in the pituitary, deciduaDecidua
Decidua is the term for the uterine lining during a pregnancy, which forms the maternal part of the placenta. It is formed under the influence of progesterone and forms highly-characteristic cells.-Etymology:...
, myometrium
Myometrium
The myometrium is the middle layer of the uterine wall, consisting mainly of uterine smooth muscle cells , but also of supporting stromal and vascular tissue...
, breast, lymphocytes, leukocytes and prostate
Prostate
The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....
.
Pituitary PRL is controlled by the Pit-1 transcription factor and ultimately dopamine, extrapituitary PRL is controlled by a superdistal promoter and apparently unaffected by dopamine.
In decidual cells and in lymphocytes the distal promoter and thus prolactin expression is stimulated by cAMP
CAMP
CAMP may stand for:* Cyclic adenosine monophosphate * Cathelicidin, or Cathelicidin antimicrobial peptide* Campaign Against Marijuana Planting* Central Atlantic Magmatic Province* CAMP , an Italian manufacturer of climbing equipment...
. Responsivness to cAMP is mediated by an imperfect cAMP–responsive element and two CAAT/enhancer binding proteins (C/EBP). Progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
has been observed to upregulate prolactin synthesis in the endometrium
Endometrium
-Function:The endometrium is the innermost glandular layer and functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a...
but decreases it myometrium
Myometrium
The myometrium is the middle layer of the uterine wall, consisting mainly of uterine smooth muscle cells , but also of supporting stromal and vascular tissue...
and breast glandular tissue. However breast and other tissues may also 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 other vetrabrates 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.
Variance in levels
There is a diurnalDay
A day is a unit of time, commonly defined as an interval equal to 24 hours. It also can mean that portion of the full day during which a location is illuminated by the light of the sun...
as well as an ovulatory
Ovulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...
cycle in prolactin secretion. In many mammals, there is also a seasonal change in prolactin release.
During pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
, high circulating concentrations of estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
and progesterone inhibit the action of prolactin on milk production. Following delivery, reduced estrogen and progesterone production allows prolactin to induce lactation.
After childbirth
Childbirth
Childbirth is the culmination of a human pregnancy or gestation period with the birth of one or more newborn infants from a woman's uterus...
, 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 in and around the nipple. These signals are carried by nerve fibers through the spinal cord to the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
, where changes in the electrical activity of neurons that regulate the pituitary gland cause increased prolactin secretion. The suckling stimulus also triggers the release of oxytocin
Oxytocin
Oxytocin is a mammalian hormone that acts primarily as a neuromodulator in the brain.Oxytocin is best known for its roles in sexual reproduction, in particular during and after childbirth...
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
Galactorrhea
Galactorrhea or galactorrhoea is the spontaneous flow of milk from the breast, unassociated with childbirth or nursing.Contemporary Maternal-Newborn Nursing Care defines galactorrhea as "nipple discharge." -Causes:...
, lactation will cease within one or two weeks of the end of demand breastfeeding
Breastfeeding
Breastfeeding is the feeding of an infant or young child with breast milk directly from female human breasts rather than from a baby bottle or other container. Babies have a sucking reflex that enables them to suck and swallow milk. It is recommended that mothers breastfeed for six months or...
.
It has also been found that compared to un-mated males, fathers and expectant fathers have increased prolactin concentrations.
High prolactin levels also tend to suppress the ovulatory cycle by inhibiting the secretion of both follicle-stimulating hormone (FSH
FSH
FSH may refer to:* Follicle-stimulating hormone* Fox Sports Houston, a regional Fox Sports Net affiliate station for the Houston, Texas area* Facioscapulohumeral muscular dystrophy* International Civil Aviation Organisation code for Flash Airlines...
) and gonadotropic-releasing hormone (GnRH). High prolactin levels can also contribute to mental health issues.
Prolactin levels peak during REM sleep, and in the early morning. Levels can rise after exercise, meals, sexual intercourse, minor surgical procedures, or following epileptic seizures.
Hypersecretion of prolactin is more common than hyposecretion. Hyperprolactinemia is the most frequent abnormality of the anterior pituitary tumors. Clinical signs include inappropriate lactation, lack of menses, infertility in females, and impotence in males.
Structure
The structure of prolactin is similar to that of growth hormoneGrowth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
and placental lactogen
Placental lactogen
Placental lactogen is a polypeptide placental hormone. Its structure and function is similar to that of growth hormone. It modifies the metabolic state of the mother during pregnancy to facilitate the energy supply of the fetus....
. The molecule is folded due to the activity of three disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
s. Significant heterogeneity of the molecule has been described, thus bioassay
Bioassay
Bioassay , or biological standardization is a type of scientific experiment. Bioassays are typically conducted to measure the effects of a substance on a living organism and are essential in the development of new drugs and in monitoring environmental pollutants...
s and immunoassay
Immunoassay
An immunoassay is a biochemical test that measures the presence or concentration of a substance in solutions that frequently contain a complex mixture of substances. Analytes in biological liquids such as serum or urine are frequently assayed using immunoassay methods...
s can give different results due to differing glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
, phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
, sulfation
Sulfation
Sulfation in biochemistry is the enzyme-catalyzed addition of sulfate to another molecule. It often refers to a phase II enzyme reaction. This biotransformation process uses its cosubstrate 3'-phosphoadenosine-5'-phosphosulfate to transfer sulfate to a xenobiotic...
, as well as degradation. The non-glycosylated form of prolactin is the dominant form of prolactin that is secreted by the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
.
There are mainly three different forms of prolactin in regard to size:
- Little prolactin is the predominant form. It has a molecular weight of appxoximately 22-kDa. It is a single-chain polypeptide of 198 amino acidAmino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s, and is apparently the result of removal of some amino acids. - Big prolactin of approximately 48 kDa. It may be the product of interaction of several prolactin molecules. It appears to have little, if any, biological activity.
- Big big prolactin of approximately 150 kDa. It appears to have a low biological activity.
The levels of larger ones are somewhat higher during the early postpartum period.
Pit-1 is a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
that binds to the prolactin gene at several sites to allow for the production of prolactin in the pituitary gland. A key regulator of prolactin production is estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
s that enhance growth of prolactin-producing cells and stimulate prolactin production directly, as well as suppressing dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
.
Human prolactin receptors are insensitive to mouse prolactin.
Prolactin receptor
Prolactin receptors 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 prolactin binds to the receptor, it causes it to dimerize with another prolactin receptor. This results in the activation of Janus kinase 2Janus kinase 2
Janus kinase 2 is a human protein that has been implicated in signaling by members of the type II cytokine receptor family , the GM-CSF receptor family , the gp130 receptor family , and the single chain receptors...
, a tyrosine kinase that initiates the JAK-STAT pathway. The activation of the prolactin receptor also results in the activation of mitogen-activated protein kinases and Src kinase.
Diagnostic use
Prolactin levels may be checked as part of a sex hormone workup, as elevated prolactin secretion can suppress the secretion of FSH and GnRH, leading to hypogonadismHypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
, and sometimes causing erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
in men.
Prolactin levels may be of some use in distinguishing epileptic seizures
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
from psychogenic non-epileptic seizures
Psychogenic non-epileptic seizures
Psychogenic non-epileptic seizures , also known as Non-Epileptic Attack Disorders, are events superficially resembling an epileptic seizure, but without the characteristic electrical discharges associated with epilepsy. Instead, PNES are psychological in origin, and may be thought of as similar to...
. The serum prolactin level usually rises following an epileptic seizure.
Units and unit conversions
The serum concentration of prolactin can be given in mass concentrationMass concentration
In astronomy or astrophysics mass concentration or mascon is a region of a planet or moon's crust that contains a large positive gravitational anomaly. In general, the word "mascon" can be used as a noun to describe an excess distribution of mass on or beneath the surface of a planet , such as Hawaii...
(µg
Microgram
In the metric system, a microgram is a unit of mass equal to one millionth of a gram , or 1/1000 of a milligram. It is one of the smallest units of mass commonly used...
/L
Litre
pic|200px|right|thumb|One litre is equivalent to this cubeEach side is 10 cm1 litre water = 1 kilogram water The litre is a metric system unit of volume equal to 1 cubic decimetre , to 1,000 cubic centimetres , and to 1/1,000 cubic metre...
or ng/mL), molar concentration (nmol/L or pmol/L) or in international unit
International unit
In pharmacology, the International Unit is a unit of measurement for the amount of a substance, based on biological activity or effect. It is abbreviated as IU, as UI , or as IE...
s (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 of prolactin. 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 WHO
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
Expert Committee on Biological Standardization
WHO Expert Committee on Biological Standardization
WHO Expert Committee on Biological Standardization is a functioning body of World Health Organization. The Expert Committee has been meeting annually since 1947.-Reports:...
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. However, in the absence of an alternative, it was used. 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. On the basis of collaborative studies involving 20 different laboratories, it was concluded that there was 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.
Reference ranges
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 prolatin 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 with, for example, age, sex, menstrual cycleMenstrual cycle
The menstrual cycle is the scientific term for the physiological changes that can occur in fertile women for the purpose of sexual reproduction. This article focuses on the human 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.
Inter-method variability
The following table illustrates variability in reference ranges of prolactin between some commonly used assay methods, 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 EssexEssex
Essex is a ceremonial and non-metropolitan county in the East region of England, and one of the home counties. It is located to the northeast of Greater London. It borders with Cambridgeshire and Suffolk to the north, Hertfordshire to the west, Kent to the South and London to the south west...
, 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 usage of table above is, if using the Centaur assay to estimate prolactin values in µg/L for females, the mean is 7.92 µg/L, and the reference range is 3.35–16.4 µg/L.
Conditions associated with elevated prolactin secretion
HyperprolactinaemiaHyperprolactinaemia
Hyperprolactinaemia or hyperprolactinemia is the presence of abnormally-high levels of prolactin in the blood. Normal levels are less than 500 mIU/L for women, and less than 450 mIU/L for men....
, 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.
Hyperprolactinemia can result from:
- ProlactinomaProlactinomaA prolactinoma is a benign tumor of the pituitary gland that produces a hormone called prolactin. It is the most common type of pituitary tumor...
- Excess thyrotropin-releasing hormoneThyrotropin-releasing hormoneThyrotropin-releasing hormone , also called thyrotropin-releasing factor , thyroliberin or protirelin, is a tropic tripeptide hormone that stimulates the release of thyroid-stimulating hormone and prolactin by the anterior pituitary...
(TRH), usually in primary hypothyroidismHypothyroidismHypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or... - All SSRI and SNRISNRISNRI may refer to:* Serotonin–norepinephrine reuptake inhibitor* Strategic Naval Research Institute...
medications - Many antipsychoticAntipsychoticAn antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
medications - Emotional stress
- PregnancyPregnancyPregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
and lactationLactationLactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing... - Some sexual disorders
Conditions associated with decreased prolactin
Hypoprolactinemia, or serum prolactin deficiency, is associated with ovarian dysfunction in women, and metabolic syndromeMetabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
, anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, arteriogenic erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
, premature ejaculation
Premature ejaculation
Premature ejaculation is a condition in which a man ejaculates earlier than he or his partner would like him to. Premature ejaculation is also known as rapid ejaculation, rapid climax, premature climax, or early ejaculation....
, oligozoospermia, asthenospermia, hypofunction of seminal vesicles, and hypoandrogenism in men. In one study, normal sperm characteristics were restored when prolactin levels were brought up to normal values in hypoprolactinemic men.
Hypoprolactinemia can result from:
- Bulimia
- Excess dopamineDopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
See also
- weaningWeaningWeaning is the process of gradually introducing a mammal infant, either human or animal, to what will be its adult diet and withdrawing the supply of its mother's milk.The process takes place only in mammals, as only mammals produce milk...
- breast-feeding
- baby foodBaby foodBaby food is any food, other than breastmilk or infant formula, that is made specifically for infants, roughly between the ages of four to six months to 2 years. The food comes in multiple varieties and tastes, can be produced by many manufacturers, or may be table food that the rest of the family...
- male lactationMale lactationMale lactation in zoology means production of milk from mammary glands in the presence of physiological stimuli connected with nursing infants. It is well documented in the Dayak fruit bat.The term male lactation is not used in human medicine...
- hormones
- Prolactin receptorProlactin receptorThe prolactin receptor—encoded by a gene on Chromosome 5p13-14—interacts with the prolactin molecule as a transmembrane receptor.Thus it contains an extracellular region that binds prolactin, a transmembrane regions, and a cytoplasmatic region....
- ProlactinomaProlactinomaA prolactinoma is a benign tumor of the pituitary gland that produces a hormone called prolactin. It is the most common type of pituitary tumor...
- HyperprolactinaemiaHyperprolactinaemiaHyperprolactinaemia or hyperprolactinemia is the presence of abnormally-high levels of prolactin in the blood. Normal levels are less than 500 mIU/L for women, and less than 450 mIU/L for men....
- PRLHPRLHProlactin releasing hormone, also known as PRLH, is a hypothetical human hormone or hormone releasing factor. Existence of this factor has been hypothesized as prolactin is the only currently known hormone for which almost exclusively negative regulating factors are known but few stimulating factors...
- Psychogenic non-epileptic seizuresPsychogenic non-epileptic seizuresPsychogenic non-epileptic seizures , also known as Non-Epileptic Attack Disorders, are events superficially resembling an epileptic seizure, but without the characteristic electrical discharges associated with epilepsy. Instead, PNES are psychological in origin, and may be thought of as similar to...
External links
- Pathophysiology of Endocrine System—Prolactin at colostate.edu—"Hyperprolactinemia"—"Prolactin Deficiency"