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.

Discovered in non-human animals around 1930 by Oscar Riddle and confirmed in humans in 1970 by Henry Friesen, prolactin is a peptide hormone, encoded by the PRL gene.

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.

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.

Function

In humans

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.

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.

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 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. Physiologic levels of prolactin in males enhance luteinizing hormone-receptors in Leydig cells, resulting in testosterone secretion, which leads to spermatogenesis.

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.

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.

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.

In other vertebrates

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. 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. 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.

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. 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.

Prolactin receptor activation is essential for normal mammary gland development during puberty in mice. Adult virgin female prolactin receptor knockout mice have much smaller and less developed mammary glands than their wild-type counterparts.

Pituitary

Pituitary prolactin is controlled by the Pit-1 transcription factor, which binds to the gene at several sites including a proximal promoter. 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.

In birds (turkeys), VIP is a powerful prolactin-releasing factor, while peptide histidine isoleucine has almost no effect.

Extrapituitary

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).

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.

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. 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. Such hormonal changes may manifest as amenorrhea and infertility in females as well as erectile dysfunction in males. It has a molecular weight of approximately 23-kDa.

Macroprolactin—approximately 150 kDa.
Other variants with the molecular masses of 14, 16, and 22 kDa.

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. 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.

Diagnostic use

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.

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.

Units and unit conversions

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. Reference ampoules of IS 84/500 contain "approximately" 2.5 μg of lyophilized human prolactin and have been assigned an activity of 0.053 International Units by calibrating against the previous standard. 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.

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.

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. 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. The circumstances surrounding a given prolactin measurement (assay, patient condition, etc.) must therefore be considered before the measurement can be accurately interpreted.

{|class="wikitable"

!rowspan = 2 valign = "bottom"| Assay method

! colspan="2" |Mean Prolactin

! colspan="2" |Lower limit 2.5th percentile

! colspan="2" |Upper limit 97.5th percentile

| mIU/L

| bgcolor="yellow" | μg/L || mIU/L || bgcolor="yellow" | μg/L || mIU/L|| bgcolor="yellow" | μg/L

! colspan="9" | Females

| Centaur || 168 || bgcolor="yellow" | 7.92 || 71 || bgcolor="yellow" | 3.35 || 348|| bgcolor="yellow" | 16.4

| Immulite || 196 || bgcolor="yellow" | 9.25 || 75 || bgcolor="yellow" | 3.54 || 396|| bgcolor="yellow" | 18.7

| Access || 192 || bgcolor="yellow" | 9.06 || 77 || bgcolor="yellow" | 3.63 || 408|| bgcolor="yellow" | 19.3

| Elecsys || 222 || bgcolor="yellow" | 10.5 || 88 || bgcolor="yellow" | 4.15 || 492|| bgcolor="yellow" | 23.2

| Architect|| 225 || bgcolor="yellow" | 10.6 || 98 || bgcolor="yellow" | 4.62 || 447|| bgcolor="yellow" | 21.1

| AIA|| 257|| bgcolor="yellow" | || 105 || bgcolor="yellow" | || 548|| bgcolor="yellow" |

! colspan="9" | Males

| Access || 146 || bgcolor="yellow" | 6.89 || 58 || bgcolor="yellow" | 2.74 || 277|| bgcolor="yellow" | 13.1

| Centaur || 167 || bgcolor="yellow" | 7.88 || 63 || bgcolor="yellow" | 2.97 || 262|| bgcolor="yellow" | 12.4

| Immulite || 158 || bgcolor="yellow" | 7.45 || 70 || bgcolor="yellow" | 3.30 || 281|| bgcolor="yellow" | 13.3

| Elecsys || 180 || bgcolor="yellow" | 8.49 || 72 || bgcolor="yellow" | 3.40 || 331|| bgcolor="yellow" | 15.6

| Architect|| 188 || bgcolor="yellow" | 8.87 || 85 || bgcolor="yellow" | 4.01 || 310|| bgcolor="yellow" | 14.6

| AIA || 211 || bgcolor="yellow" | || 89|| bgcolor="yellow" | || 365|| bgcolor="yellow" |

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).

Conditions

Elevated levels

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.

Causes of Elevated Prolactin Levels

Physiological

Coitus
Exercise
Lactation
Pregnancy
Sleep
Stress
Depression

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

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

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

Decreased levels

Hypoprolactinemia, or serum prolactin deficiency, is associated with ovarian dysfunction in women,

In medicine

Prolactin is available commercially for use in other animals, but not in humans. It is used to stimulate lactation in animals. 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 the pituitary gland and induce lactation in humans.