PROLACTIN, HUMAN

Discovery

The classical PRL (PRL1) was first discovered in rabbits and pigeons as the milk-secreting factor around 1930, and confirmed in humans in 1971. To date, PRL1 has been reported in all major gnathostome classes while PRL1s in amniotes and fish are encoded by distinct genes (PRL1A and PRL1B, respectively). It is most likely that the fish-type PRL1B gene was duplicated in an early amphibian to generate the amniote-type PRL1A gene. The amphibians are the only extant vertebrates that maintain both the fish- and amniote-type PRL1 genes; the PRL1B gene was lost in the amniotes. Some teleosts have an additional copy of the PRL1 gene, suggesting that the PRL1B gene went through a further duplication event in these species, but the time point and the possible involvement of the proposed teleost-specific tetraploidization are unclear. PRL2 was identified in 2009 in nonmammalian vertebrates by bioinformatic analysis, and the classical PRL was subsequently renamed PRL1. Only a few features of PRL2 are known, and some of the following sections lack a description on PRL2.

Structure

PRL1 consists of about 200 aa residues in most species. In tetrapods, sturgeon, and lungfish, PRL1 has three disulfide bonds, the first forming a small loop near the N-terminus, the second linking distant parts of the polypeptide chain, and the third forming a loop close to the C-terminus. In cartilaginous fish and Halecomorphi (teleosts and the Amiiformes), PRL1 lacks the first disulfide bond at the N-terminus. Molecular heterogeneity in regard to glycosylation, phosphorylation, and sulfation has been described. The nonglycosylated form of PRL1 is the dominant form of PRL1 that is secreted from the pituitary. PRL2 is similar to PRL1 in its length and structure. It also contains three disulfide bonds, with the only exception being the shark PRL2, which lacks the one in the N-terminal region3. The evolution of PRL1 in mammals shows a similar pattern to that for GH, with a fairly slow basal evolutionary rate but accelerated evolution in lineages leading to humans, ruminants, elephants and rodents. In fish, including teleosts and sturgeon, PRL1 shows a great deal of structural variation, as seen for GH. The amino acid sequence identity between PRL1 and PRL2 is approximately 30%.

Gene, mRNA, and precursor

The human PRL1 gene, PRL, location 6p22.3, consists of five exons. Alternative splicing gives rise to variant mRNAs and therefore proteins. The chicken and zebrafish PRL1 genes are located on chromosome 2 and 3, respectively. The PRL2 genes of these species are also comprised of five exons, located on chromosome 1 (chicken) and 4 (zebrafish). PRL1 mRNA is detected most abundantly in the acidophilic lactotropes in the anterior pituitary. Transcripts are also found in the decidua, myometrium, breast, lymphocytes, leukocytes, intestine, and prostate. On the other hand, the gene expression of PRL2 is restricted to the extrapituitary tissues.

Synthesis and release

Pit-1 is a transcription factor that binds to several sites in the promoter of the PRL1 gene to allow for the synthesis of PRL1 in the anterior pituitary. Most extrapituitary production of PRL1 is controlled by a superdistal promoter. Neurosecretory dopamine neurons inhibit PRL1 secretion via D2 receptors. Estrogens are also key regulators of PRL1 production by enhancing PRL1 cell growth as well as by stimulating PRL1 production directly. Thyrotropin-releasing hormone and PRLreleasing peptide-2 have a stimulatory effect on PRL1 release. Vasoactive intestinal peptide regulates prolactin secretion in humans. Unlike PRL1 expressed predominantly in the pituitary, the 50 -flanking region of the chicken PRL2 gene exhibits a strong promoter activity in nonpituitary-derived cells.

Receptors

The PRL receptor (PRLR) belongs to the class I cytokine receptor family, and consists of an extracellular region that binds PRL, a transmembrane region, and a cytoplasmic region. There is a variation of PRLR isoforms among different tissues due to expression from multiple promoters and alternative splicing. When PRL binds to its receptor, it causes dimerization of the receptor. This results in the activation of JAK2, a tyrosine kinase that initiates the JAK/STAT pathway. Activation of the PRL receptor also results in the activation of MAPK and Src kinase.

Antagonists

Various candidates have been generated by different laboratories, but none has yet entered clinical trials. One of them, namely Δ1–9-G129R-hPRL, appears to be promising, as it is the only one displaying both PRLR specificity and pure antagonism.

Biological functions

PRLRs are present in various tissues, including the mammary glands, ovary, pituitary, heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal gland, uterus, skeletal muscle, skin, gill, and central nervous system. Although PRL1 is often associated with milk production,it has a wide range of physiological roles in humans and other vertebrates. Control of water and salt balance is an important function, especially in teleost fish. PRL1 controls the levels of sex steroids as a gonadotropic hormone. PRL1 has important cell cycle-related functions, acting as growth, differentiating, and antiapoptotic factors, especially in hematopoiesis, angiogenesis, and the immune system. Tumors in peripheral tissues synthesize PRL1 to stimulate its own growth via paracrine/autocrine pathways. PRL1 also stimulates the proliferation of oligodendrocyte precursor cells that differentiate into oligodendrocytes responsible for the formation of myelin coating in the central nervous system, and may control behavior. In zebrafish, PRL2 can activate only one of two PRLR isoforms. Although the physiological function of PRL2 is not clear, it may play a role in the local regulation of extrapituitary tissues via PRLRs.

Clinical implications

Hyperprolactinemia or excess serum PRL1 is associated with hypoestrogenism, anovulatory infertility, oligomenorrhoea, amenorrhea, unexpected lactation, and loss of libido in women, and erectile dysfunction and loss of libido in men. Hypoprolactinemia is associated with ovarian dysfunction in women, and metabolic syndrome, anxiety, arteriogenic erectile dysfunction, premature ejaculation, oligozoospermia, asthenospermia, hypofunction of seminal vesicles, and hypoandrogenism in men. In hypoprolactinemic men, normal sperm characteristics were restored when PRL1 levels were brought up to normal values.

Description

The hormone from the adenohypophysis, consisting of single chain of 198 amino acid residues with three disulphide linkages that stimulates lactation by the mammary glands, in conjunction with the effects of estrogen, progesterone, and oxytocin. Prolactin secretion is normally suppressed by the hypothalamic prolactin inhibitory factor until after parturition. In birds stimulates secretion of crop milk by the crop glands.

Chemical Properties

PRL is best known for its role in enabling female mammals to produce milk, and in a variety of biological functions in vertebrates, including an essential role in the control of water and salt balance, metabolism, and regulation of the immune system. Prolactin 2 is a prolactin-like molecule produced in extrapituitary tissues, and is the most recently discovered member of the GH/PRL family.

Uses

Prolactin is glycosylated.

Indications

Human prolactin is similar in structure to human growth hormone, and both are good lactogens. In women, prolactin acts with other hormones on the mammary gland during pregnancy to develop lactation and after birth to maintain it. Hyperprolactinemia causes impotence in men and amenorrhea and infertility in women. Chronically elevated levels of circulating prolactin are associated with suppression of 17-β-estradiol and testosterone production in the ovaries and testes.
Prolactin serum levels increase during pregnancy and breast-feeding, at least immediately after the birth. In both men and women, prolactin increases after sleep starts, continues to increase during the night, and increases markedly during stress. Prolactin release is episodic during the day. More than 20 hormones and neurotransmitters affect prolactin production, but the dominant physiological control is primarily negative, mediated by dopamine from the hypothalamus. Dopaminergic agonists inhibit prolactin release and antagonists, such as the antipsychotic drugs, increase release.

General Description

Prolactin (PRL), a hormone secreted by the anterior pituitary,was discovered in 1928. It is a 198-residue polypeptidewith general structural features similar to those of GH.PRL stimulates lactation of parturition.

Biochem/physiol Actions

Prolactin is a neuroendocrine hormone. The prolactin receptor is a transmembrane glycoprotein that belongs to the cytokine hematopoietic receptor family. A large number of cells and organs express the receptor, including B cells, T cells, macrophages, monocytes and neutrophils. Prolactin signal transduction involves the JAK/STAT families and the src kinase family. Induces lactation; inhibits secretion of gonadotropins; release is inhibited by dopamine.

Clinical Use

PRL1 levels are checked as part of a sex hormone work-up because elevated PRL1 secretion can suppress the secretion of follicle-stimulating hormone (FSH) and gonadotropin-releasing hormone (GnRH), leading to hypogonadism and erectile dysfunction in men. Serum PRL1 levels are of some use in distinguishing epileptic seizures from psychogenic nonepileptic seizures, as the levels rise following an epileptic seizure. In addition, the measurement of PRL1 is important for the diagnosis of prolactinoma. Of the pituitary adenomas, prolactinoma is the only adenoma for which drug therapy is the first choice.