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Prolactin

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 Prolactin
Hallgeir Rui*
Department of Pathology, Uniformed Services University, 4301 Jones Bridge Road,
Bethesda, MD 20814, USA
* corresponding author tel: 301-295-3801, fax: 301-295-1640, e-mail: hrui@usuhs.mil
DOI: 10.1006/rcwy.2000.03013.
SUMMARY
Prolactin is a tetrahelical cytokine most closely
related to growth hormone and placental lactogens.
It binds to specific prolactin receptors that belong to
the WS-motif cytokine receptor family. Prolactin is
secreted in a highly regulated manner into the circula-
tion by the anterior pituitary, and acts on peripheral
target tissues as a hormone. In addition, prolactin is
expressed at many extrapituitary sites, particularly
within the female and male reproductive organs and
the cells of the immune system, acting locally as an
autocrine or paracrine cytokine. Because of the ubiq-
uitous expression of prolactin receptors, prolactin has
a wide range of cellular and physiological effects. In
mammals, prolactin is particularly critical for the
differentiation of the mammary gland and for lacta-
tion. Hyperprolactinemia, the most common pituitary
disorder, causes infertility and decreased libido in both
men and women. Prolactin may also influence the
progression of certain autoimmune diseases, and has
been implicated as a promoter of neoplastic growth.
BACKGROUND
Discovery
A distinct anterior pituitary hormone with `lacto-
genic' activity was originally discovered by Stricker
and Grueter (1928), the factor being purified and
given the name prolactin shortly thereafter (Riddle
and Braucher, 1931; Riddle et al., 1932, 1933). Several
sources provide reviews and historical references
concerning this landmark discovery and the ensuing
research on the actions of prolactin in mammals, birds,
reptiles, amphibians, and fish (Riddle, 1963; Bern and
Nicoll, 1968; Li, 1978; Nicoll, 1980). Because human
growth hormone, in contrast to growth hormone
from nonprimate mammals, binds to prolactin recep-
tors and has a potent lactogenic activity, it was not
until the early 1970s that human prolactin was
definitively identified as a separate entity (Lewis et al.,
1971; Hwang et al., 1972).
An essentially complete peptide sequence of human
prolactin was first derived by the Edman degradation
of tryptic fragments (Shome and Parlow, 1977), and
the entire amino acid sequence, including a 28 residue
signal peptide, was deduced from the nucleotide
sequence of human cDNA cloned by Cooke and col-
leagues (1981). Furthermore, the extrapituitary pro-
duction of prolactin was first detected in decidualized
endometrial cells (Riddick et al., 1978) and subse-
quently in many other reproductive tissues, immune
cells and brain. Because of its widespread expression
and the realization that prolactin belongs to a family
of tetrahelical polypeptides that activate a corre-
sponding family of cytokine receptors, prolactin too
is now regarded as a ubiquitous cytokine with auto-
crine and paracrine roles.
Alternative names
Prolactin has been referred to as luteotropic hormone,
luteotropin, mammotropic hormone, and mammo-
tropin. To better reflect the diverse and pleiotropic
effects of prolactin, the alternative names versatilin
and omnipotin also have been suggested (Bern and
Nicoll, 1968).
Structure
A comparison of the amino acid sequences of pro-
lactin from human and mouse is presented in Figure 1.
After the processing of a 28 residue signal peptide, the
mature human prolactin molecule is secreted as a
268 Hallgeir Rui

Figure 1 Comparison of the amino acid sequences of human and

mouse prolactin.

Figure 2 Putative three-

dimensional structure of pro-
lactin based on that of growth
hormone.

D A
C
B

polypeptide with 199 amino acid residues, whereas
mouse prolactin is two residues shorter (Cooke,
1989). In both species, six cysteines form three intra-
molecular disulfide bridges. The molecular weight
of human prolactin is approximately 23 kDa, but a
26 kDa glycosylated form is also produced.
A three-dimensional structure of prolactin has not
been reported, but an extensive modeling and struc-
tural analysis of prolactin has been provided by
Goffin and colleagues (1996). A similar model of the
prolactin molecule based on the three-dimensional
structure of growth hormone is shown in Figure 2.
Prolactin is expected to conform structurally to the
tetrahelical cytokine fold, with a molecular core
consisting of four antiparallel  helices, A, B, C, and
D, in an up-up-down-down arrangement (Goffin et al.,
1996). Mutational analyses support this three-dimen-
sional structure and have revealed putative interac-
tion sites with prolactin receptors (for a review, see
Goffin et al., 1996). Cysteine bonds formed by the
pairwise coupling of residues Cys4-Cys11, Cys58-
Cys174, and Cys191-Cys199 are not shown in Figure 2.
Prolactin circulates in blood as monomers of 23±
26 kDa (Lewis et al., 1985). In addition, larger
`macroprolactins' (big-prolactin and big-big prolac-
tin) represent both homo-oligomeric aggregates and
immunoglobulin-complexed prolactin (reviewed by
Sinha, 1995). Furthermore, the physiological proteo-
lysis of prolactin to a C-terminally truncated 16 kDa
variant results in a molecule with distinct biological
activities that may activate unique receptors (Mittra,
1980; Clapp and Weiner, 1992; Clapp et al., 1993;
D'Angelo et al., 1999).
Main activities and
pathophysiological roles
Prolactin is expressed in mammals, birds, reptiles,
amphibians, and fish, and has a wide spectrum of
effects (Nicoll, 1980). In fact, more than 300 distinct
biological activities of prolactin have been recorded,
in large part because of the ubiquitous expression of
prolactin receptors (Bole-Feysot et al., 1998). In
addition to endocrine effects mediated by pituitary
prolactin secretion, it has become increasingly evident
that prolactin is synthesized at many extrapituitary
sites, particularly in reproductive organs, immune
cells, and brain (for a review, see Ben-Jonathan et al.,
1996). It is therefore clear that prolactin can act as a
local paracrine and autocrine factor in diverse tissues
and cells.
At the cellular level, prolactin regulates the growth,
survival, differentiation, and activation state of target
cells. At the physiological level, the effects of prolactin
Prolactin 269
may be divided into seven partially overlapping areas:
(1) reproduction, (2) immune function, (3) water/
electrolyte balance (osmoregulation), (4) stress adap-
tion, (5) behavior/brain/psychology, (6) metabolism,
and (7) skin function. Of these, the behavioral and
psychologic effects of prolactin, and its effects on
skin, may be coupled to reproduction and reproduc-
tive cycles. The biological effects of prolactin are
reviewed in more detail below.
In humans, prolactin is important for both the
physiological and psychological aspects of reproduc-
tive function, and the hormone also affects certain
aspects of immune cell function. Evidence for this
involvement of prolactin in humans has to a large
extent been disclosed by symptoms and signs asso-
ciated with hyperprolactinemia, the most frequent
endocrine disturbance of the pituitary. Galactorrhea,
anovulation and consequent amenorrhea, decreased
libido, and impotence are typical effects of chronic
hyperprolactinemia (Thorner et al., 1998). On the
other hand, as illustrated by hypophysectomy or
isolated idiopathic prolactin deficiency, a lack of pit-
uitary prolactin in adults is not associated with vital
deficiencies beyond fertility problems (Turkington,
1972; Kauppila et al., 1987).
GENE AND GENE REGULATION
Accession numbers
Mouse prolactin gene: K03236, X02892, X04418
Human prolactin gene: E02152, D00411, S74425,
X00368, L33865, M58594, M31661, M29386
Chromosome location
The human prolactin gene is present as a single copy
on chromosome 6 (Owerbach et al., 1981). By the use
of somatic cell hybridization, the assignment of the
prolactin gene was narrowed to 6pter-p21.1 (Taggart
et al., 1987). Evans and colleagues went on to locate
prolactin in the interval 6p22.2-p21.3, distal to HLA-C
(Evans et al., 1989). The mouse prolactin gene maps
to chromosome 13, clustered with genes encoding
mouse placental lactogens and other prolactin-like
genes (Jackson-Grusby et al., 1988).
Relevant linkages
The human prolactin gene is located in close proxi-
mity to the HLA complex. This colocalization is of
interest because of a possible association between
prolactin-secreting adenomas and specific HLA alleles
270 Hallgeir Rui
(Farid et al., 1980), as well as a proposed genetic
linkage between prolactin and rheumatoid arthritis
(Brennan et al., 1996). Furthermore, a woman with
recurrent spontaneous abortions was found to have
idiopathic hypoprolactinemia and mosaicism for a
partial deletion of chromosome 6p, the breakpoint
being located at 6p23 (D'Alessandro et al., 1992).
Regulatory sites and corresponding
transcription factors
The human prolactin gene is more than 15 kb long
and contains six exons (Truong et al., 1984). The
transcription of the gene is driven by two tissue-
specific promoters, a proximal promoter that is used
in the pituitary and a very distal promoter that is used
in extrapituitary cells and tissues, such as decidua,
myometrium, and lymphoid cells (DiMattia et al.,
1990; Berwaer et al., 1994; Gellersen et al., 1994). A
noncoding exon 1a is only expressed in extrapituitary
tissues and has a transcriptional start site 5.8 kb
upstream of the pituitary start site (Berwaer et al.,
1994). In extrapituitary sites, exon 1a is spliced to the
first pituitary exon 1b, generating a transcript that
is approximately 150 bp larger than its pituitary
counterpart (Gellersen et al., 1989), differing only in
the 50 untranslated region.
The downstream promoter that directs transcrip-
tion in pituitary lactotrophs is under the control of
the POU homeodomain transcription factor Pit-1.
There are two clusters of three and eight Pit-1-binding
sites within the pituitary promoter of the human
prolactin gene. In addition, there is an AP-1 site
(Peers et al., 1990) and a degenerate ERE sequence
(Gellersen et al., 1995; reviewed by Ben-Jonathan
et al., 1996). Transcriptional control of the distal,
nonpituitary start site in endometrial stromal cells is
linked to decidual differentiation during the secretory
phase of the ovulatory cycle (DiMattia et al., 1990;
Gellersen et al., 1994). Two consensus binding sites
for CCAAT/enhancer-binding proteins (C/EBP)
mediate the cAMP/PKA-induced activation of this
nonpituitary prolactin gene promoter in human
decidual cells (Pohnke et al., 1999). Cyclic AMP,
alone or in synergy with PHA, also stimulated the
activation of this upstream prolactin gene promoter
in Jurkat T cells, possibly through the activation of C/
EBP proteins (Reem et al., 1999).
Cells and tissues that express
the gene
See Table 2.
PROTEIN
Accession numbers
Mouse prolactin protein: P06879 (SwissProt)
Human prolactin protein: 4506105, 4234766, 385771,
1658518, 1620399, 385771, 758096, 531103, 531101,
190356
Sequence
See Figure 3.
Description of protein
The amino acid sequences of prolactin from human
and mouse are aligned in Figure 1.
As reported above, prolactin circulates in blood
as monomers and as larger `macroprolactins'
(big-prolactin, big-big prolactin), representing both
homo-oligomeric aggregates and immunoglobulin-
complexed prolactin. In certain asymptomatic sub-
jects with hyperprolactinemia, stable circulating
complexes of immunoglobulin and prolactin have
been identified (Bonhoff et al., 1995; Hattori and
Inagaki, 1998), suggesting that antiprolactin auto-
antibodies may occasionally neutralize the activity of
the hormone. Furthermore, the proteolysis of pro-
lactin to its 16 kDa variant (see above) results in a
molecule with distinct activities that may activate
unique receptors.
Discussion of crystal structure
As discussed in the section on Structure, a three-
dimensional structure of prolactin has not been
reported although models have been proposed based
on growth hormone. See Figure 2.
Important homologies
Human prolactin is most homologous to growth
hormone (16% amino acid identity) and placental
lactogen (13% amino acid identity). In rodents, pro-
lactin is more closely related to a series of prolactin-
like genes that are expressed in placenta in temporally
defined patterns during the course of pregnancy (for
reviews, see Forsyth, 1994; Soares et al., 1998; see also
Table 1).
 Prolactin 271

Figure 3 Amino acid sequence of human and mouse prolactin protein (signal peptide underlined).

Table 1 Mouse prolactin family disulfide bonds. C-terminal, central, and N-terminal
bridges are formed by the pairwise coupling of
Prolactin cysteine residues Cys4-Cys11, Cys58-Cys174, and
Placental lactogen I Cys191Cys199.
Placental lactogen II
Prolactin-like protein-A
Proteolysis
Prolactin-like protein-B Mature prolactin, formed by proteolytic removal of a
Prolactin-like protein-C variant
28 kDa signal peptide, can be further modified by pro-
teases (see the review by Sinha, 1995). Cathepsin-D
Prolactin-related protein proteolysis at position 133 generates two fragments of
Proliferin 16 and 8 kDa respectively, which may exist as
Proliferin-related protein both disulfide-linked heterodimers and monomers
Prolactin-like protein-F
(Mittra, 1980; Cole et al., 1991; Baldocchi et al.,
1993). Kallikrein, a trypsin-like protease, cleaves
Prolactin-like protein-G prolactin at position 173 to remove the C-terminal
disulfide loop and give rise to a 22 kDa fragment
Adapted from Soares et al. (1998).
(Anthony et al., 1993). Particular interest has arisen
with respect to the anti-angiogenic effect of the
16 kDa prolactin fragment (Clapp et al., 1993; Clapp
and Weiner, 1992; D'Angelo et al., 1999).

Posttranslational modifications
Oxidation
The six cysteine residues in prolactin undergo oxi-
dation and form stable, successive intramolecular
Glycosylation
A proportion of pituitary and circulating prolactin is
glycosylated in most species. Approximately 20% of
circulating human prolactin is glycosylated through
272 Hallgeir Rui

N-linkage at position 31 (Lewis et al., 1985; Champier Table 2 Cells and tissue that express prolactin
et al., 1987). Mouse prolactin is also glycosylated, but
the extent and linkage site remain to be determined Tissue Cell types
(Sinha, 1995). The physiological function of glycosy- Brain Pituitary Lactotrophs
lation of prolactin may be to reduce biological
Somatolactotrophs
potency, while extending the half-life of the molecule
(Hoffman et al., 1993). Hypothalamus
Pons-medulla
Phosphorylation Other regions
Reproductive Uterus Decidualized
A significant proportion of prolactin molecules are system endometrial
phosphorylated on their serine and threonine stromal cells
residues. In bovine pitiutary, between 20% and 80%
Ovary
of the prolactin was phosphorylated, particularly on
Ser90, with Ser26 and Ser34 constituting minor sites Testis Leydig cells
(Kim and Brooks, 1993). In rat prolactin, Ser177 was Mammary Epithelial cells
found to be the major site of phosphorylation (Wang Prostate Epithelial cells
et al., 1996), and this site is positionally conserved in
Immune/ T lymphocytes
prolactin from all species. hematopoietic
In general, the phosphorylation of prolactin is system
associated with reduced bioactivity (Wang and B lymphocytes
Walker, 1993; Brooks and Saiduddin, 1998), but
does not affect the biological half-life (Brooks and NK cells
Saiduddin, 1998). Furthermore, substitution of the Mononuclear cells
positionally conserved serine residue Ser179 in human Thymic epithelial cells
prolactin with either Asp or Glu, which are structural Other organs Skin Dermal fibroblasts
mimics of phosphoserine, led to a loss of bioactivity
in both mutants. Indeed, the Ser179Asp mutant acted Kidney Parietal cells
as a potent prolactin antagonist (Chen et al., 1998). Adrenal
However, antagonist activity was not detected in
phosphorylated bovine prolactin (Brooks and
Adapted from Ben-Jonathan et al. (1996).
Saiduddin, 1998). Because prolactin is phosphory-
lated in secretory granules during its release from
pituitary lactotrophs, it is possible that phosphoryla-
tion serves to reduce local bioactivity during secre- B-lymphoblastoid IM-9-P3 cell line secretes consid-
tion. Further work is needed to establish the erable amounts of prolactin (DiMattia et al., 1988).
physiological role of prolactin phosphorylation.

Eliciting and inhibitory stimuli,

CELLULAR SOURCES AND
TISSUE EXPRESSION
Cellular sources that produce
Prolactin is produced by lactotrophs and somatolac-
totrophs of the anterior pituitary. In addition, local
production occurs in a broad range of cell types,
particularly in uterus, mammary gland, prostate, cells
of the immune system and certain brain regions (see
Table 2).
Immortalized pituitary cell lines that secrete pro-
lactin include the highly studied rodent GH3,
GH4C1, and MMQ cell lines (Gautvik et al., 1983;
Kineman and Frawley, 1994). In addition, the human
including exogenous and
endogenous modulators
A multitude of inhibitors and stimulators of pituitary
prolactin secretion have been identified (for a review,
see Thorner et al., 1998). The secretion of prolactin,
unlike that of other pituitary hormones, is under tonic
inhibition by hypothalamic dopamine. TRH, VIP,
and prolactin-releasing peptide are potent stimulatory
peptides (Hinuma et al., 1998; Thorner et al., 1998).
In addition, estrogens are strong stimulators of
pituitary prolactin secretion (Day et al., 1990;
Murdoch et al., 1995). Table 3 summarizes the most
established regulators of pituitary prolactin secretion
(adapted from Thorner et al., 1998).

Steroid hormones frequently modulate the effects
of prolactin. For example, estrogen and progesterone
from the placenta suppress the lactogenic effect of
pituitary prolactin in the mammary gland, whereas
glucocorticoids exert a synergistic effect. Thus, for
milk production to begin, the reduction in estrogen
and progesterone levels associated with the shedding
of the placenta at parturition is needed. However,
interactions between prolactin and steroids are highly
dependent on cell type and hormonal milieu. Whereas
prolactin is antiapoptotic in lymphoid cells, and
glucocorticoids are proapoptotic, prolactin and glu-
cocorticoids appear to have a synergistic antiapopto-
tic effect in differentiated mammary gland.
In addition, ergot-derivatives (e.g. bromocriptine)
act as dopamine agonists and inhibit pituitary
prolactin release, and many psychopharmaceutical
drugs stimulate prolactin secretion (see Table 3).
RECEPTOR UTILIZATION
Prolactin could be considered to be a monogamous
cytokine in that it binds exclusively to prolactin
receptors. In contrast, human growth hormone binds
to growth hormone receptors as well as prolactin
receptors (Kossiakoff et al., 1994). However, the
prolactin receptor gene gives rise to alternatively
spliced variants with identical extracellular binding
domains but with long or short cytoplasmic domains
(reviewed by Bole-Feysot et al., 1998). This is of
functional importance because of the different
signaling capacities of the receptor splice variants.
Furthermore, the proteolytic 16 kDa prolactin
variant may interact with a unique, yet-to-be identi-
fied receptor (Clapp and Weiner, 1992).
IN VITRO ACTIVITIES
In vitro findings
Because prolactin receptors are expressed ubiqui-
tously, and couple to several parallel signal transduc-
tion pathways downstream of the JAK2 tyrosine
kinase (Lebrun et al., 1994; Rui et al., 1994), prolactin
affects the function of a variety of cells. The effects
are cell and context dependent, and include the regu-
lation of growth, survival, differentiation, and activa-
tion state types, particularly on cells of the mammary
gland and other reproductive organs (mammary and
prostate epithelial cells, Leydig cells, granulosa cells),
and in the immune system (T cells, B cells, NK cells)
Prolactin 273
(see the reviews by Topper et al., 1986; Groner and
Gouilleux, 1995; Ben-Jonathan et al., 1996; Ferrag
et al., 1997; Yu-Lee, 1997; Clevenger et al., 1998;
Yu-Lee et al., 1998).
Regulatory molecules: Inhibitors
and enhancers
Steroid hormones are frequently potent modulators
of prolactin effects, and may be inhibitory or synergis-
tic depending on cell type or hormonal milieu (Topper
et al., 1986; Groner and Gouilleux, 1995). In addition,
interactions have been described with polypeptide
growth factors such as EGF, IGF-1, and insulin.
Bioassays used
The Nb2 lymphoma (Gout et al., 1980) and pigeon
cropsac (Riddle et al., 1933; Horseman and Buntin,
1995) assays are used.
IN VIVO BIOLOGICAL
ACTIVITIES OF LIGANDS IN
ANIMAL MODELS
Normal physiological roles
The physiological effects of prolactin on the seven
areas previously mentioned are described below.
Reproduction
In the mammary gland, prolactin plays a critical role
in stimulating mammary gland differentiation in
pregnant mammals, and is important for the
initiation and maintenance of milk production
(Topper et al., 1986; Rosen et al., 1994; Groner and
Gouilleux, 1995). An interesting comparative func-
tion of prolactin in a submammalian species is the
induction of cropmilk in the cropsac of nursing pige-
ons (reviewed by Horseman and Buntin, 1995). In
mammals, prolactin-induced mammary differentia-
tion occurs in synergy with insulin and corticoster-
oids, and only after circulating estrogens and
progesterone levels fall at parturition will prolactin
induce milk secretion (for extensive reviews, see
Hennighausen et al., 1991; Rosen et al., 1994; Groner
and Gouilleux, 1995).
Gene knockout studies in mice have verified the
critical roles that prolactin and prolactin receptors play
274 Hallgeir Rui
in mammary differentiation and lactation (Ormandy
et al., 1997; Goffin et al., 1998; Steger et al., 1998;
Horseman, 1999). Specifically, prolactin was found to
affect mammary gland morphogenesis by controlling
ductal side branching and terminal end bud regres-
sion in virgin mice through indirect mechanisms, but
it acted directly on the mammary epithelium to
induce lobuloalveolar development during pregnancy
(Brisken et al., 1999). Furthermore, gene knockout
studies have also demonstrated that transcription
factor STAT5a is a central downstream mediator of
prolactin action in mammary glands (Hennighausen
et al., 1997; Liu et al., 1997).
In the gonads, prolactin may regulate ovarian and
testicular function both directly through gonadal
prolactin receptors and indirectly by modulating
gonadotropin secretion (Smith, 1980; Ben-Jonathan
et al., 1996). Prolactin stimulates dopamine release in
the hypothalamus and influences gonadotropin secre-
tion, and physiological hyperprolactinemia during
pregnancy and lactation, as well as pathological
hyperprolactinemia, are associated with suppression
of the hypothalamic-pituitary-gonadal axis. The
inhibition of the pulsatile secretion of GnRH from
the pituitary by prolactin results in impaired gona-
dotropin secretion and the inhibition of gonadal
function (Thorner et al., 1998). However, fertility and
circulating testosterone levels were normal in male
prolactin knockout mice, whereas ovarian steroid
production was insufficient for fertility in females
(Steger et al., 1998).
The direct effect of prolactin on testicular function
appears to be particularly pronounced in seasonally
breeding animals, in which prolactin may act directly
on the testes as a gonadotropin (Jabbour et al., 1998).
Prolactin receptors are expressed in Leydig cells as
well as in steroid-producing cells in the ovary
(Rolland and Hammond, 1975; Charreau et al., 1977),
and evidence suggests direct effects of prolactin on
rodent ovarian function, particularly in the regulation
of progesterone metabolism (Martel et al., 1994;
Zhong et al., 1997).
In the uterus and placenta, prolactin is produced in
myometrial cells and decidualized endometrial cells
(Riddick et al., 1978; DiMattia et al., 1990; Gellersen
et al., 1991, 1994; Stewart et al., 1995). Prolactin
produced locally in the uterus is thought to be
important for the establishment and progression of
pregnancy (for a review, see Soares et al., 1998),
although the exact roles of decidual prolactin in this
process remain to be established. Two proposed
functions involve a regulation of the water/electrolyte
balance of the amnion and local immune reactions to
prevent the rejection of the implant. Furthermore,
another specific role that has been proposed for
decidual prolactin is to induce the extensive angio-
genesis of the placenta associated with trophoblast
invasion, based on the observation that prolactin
markedly stimulated the local expression of the
angiogenic factor bFGF (Srivastava et al., 1998).
In the prostate, a number of stimulatory effects of
prolactin have been reported on prostate growth and
differentiation in rodents (for reviews, see Costello
and Franklin, 1994; Reiter et al., 1999). These effects
can, however, to a large extent be compensated for in
mice defective in either prolactin or prolactin receptor
expression (Bole-Feysot et al., 1998; Steger et al.,
1998). Only a moderate size reduction of the ventral
prostate was observed in prolactin-null mice (Steger
et al., 1998), whereas male accessory organs appeared
normal in prolactin receptor knockout mice. On the
other hand, mice rendered chronically hyperprolacti-
nemic by the overexpression of prolactin had
dramatically enlarged prostate glands, although this
effect might in part be mediated via a moderately
elevated testosterone level (Wennbo et al., 1997a).
The parallel observation of the local production of
prolactin within the epithelial compartment of rodent
and human prostate has further suggested the
physiological involvement of prolactin in prostate
growth and differentiation (Nevalainen et al., 1997a,
1997b). In fact, certain data point to prolactin as a
tumor promoter in rodent prostate (Nakamura et al.,
1990; Reiter et al., 1999).
Immune Function
An extensive literature has documented effects of
prolactin on various functions of immune cells,
including lymphoid cells (T cells, B cells, and NK
cells), monocytes, macrophages, and thymic epithelial
cells (for extensive reviews, see Russell, 1989; Berczi,
1994; Dardenne and Savino, 1994; Ferrag et al., 1994;
Leite-de-Moraes et al., 1995; Murphy et al., 1995;
Weigent, 1996; Ferrag et al., 1997; Yu-Lee, 1997;
Clevenger et al., 1998; De Mello-Coelho et al., 1998;
Velkeniers et al., 1998; Yu-Lee et al., 1998). Recent
work involving gene targeting in mice has, however,
suggested that the ancestral and fundamental roles of
prolactin as a regulator of hematopoiesis and immune
function have been effectively shared by other and
more specialized tetrahelical cytokines.
In knockout mice lacking either the gene for
prolactin or the prolactin receptor, a redundancy of
prolactin function in the immune system was revealed
by the finding of normal immunity and hematopoietic
parameters (Ormandy et al., 1997; Goffin et al., 1998;
Horseman et al., 1998; Bouchard et al., 1999).
Although prolactin was not found to be critical for
immune function in mice, redundant functions of

prolactin on immune cells will be more difficult to
uncover and may require combination knockout
strategies. Nonetheless, a series of research docu-
ments that hyperactivity of the prolactin-prolactin
receptor axis affects immune function, particularly
autoimmunity, hematopoietic cell growth promotion,
and leukemogenesis (for a review, see Hooghe et al.,
1998; Neidhart 1998).
Osmoregulation
The regulation of water/electrolyte balance seems to
be the most prominent role of prolactin in fish and
reptiles, and might represent the most ancient
function of prolactin (for a review, Bern and Nicoll,
1968; Nicoll, 1980; Ben-Jonathan et al., 1996). In
mammals, a role for prolactin in osmoregulation is
perhaps reflected in the local production of prolactin
and expression of prolactin receptors in the kidney
(Sakai et al., 1999) and in secretory organs such as the
mammary, prostate, and lacrimal glands (Shennan,
1994). Furthermore, decidual prolactin present in
amniotic fluid has been suggested to regulate fluid
balance (Handwerger and Freemark, 1987).
Stress
Prolactin is a stress hormome (Drago et al., 1989).
The circulating prolactin level rises rapidly in
response to emotional and physical stress, both in
Prolactin 275
stressed and hyperprolactinemic subjects is perhaps
an endurance-preserving stress adaption response.
Behavior and Psychological Effects
The behavioral effects of prolactin in vertebrates are
primarily linked to reproduction. Prolactin stimulates
parental behavior such as nesting and egg hatching in
birds, and nest building and the nursing of pups in
mice, rats, and rabbits (for reviews, see Scapagnini
et al., 1985; Dutt et al., 1994; Horseman and Buntin,
1995). Confirming this long-standing notion of the
behavioral effects of prolactin, which were first
observed by Riddle and colleagues (1935), elegant
studies of prolactin receptor knockout mice demon-
strated a reduction in maternal behavior in these
animals (Lucas et al., 1998).
Metabolism
The liver is involved in the clearance of circulating
prolactin, and the expression on liver cells of dis-
proportionally high levels of the putative `nonsignal-
ing' short prolactin isoform may facilitate this function
(Jahn et al., 1997; Perrot-Applanat et al., 1997). Pro-
lactin, however, also has some growth hormone-like
effects on the liver, and stimulates IGF-1 production
(Murphy et al., 1988; Strain and Ingleton, 1990).
Independently, prolactin and growth hormone stimu-
humans and other mammals (Meites and Clemens,
1972; Noel et al., 1972; Siegel et al., 1980). In soldiers
undergoing an extensive combat course, prolactin
levels were elevated at the start of the course, pre-
sumably in anticipation of stress, but underwent a
decrease over the 3 days of continuous physical strain
(Aakvaag et al., 1978). Consistent with these and
other observations, it has been postulated that stress
situations associated with passive coping are accom-
panied by an increased plasma prolactin level,
whereas stress situations associated with active coping
are associated with an unchanged or even lowered
level (Theorell, 1992).
Furthermore, data indicate that prolactin affects
neuroendocrine, behavioral, and autonomic
responses to stress, such as changes in the motility
of the gastric musculature and gastric acid secretion,
and in thermoregulation (Drago et al., 1990, 1993;
Drago and Amir, 1984). In the rat, hyperprolactinemia
has been demonstrated to protect against stress-
induced ulcers (Drago et al., 1985). These and other
data suggest that stress-induced hyperprolactinemia is
not a mere consequence of stress activation, but may
play a role in physiological mechanisms leading to the
restoration of body homeostasis. Decreased libido in
late  cell proliferation and insulin production in
Langerhans islets (Billestrup and Nielsen, 1991;
Sorenson and Brelje, 1997; Nielsen et al., 1999).
Furthermore, softened bones in prolactin receptor
null mice, combined with the detection of prolactin
receptors on osteoblasts but not osteoclasts, sug-
gested an involvement of prolactin in bone metabo-
lism (Bouchard et al., 1999). In light of previously
reported effects of prolactin on cholecalciferol secre-
tion by the kidney (MacIntyre et al., 1978; Haug
et al., 1982), an indirect effect of prolactin on cal-
cium metabolism also might be involved in this
phenotype.
Skin
In seasonal animals such as blue fox and red deer,
evidence indicates that prolactin stimulates the
transition from the winter to the summer coat (for a
review, see Curlewis, 1992). Furthermore, prolactin
may promote the proliferation of skin epithelial cells
and support hair growth (Paus, 1991; Stenn and Paus,
1999). These findings are relevant for the occasional
finding of hirsutism in cases of hyperprolactinemia
(Thorner et al., 1998).
276 Hallgeir Rui
Species differences
The predominant functions of prolactin differ
between vertebrates:
1. Mammals ± milk production
2. Birds ± cropmilk production, maternal behavior
3. Amphibians and reptiles ± osmoregulation
4. Fish ± osmoregulation.
Knockout mouse phenotypes
The prolactin gene was disrupted by homologous
recombination in mice by Horseman and colleagues
(1997). The following phenotypic observations were
made:
1. Female null mice were infertile.
2. The mammary glands of mutant female mice
developed a normal ductal tree, but ducts failed to
develop lobular decorations, which is a character-
istic of the normal virgin adult mammary gland.
3. Male prolactin knockout mice showed normal
fertility.
4. Male prolactin knockout mice had a significantly
reduced median eminence dopamine content,
plasma LH level, and LH and FSH secretion
in vitro.
5. Plasma testosterone levels were normal in male
prolactin knockout mice.
6. The weights of the seminal vesicles and ventral
prostate were moderately reduced in prolactin
knockout mice.
7. These results indicate that absence of prolactin
reduces pituitary LH release, attenuates median
eminence dopaminergic activity, and affects the
growth of the seminal vesicles and ventral prostate.
8. Prolactin knockout mice demonstrated normal
myelopoiesis and primary lymphopoiesis.
9. Pituitary weight in prolactin knockout mice was
doubled, presumably as a result of reduced feed-
back inhibition and hypertrophy and/or hyper-
plasia of nonfunctional lactotrophs.
In conclusion, the data suggested that prolactin is
critical for fertility and mammary development in
female mice, whereas prolactin deficiency can be
compensated with regard to male fertility and general
hematopoiesis and immune system development.
These observations in prolactin knockout mice
harmonize with the extended analysis of prolactin
receptor-null mice developed in Kelly's laboratory
(Ormandy et al., 1997).
Briefly, prolactin receptor knockout mice pre-
sented multiple reproductive defects in female mice,
including:
1. sterility caused by a complete failure of embryonic
implantation;
2. irregular cycles, reduced fertilization rates, defec-
tive preimplantation embryonic development, and
lack of pseudopregnancy;
3. in heterozygous female mice, an almost complete
loss of lactation after the first but not subsequent
pregnancies.
Furthermore, half of the male prolactin receptor
knockout mice were infertile or showed reduced
fertility.
When transplanted into the fat pads of prolactin
receptor‡/‡ mice, mammary gland tissue from
receptor-negative mice showed normal side branching
and the formation of alveolar buds, but no lobu-
loalveolar development during pregnancy. Thus,
prolactin affects mammary morphogenesis in two
different ways: by controlling ductal side branching
and terminal end bud regression in virgin animals via
indirect mechanisms, and by acting directly on the
mammary epithelium to produce lobuloalveolar dev-
elopment during pregnancy (Briskin et al., 1999).
Homozygous mutant and heterozygous mutant
nulliparous females showed a deficiency in pup-
induced maternal behavior. Moreover, primiparous
heterozygous females exhibit a profound deficit in
maternal care when challenged with foster pups.
These studies clearly establish the prolactin receptor
as a regulator of maternal behavior (Lucas et al.,
1998).
Finally, prolactin receptor-negative embryos of
mice showed a reduced degree of bone development
of their calvaria. In adults, the absence of prolactin
receptors was associated with a decrease in the bone
formation rate and a reduction of bone mineral den-
sity. This suggests that an effect of prolactin on
osteoblasts could be required for normal bone for-
mation and the maintenance of bone mass (Bouchard
et al., 1999).
Transgenic overexpression
The introduction of a prolactin transgene into mice
under the control of a constitutive metallothionine
promoter led to chronic hyperprolactinemia, leading
to an increased rate of mammary tumor formation in
females (Wennbo et al., 1997b). In addition, advanced
prostate hyperplasia was observed in male mice, an
effect that was associated with a moderate elevation
of circulating testosterone level (Wennbo et al., 1997a).

Pharmacological effects
There has been no reported clinical use of prolactin in
humans. However, based on animal studies, the
application of prolactin and growth hormone as low-
toxicity adjuvants to aid bone marrow recovery has
been proposed (Murphy et al., 1999).
Interactions with cytokine network
In general, because prolactin activates the transcrip-
tion factor STAT5 in most target cells, prolactin tends
to interact positively and in a redundant manner with
other cytokines that also activate STAT5 (e.g. IL-2,
IL-3, IL-5, IL-7, IL-9, IL-15, GM-CSF, erythropoie-
tin, thrombopoietin, and growth hormone). For
example, prolactin and IL-2 stimulate growth in an
additive fashion in Nb2 lymphocytes (Kirken et al.,
1994).
Endogenous inhibitors and
enhancers
See Table 3.
PATHOPHYSIOLOGICAL ROLES
IN NORMAL HUMANS AND
DISEASE STATES AND
DIAGNOSTIC UTILITY
Normal levels and effects
Basal levels of prolactin in adults vary considerably,
with levels of 4.0±25.0 mg/L in nonpregnant women
(median 10.0 mg/L), and levels of 0.5±19.0 mg/L in
men (median 8.5 mg/L) (Le Moli et al., 1999). Serum
prolactin, which increases throughout pregnancy,
falls with the onset of labor and then exhibits variable
patterns of secretion, depending on whether breast-
feeding occurs.
Role in experiments of nature and
disease states
Reproduction
Among pituitary tumors, 60% secrete prolactin and
cause a state of chronic hyperprolactinemia. Pituitary
Prolactin 277
adenomas reveal pathophysiologic effects of prolactin
in men by inducing decreased libido, impotence,
gynecomastia, galactorrhea, hypospermia, and occa-
sionally reduced beard growth (Thorner et al.,
1998). In premenopausal women, the cardinal effects
of hyperprolactinemia are amenorrhea, a cessation
of the normal cyclic ovarian function, galactorrhea,
decreased libido, occasional hirsutism, and an in-
creased long-term risk of osteoporosis (Palermo et al.,
1994; Thorner et al., 1998). Specifically, pathologic
milk discharge, galactorrhea, is a result of hyperpro-
lactinemia in both men and women, and attests to the
importance of prolactin in lactation.
A few cases of isolated, idiopathic prolactin defi-
ciency in women have been reported, fertility prob-
lems and alactogenesis being the most significant
consequences (Turkington, 1972; Falk, 1992; Kauppila,
1997). In addition, one case of prolactin deficiency
has been reported that was associated with alactogen-
esis in a woman who had two normal pregnancies
that were conceived without the use of ovulation-
inducing drugs (Kauppila et al., 1987). Furthermore,
in rodent models, a chronically elevated prolactin
level is associated with an increased formation of
mammary tumors (Wennbo et al., 1997b), and there is
renewed interest in prolactin as a breast cancer-
promoting factor in humans (Reynolds et al., 1997;
Vonderhaar, 1998; Goffin et al., 1999). Prolactin is
also produced by the myometrium (Riddick et al.,
1978), and is expressed in leiomyomas, possibly acting
as a growth factor (Nowak et al., 1999).
Autoimmune Diseases
Accumulating data suggest that an elevated prolactin
level represents a risk factor for certain autoimmune
diseases in humans and rodents. These include adju-
vant arthritis in rats, collagen type II-induced arthritis
in rats and mice, type I diabetes in mice, and systemic
lupus erythematosus (SLE) in mice and humans (for
reviews, see McMurray, 1996; Neidhart, 1998; Walker
et al., 1998; Ostensen, 1999). Furthermore, a connec-
tion between an elevated prolactin level and rheuma-
toid arthritis (RA) also has been suggested, but this
correlation is less clear. Interestingly, there is a genetic
association between RA and genes encoded in the
HLA complex, particularly HLA DR4, and the
human prolactin gene is located in close proximity to
the HLA region on the short arm of chromosome 6.
The hypothesis has been put forth that associations
between HLA DR4 and reproductive risk factors in
RA are caused by a linkage disequilibrium between
DR4 and an abnormally regulated prolactin gene
polymorphism (Brennan et al., 1996).
278 Hallgeir Rui

Table 3 Stimuli that regulate pituitary prolactin secretion

Enhancers Inhibitors

Physiological
Pregnancy (estrogen effect)
Nursing/suckling
Neurogenic:
Nipple stimulation/chest wall trauma/
breast manipulation /spinal cord lesions
Sleep
Stress (hypoglycemia)
Exercise
Seizures
Hypothyroidism (elevated TRH)
Pituitary stalk lesions
Pituitary tumors
Renal failure
Liver failure
Pharmacologic
Estrogen Dopamine agonists (bromocriptine, levodopa)
TRH GABA
Prolactin-releasing hormone/peptide
VIP
Dopamine antagonists (phenothiazines,
haloperidol, metoclopramide, reserpine,
methyldopa, amoxapine, opiates)
-Endorphin
Opioids
Monamine oxidase inhibitors
Cimetidine (intravenous)
Verapamil
Pathologic
Pituitary tumors Pseudohypoparathyroidism
Hypothalamic/pituitary stalk lesions Pituitary destruction/removal
Neuraxis irradiation Lymphocytic hypophysitis
Chest wall lesions
Spinal cord lesions
Hypothyroidism
Chronic renal failure
Severe liver disease

Adapted from Thorner et al. (1998).


Hematopoietic Cancer
An involvement of prolactin in the development and
progression of leukemia and lymphoma has also been
suggested (for a review, see Hooghe et al., 1998). For
example, a hyperactive, mutant prolactin receptor has
been described in the prolactin-dependent Nb2
lymphoma (Ali et al., 1991). Furthermore, the auto-
crine production of prolactin is detectable in several
transformed human lymphocytic lines, including
IM-9-P3, Jurkat, Hut-78, U937, and YT (DiMattia
et al., 1988; Pellegrini et al., 1992). The fact that
tyrosine kinase JAK2, the principal downstream
mediator of prolactin action (Lebrun et al., 1994; Rui
et al., 1994), is oncogenic in cells of both lymphoid
and myeloid origin (Peeters et al., 1997), lends
support to the notion that prolactin may promote the
growth of hematopoietic cancers. In fact, elevated
serum prolactin was detected in more that 50% of
patients with acute myeloid leukemia (Hatfill et al.,
1990), although this observation might be the result
of an associated stress response.
Osmoregulation
An excessive levels of amniotic fluid, polyhydramnios,
is often associated with diabetes mellitus, multiple
pregnancies, or fetal malformation. Interestingly,
amniotic fluid in polyhydramnios is characterized by
a selectively reduced level of prolactin but not of
other hormones (Luciano and Varner, 1984;
Saandakou et al., 1992). At the same time, patients
with chronic polyhydramnios showed a reduced
number of prolactin receptors within the chorion
laeve (Healy et al., 1985).
IN THERAPY
Preclinical ± How does it affect
disease models in animals?
Prolactin treatment aids bone marrow recovery in
transplanted mice (Woody et al., 1999). Prolactin
treatment in mice worsens the symptoms of certain
experimental autoimmune diseases (e.g. adjuvant
arthritis; Neidhart, 1998).
Effects of therapy: Cytokine,
antibody to cytokine inhibitors, etc.
There are no reported results of clinical trials with
human prolactin.
Prolactin 279
Pharmacokinetics
The pituitary prolactin secretory rate is approxi-
mately 18.6 nmol per day (400 mg per day). The
hormone is cleared by the liver (75%) and the kidney
(25%), and its half-life in plasma is approximately 50
minutes (Thorner et al., 1998).
Toxicity
Not reported. Iatrogenic hyperprolactinemia may be
expected to mimic symptoms of chronic pituitary
hyperprolactinemia, although the effects of acute
hyperprolactinemia are hard to predict.
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LICENSED PRODUCTS
Genzyme, Inc.
Product Code: 80-3910-01
Vial size: 50 mg
Expression system: C127 mammalian cell line
Bioassay: Nb2 (rat T cell line) proliferation assay
Cross-reactivity: Active in human, mouse and rat
systems
Physical state: Lyophilized
Shelf life: One year at 2±8 C
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