Reviews

Prolactin — a pleiotropic factor

in health and disease
Valérie Bernard1,2, Jacques Young1,3 and Nadine Binart 1
*
Abstract | The principal role of prolactin in mammals is the regulation of lactation. Prolactin is
a hormone that is mainly synthesized and secreted by lactotroph cells in the anterior pituitary
gland. Prolactin signalling occurs via a unique transmembrane prolactin receptor (PRL-​R).
The structure of the PRL-​R has now been elucidated and is similar to that of many biologically
fundamental receptors of the class 1 haematopoietic cytokine receptor family such as the growth
hormone receptor. The PRL-​R is expressed in a wide array of tissues, and a growing number of
biological processes continue to be attributed to prolactin. In this Review, we focus on the newly
discovered roles of prolactin in human health and disease, particularly its involvement in metabolic
homeostasis including body weight control, adipose tissue, skin and hair follicles, pancreas, bone,
the adrenal response to stress, the control of lactotroph cell homeostasis and maternal behaviour.
New data concerning the pathological states of hypoprolactinaemia and hyperprolactinaemia will
also be presented and discussed.

1
Inserm U1185, Faculté de
Médecine Paris Sud,
Université Paris-​Saclay,
Le Kremlin Bicêtre, France.
2
Hôpital Saint Antoine, Service
d’Endocrinologie et des
Maladies de la Reproduction,
Paris, France.
3
Hôpital Bicêtre, Service
d’Endocrinologie et des
Maladies de la Reproduction,
Paris, France.
*e-​mail: nadine.binart@
inserm.fr
https://doi.org/10.1038/
s41574-019-0194-6
Prolactin is a polypeptide hormone that is mainly syn-
thesized and secreted by lactotroph cells of the anterior
pituitary gland. The actions of prolactin are mediated
by its transmembrane receptor, PRL-​R1. This receptor
is widespread and belongs to the haematopoietic type 1
cytokine receptor superfamily, and its full structure was
elucidated in 2016 (ref.2). The principal role attributed to
prolactin is to stimulate the proliferation and differen-
tiation of the mammary cells required for lactation, but
studies in animal models have assigned more than 300
separate actions to this hormone in multiple species1,3,4.
We discussed insights into the functions of prolactin and
its receptor in an earlier article5, but much progress in
our understanding has been made in the past few years.
This new Review focuses on the implications of prol-
actin in metabolic homeostasis, including body weight
control and its role in adipose tissue and the pancreas.
The role of prolactin in skin and hair follicles, phospho-
calcic metabolism, maternal behaviour and the adre-
nal response to stress is also addressed. Novel findings
regarding the regulation of prolactin secretion and lac-
totroph homeostasis are presented. Finally, data enabling
an improved understanding of the causes and conse-
quences of the pathological states of hypoprolactinaemia
and hyperprolactinaemia in humans are discussed.
Prolactin and the PRL-​R
Prolactin is produced by the pituitary lactotroph cells
(referred to as lactotrophs). In healthy human pituitary
glands, lactotrophs account for approximately 15–25%
of the total number of cells. The number of lactotrophs
is similar in both sexes and does not change significantly
with age6. The secretion of prolactin by lactotrophs drives
a range of responses that are crucial for the feeding of
offspring, including mammary epithelial cell prolifera­
tion and differentiation as well as neurogenesis7, which
is essential for maternal behaviour in both mammals and
nonmammalian species8.
Cell proliferation is very low in the healthy adult
pituitary gland, and most cells positive for proliferation
markers in this gland do not express markers of the
hormone-​producing lineages. However, genetic lineage
tracing studies showed little cell differentiation from
progenitors9. Another study showed that lactotrophs
are arranged as a network in the pituitary, permitting
functional adaptation of hormone release following
repeat stimulation10. During pregnancy and subsequent
lactation, lactotroph hyperplasia can be observed pre-
sumably as a result of lactotroph proliferation, transdif-
ferentiation of somatotrophs and expansion from a stem
cell population11. This hyperplasia stops within several
months after delivery, although breastfeeding slows
this process12.
Prolactin binds to its cell surface receptor (PRL-​R)
and initiates an intracellular signalling cascade5. The
PRL-​R consists of an extracellular domain for ligand
binding, a helical transmembrane portion and an intra-
cellular region. Multiple isoforms of membrane-​bound
PRL-​R that result from alternative splicing of the pri-
mary mRNA transcript have been identified in rodents
and humans1,13–15. These isoforms have identical extracel-
lular domains but differ in the size and sequence of the

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Key points
• Prolactin exerts its actions via a transmembrane prolactin receptor (PRL-​R),
the structure of which has now been elucidated.
• Prolactin signalling is essential for the ontogenesis of pancreatic stem cells for
the establishment of a functional β-​cell reserve.
• In addition to its role in increasing dopaminergic inhibitory tone, prolactin exerts
autocrine and paracrine feedback on lactotroph cells.
• Prolactin deficiency is rare and causes failure of lactation.
• Hyperprolactinaemia can be caused by medications or pituitary disease, can have
systemic causes or can be idiopathic; this condition frequently leads to hypogonadism
and infertility.
intracellular portion, which can be short, intermediate
or long1,13–15.
The main isoform of PRL-​R found in humans is a
long protein made up of 598 amino acids. Human PRL-R
can bind at least three ligands (prolactin, placental
lactogen and growth hormone), which could make it
difficult to determine the specific effects of prolactin
in vivo16,17. Human PRL-​R dimers are constitutively
expressed on the cell surface, associated via the trans-
membrane domains18,19. Signalling is initiated by the
binding of a single ligand molecule (prolactin) to two
extracellular interaction sites of different affinities called
binding domain 1 and binding domain 2, which triggers
a change in the conformation of the receptor dimer20.
PRL-​R does not have intrinsic tyrosine kinase activity
but transmits a signal through associated cytoplasmic
proteins. Determination of the architecture of human
PRL-​R revealed the existence of multiple short motifs
in its intracellular domain, providing a structural basis
for the idea that it can interact with several kinases or
signal partners at the same time2. The activation of
downstream signalling pathways can produce different
cell responses, which partly explains the versatility of the
actions of prolactin reported in some tissues.
The first comprehensive structural characteriza-
tion of the PRL-​R intracellular domain shows that it is
intrinsically disordered through its entire length and
interacts specifically with hallmark lipids of the inner
plasma membrane through conserved basic clusters21.
The full receptor structure was generated a few years ago
by combining experimental and computational find-
ings with previously published data, including solution
nuclear magnetic resonance spectroscopy, small-​angle
X-ray scattering, native mass spectrometry and molecu­
lar modelling2. The results provided the first full view
of a class 1 cytokine receptor, which exemplifies the
architecture of more than 40 different receptors.
The intracellular domain of the receptor is now
known to be more than twice as extended in the direction
of the normal membrane compared with the extracellu-
lar and the transmembrane domains together2. The cyto-
plasmic domain can reach and interact with numerous
interaction partners owing to its structural flexibility.
This innovative view of the receptor reveals that the
extracellular domain is merely the tip of an enormous
molecular iceberg2 (Fig. 1). The molecular mechanism of
PRL-​R activation is similar to that of growth hormone
receptor activation and involves multiple scissor-​like
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steps in which conformational changes within the
receptor dimer ultimately lead to receptor activation22.
Physiological roles of prolactin
Prolactin has many different targets and pleiotropic
functions in health and disease. In addition to its cru-
cial role in lactation, many other functions have been
attributed to prolactin in multiple species, including
roles in metabolism, skin and hair follicles, bone homeo­
stasis, maternal care and adrenal function (Fig. 2). Most
current knowledge on prolactin has been obtained from
studies of animal phenotypes in particular conditional
or complete Prlr−/− mouse models. Although this infor-
mation is indispensable for understanding prolactin in
human health and disease, sufficient disparity exists
in the control of the production, distribution and physio­
logical functions of prolactin between these species to
warrant careful and judicial extrapolation of findings
to humans.
Prolactin and metabolic homeostasis. A large body of
literature in rodents reported that prolactin has pivotal
roles in glucose metabolism through effects on pancre-
atic β-​cell mass and insulin production23,24. Prolactin also
has a role in peripheral insulin sensitivity25 and has orexi-
genic actions on the central nervous system, promoting
positive energy balance26–29. In addition, prolactin might
also affect energy homeostasis through modulation of
lipid metabolism30. Direct evidence is now available that
prolactin has a pivotal role in energy balance through
control of adipocyte differentiation and fate. Prlr−/−
mutant mice displayed reduced fat mass associated with
the appearance of massive brown-​like adipocyte foci
in perirenal fat deposits under conditions of a high-​fat
diet31. Lack of PRL-​R causes resistance to high-​fat-diet-​
induced obesity owing to enhanced energy expenditure
and increased metabolic rate. These results provide
direct genetic evidence that the PRL-​R affects energy
balance and metabolic adaptation in rodents via effects
on brown adipose tissue differentiation and function.
Prolactin and placental lactogens also stimulate β-​cell
replication as well as insulin production in pancreatic
islets and insulinoma cells32. However, the contribution
of PRL-​R signalling to β-​cell ontogeny and function in
perinatal life is poorly understood. The effects of lacto-
gens on adaptive islet growth are also not well under-
stood. Recent data provide evidence that expansion of
β-​cell mass during both embryogenesis and the post-
natal period is impaired in the Prlr−/− mouse model33.
Thus, prolactin signalling is essential for the ontogene-
sis of pancreatic stem cells during the critical perinatal
window responsible for the establishment of a functional
β-​cell reserve.
The reduced β-​cell pool in the perinatal period in
Prlr−/− newborn mice might lead to inadequate responses
to metabolic stresses in later life (for example, obesity,
pregnancy, glucocorticoid therapy and ageing) and
could lead to failure of β-​cell function, insufficient insu-
lin production and glucose intolerance, which could
predispose to diabetes. To date, some data suggest that
the human β-​cells are less responsive than mouse β-​cells
to prolactin, as notable differences in the cell surface
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Reviews

Ligand-binding domain

Extracellular
domain
Transmembrane
WS motif
domain

Box 1

Box 2
Intracellular
domain

Lipid interaction
domain

Fig. 1 | Topology of the human PRL-​R. The active complex of the prolactin receptor (PRL-​R) is formed by one molecule
of ligand and two molecules of receptor, each containing the extracellular domain, the transmembrane domain and the
intracellular domain. The membrane-​embedded part of the receptor is coloured light pink and the water-​soluble
extracellular and intracellular domains are dark blue. Two conserved sequence motifs, box 1 and box 2, are shown in red
and green, respectively, and three recently identified lipid interaction domains are shown in light blue. The WS motif is
shown in light green. Adapted from ref.2, CC-​BY-4.0.

receptor between human and mouse β-​cells have been
reported34–36. Further studies are needed to clarify the
potential role of prolactin in human metabolism.
Maternal adaptations to pregnancy include changes
in glucose metabolism and development of insulin
resistance as a physiological response shunting nutrients
to the fetus. Both human and animal studies have shown
that the presence of gestational diabetes increases the
risk of abnormal glucose homeostasis in the offspring37.
A 2016 study showed that mice lacking PRL-​R in pan-
creatic β-​cells developed hallmark features of gestational
diabetes mellitus38. The results of these studies contri­bute
to establish the important role of the PRL-R in β-cells
for modulating the expression of genes necessary for
proliferation of β-​cells during pregnancy.
Prolactin in skin and hair follicles. Prolactin is produced
in both human skin and hair follicles and is now known
to have an important role in human cutaneous bio­l­
ogy, ranging from the regulation of keratin expression
via hair growth modulation to the control of epithelial
stem cell function39. Specifically, prolactin promotes hair
growth in human hair follicle organ culture, upregulates
expression of keratin 15 in adult human epithelial stem
cells ex vivo and stimulates epidermal keratinocyte pro-
liferation in cell culture39. In mice, prolactin has been
shown to modulate the seasonally independent hair
follicle cycling40. Indeed, analysis of Prlr−/− mice showed
a striking hair phenotype characterized by longer and
coarser hair, premature fur moulting and premature
entry of hair follicles into the next hair40.
Sweat glands have an important role in thermoregula-
tion and osmoregulation. Ideas about the possible role of
prolactin in human sweat gland regulation can be drawn
from nonmammals. In fish skin, for example, prolactin
has an important role in osmoregulation by preventing
both the loss of ions and the excessive uptake of water41.
Therefore, prolactin seems to mediate epidermal
adaptation to environmental stress, at least in fish.
Interestingly, prolactin has been shown to have a
direct effect on thermoregulation and hair morphology
phenotypes in dairy cattle42,43. A truncated autosomal
dominant mutation, located in the tenth exon of PRLR,
was shown to contribute to heat tolerance adaptation
in Senepol cattle and resulted in short hair known as
slick43. Some associations between prolactin and ther-
mal stress have been observed in humans43, but a direct
modulatory role for prolactin in human thermoregu-
lation has remained unproven44. Given the key role of
prolactin signalling in hair follicle growth and cycling
in mice40, the identification of the mutation shown to
contribute to heat tolerance in cattle was in agreement
with its impact on hair development and homeothermy.
This mutation might have been increased through natu­
ral selection because of the advantage conferred in hot
tropical environments45.
Osteoporosis, phosphocalcic metabolism and prolactin.
Numerous lines of evidence suggest that abnormalities
in prolactin levels are frequently associated with abnor-
mal bone metabolism46. Although no particular growth
phenotype was observed in Prlr−/− animals, examina-
tion of the calvariae of Prlr−/− mouse embryos indicates
lower ossification than in controls47. Histomorphometric
analysis showed that Prlr−/− adult mice had decreased
bone formation rate and reduced BMD47. A direct effect
of prolactin on osteoblasts might be required for nor-
mal bone formation and maintenance of bone mass in
mice47. However, low sex steroid levels in these animals
also account for low BMD. A 2018 paper highlights the
role of both cytokines and prolactin as key regulators of
bone resorption during lactation and as local receptor

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Hair cycle
Pituitary
regulation
gland
Behaviour
• Food intake Prolactin
• Maternal nursing
Lactotroph
homeostasis
Stress and
adrenal function
Metabolism
• β-Cells
• White and brown
adipocytes
Bone homeostasis
Fig. 2 | New acceptance of prolactin physiological roles. In addition to its crucial role
in lactation, many other functions have been attributed to prolactin in multiple species,
including implications in metabolism, hair cycle regulation, bone homeostasis, behaviour,
adrenal response to stress and lactotroph homeostasis.
activators of the nuclear factor-​κB ligand (RANKL)–
osteoprotegerin (OPG; also known as TNFRSF11B)
system in mice48.
Several clinical studies indicate that hyperprolactin­
aemia (Box 1) is associated with deleterious effects on
bone in humans. Women and men with hyperprolactin­
aemia and hypogonadism have decreased BMD and
increased risk of vertebral fractures49–52. Dopaminergic
agonist therapy suppresses prolactin excess and leads to
improvements in BMD53. Of note, women with hyper-
prolactinaemia who have regular menstrual cycles
also have normal BMD54. These data are most con-
sistent with the hypothesis that sex steroid deficiency
induced by prolactin, but not prolactin excess per se,
causes the development of low BMD in patients with
hyperprolactinaemia54.
A case of hypercalcaemia has been described sec-
ondary to prolactin-​induced mammary gland produc-
tion of parathyroid hormone-​related protein (PTHrP)
during pregnancy, a physiological state of hyperpro­
lactinaemia55. In this very rare context, treatment with
dopamine agonists to decrease prolactin levels led to
complete remission of hypercalcaemia and resulted in a
pregnancy carried to full term without complications55.
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In summary, prolactin exerts direct and indirect effects
on bone remodelling by modulating sex hormone levels.
Maternal nursing behaviour. A role for prolactin in
the induction of maternal behaviour in female rats was
demonstrated in the 1980s56. Furthermore, treatment
of hypophysectomized female rats with anterior pitui-
tary gland grafts, mimicking prolactin administration,
resulted in rapid induction of maternal care towards fos-
ter young56. Prolactin is present in the milk of lactating
rodents, and when ingested by the pups, the prolactin
goes into their systemic circulation57. Prolactin defi-
ciency during the early postpartum period can affect the
normal activity of the tuberoinfundibular dopaminergic
(TIDA) system58.
Studies in mice further support a role for prolac-
tin and the PRL-​R in maternal behaviour59. Over the
course of pregnancy, the maternal brain is exposed to
elevated concentrations of a range of lactogens and
prolactin, proteins that have the capacity to stimulate
maternal behaviour60. The PRL-​R present in the cho-
roid plexus was previously thought to be involved in the
transport of prolactin into the brain61, but a more recent
study characterized the transport of prolactin from the
blood into the brain of female mice, and the authors
proposed that the PRL-​R is not required for transport
of prolactin into the brain62. This finding suggests that
prolactin transport involves another as yet unidentified
transporter molecule. Using a Prlr−/− mouse model,
virgin females were shown to have deficits in their
responses to foster young59. The most notable deficits
were present in homozygous animals, and intermedi-
ate responses were present in heterozygotes relative to
wild-type controls59.
Prolactin helps establish a nurturing link between
the mother and her newborn baby. A 2017 study using
conditional knockout of the Prlr in medial preoptic area
neurons in mice showed for the first time that prolactin
establishes and maintains the normal parental care that
ensures offspring survival63. Indeed, these female mice
were able to become pregnant and give birth normally
but abandoned their litters 1 day after birth. The develop-
ment of maternal behaviour in female rats is also depend-
ent on prolactin64. When prolactin secretion is reduced
in lactating rats, their offspring later display deficits in
their latencies to respond to foster pups. The exposure to
prolactin in the mother’s milk might facilitate maternal
care when the young reach adulthood64. This study sup-
ports the hypothesis that prolactin is able to influence the
development of the neuronal system of the offspring that
underlies the control of maternal behaviour.
The effect of prolactin exposure after and perhaps
before birth might result in long-​term developmen-
tal programming affecting the expression of maternal
behaviour. Unfortunately, less is known on the potential
role of the prolactin system in maternal care in primates
and humans, although the possibility that the situation
is similar certainly deserves consideration. For instance,
studying the maternal behaviour of women presenting
with a deficit of pituitary prolactin after Sheehan syn-
drome (postpartum hypopituitarism) could be interest-
ing. To date, no consequence on maternal care has been
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Box 1 | Definition of hyperprolactinaemia
• Hyperprolactinaemia is defined as any situation in
which circulating prolactin levels are higher than those
in the reference population
• In clinical practice, the term hyperprolactinaemia is
typically used when the prolactin level is chronically
increased
• Values >20–25 ng per ml (420–500 mIU per L) are
considered pathological, but the threshold value
depends on the type of assay used
reported in this patient population. It is possible that
the defects in pituitary prolactin in these women could
be compensated by lactogenic actions in the brain pro-
vided by placental lactogens, as these are a major ligand
for PRL-​R during the peripartum period65. A study has
tested this hypothesis in female mice66. Prolactin activity
patterns in female mice and their variation throughout
pregnancy and lactation were characterized by analysing
the brain immunoreactivity of a key molecule in the sig-
nalling cascade of PRL-​R66. Nonhypophyseal lactogenic
activity during pregnancy was also evaluated by admin-
istering bromocriptine, which suppresses pituitary pro­
lactin release. Late-​pregnant and lactating females showed
significantly increased brain immunoreactivity compared
with nonpregnant mice. During late pregnancy, this pat-
tern was not affected by the administration of bromocrip-
tine, suggesting that it is elicited mostly by circulating
PRL-​R ligands such as placental lactogens66.
Stress and adrenal function. Prolactin secretion is pri-
marily regulated by a negative feedback loop. Prolactin
activates TIDA neurons, increasing their release of
dopamine, which accesses the pituitary via the median
eminence and the hypothalamic–pituitary blood system
to suppress further prolactin secretion67. Circulating
prolactin is secreted in response to stress, although the
mechanism by which this is achieved, or its cellular
targets, remains unknown68.
A brief period of restraint stress in male mice has
been shown to cause an increase in circulating prolactin
concentration69. This stress-​induced increase in prolac-
tin interacts with both central targets (the arcuate nucleus
and median eminence) and peripheral targets (the zona
fasciculata of the adrenal cortex). On the other hand,
restraint stress resulted in reduced prolactin signalling in
the TIDA neurons, which suggests that there might be a
decline in their inhibitory influence on prolactin secretion
under these conditions, suggesting a potential mechanism
by which stress can elevate prolactin secretion69.
In humans, numerous links have been reported
between prolactin, the environment and psychologi-
cal stress (including diseases, pharmacological hypo-
glycaemia, acute experimental prolactin responses to
psychological stress and chronic hyperprolactinaemia
associated with states, traits or coping strategies)70.
The effect of prolactin on the secretion of andro-
gens by the human adrenal gland is highly debated.
Hyperandrogenism of adrenal origin (measured by
elevated dehydroepiandrosterone sulfate (DHEA-​S)
concentrations) has been reported in women with
360 | JUNE 2019 | volume 15
hyperprolactinaemia71, but these data are not concordant
with other study findings72,73. Increases in testosterone
levels can also occur in some patients as a consequence
of conversion from androgenic precursors. Hirsutism
arises in some women with high prolactin levels, but
it is not clear whether increased DHEA-​S concentra-
tion is also associated with hirsutism74. Treatment with
bromocriptine, which is able to suppress prolactin
excess, can lead to a decrease in DHEA-​S levels75.
Regulation of prolactin secretion
Role of prolactin in lactotroph homeostasis. As noted
above, lactotroph cell secretion and proliferation are under
the control of dopamine, which is synthesized by hypotha-
lamic TIDA neurons and secreted into the pituitary portal
blood76. The inhibitory effects of dopamine on prolactin
secretion are exerted via dopamine D2 receptors (D2Rs)
located on the surface of lacto­troph cells. Conversely, pro-
lactin stimulates hypothalamic dopamine secretion via
PRL-​Rs located on TIDA membranes, exerting a negative
feedback effect on its own secretion. Both Drd2−/− mice
and Prlr−/− mice develop hyperprolactinaemia and lacto­
troph adenomas, also called prolactinomas, confirm­
ing the importance of hypothalamic dopaminergic
tone in the regulation of lactotroph homeostasis77–80.
The molecular mechanisms and signalling pathways
involved in the development of pituitary lactotroph
tumours and prolactin hypersecretion in Prlr−/− mice
have now been studied80. Gene-​set enrichment analy-
sis suggested that dysregulation of several signalling
pathways results in the late development of lactotroph
adenomas in mice80. Gene-​set enrichment analysis aims
to identify candidate genes that could be involved in
prolactin pituitary tumour initiation. Examples of can-
didate genes that remain to be evaluated in human pro­
lactinoma pathophysiology include Brd4, which encodes
a member of the BET family of nuclear proteins carrying
bromodomains that are implicated in chromatin interac-
tions, and Erbb4, which encodes a member of the ERBB/
EGFR tyrosine kinase receptor family. These candidate
genes could constitute interesting therapeutic targets for
lactotroph tumours resistant to dopaminergic agonists.
Indeed, tyrosine kinase inhibitors (TKIs) have already
demonstrated their efficacy in the targeted treatment
of various tumours81. In particular, lapatinib, a TKI that
inhibits both EGFR and HER2 signalling, demonstrated
its efficacy in vivo in the treatment of ERBB receptor-​
driven prolactinomas in female transgenic mice82. JQ1,
a BRD4 inhibitor, has been shown in vivo to reduce
pituitary tumour growth in mice83. To our knowledge,
no study has yet evaluated the effect of JQ1 in human
dopamine-​agonist-resistant prolactinoma.
In addition to its role in increasing dopaminergic
tone, prolactin has also been shown to exert auto-
crine or paracrine actions on lactotroph cells in vivo84.
Conditional deletion of the Prlr in lactotroph cells was
described in mice: females exhibited normal prolactin
levels and did not develop pituitary lactotroph adeno-
mas, even at 20 months of age. Nevertheless, they showed
increased dopaminergic inhibitory tone compared with
control mice, confirming the presence of autocrine or
paracrine feedback of prolactin in lacto­troph cells in vivo
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that can be fully compensated by an intact hypothalamic
feedback system84. In physiological situations in which
dopamine output is impaired, such as during lactation or
ageing10,85,86, pituitary autoregulation might be important
for minimizing the occurrence of adenomas.
Human models of neuroendocrine regulation of pro­
lactin secretion. Prolactin is the sole pituitary hormone
for which release is controlled by hypothalamic inhibi-
tory tone. Classically, other factors such as oestrogens,
TSH-​releasing hormone (TRH) or vasoactive intestinal
peptide might have some role in stimulating prolactin
secretion75. Under physiological conditions, dopamine
is the most important inhibitor of prolactin secretion,
but other inhibitors of prolactin secretion have been
proposed, including gonadotropin-​releasing hormone
(GnRH)-associated peptide (GAP) in experimental para­
digms75, but the relevance of the findings in rodents and
humans is unclear. Indeed, GAP, encoded by GNRH1,
was reported to be a potent inhibitor of prolactin secre-
tion in cultures of rat pituitary cells87. Notably, humans
carrying GNRH1 homozygous frameshift mutations
have been shown to have normal or even low plasma
prolactin levels, although these patients lack the GAP
peptide sequence, indicating that in the physiological
state, GAP does not act on the pituitary gland to regu­
late prolactin secretion in humans88. By contrast, in the
Hpg mouse model lacking the Gnrh1 gene, the absence
of GAP is associated with a sharp decrease in pituitary
prolactin content in Hpg females89,90, a finding that argues
against a major physiological role for GnRH and GAP in
regulating prolactin secretion. In the same way, we can
say that the TRH receptor does not have a relevant stimu­
latory physiological role in prolactin secretion, given that
the TRHR loss-​of-function mutation in humans and
mice is associated with normal (not decreased) prolactin
levels91,92. Therefore, TRH action is not required for pitu-
itary development, nor is it required for expression of the
PRL gene, meaning that TRH does not have a major role
as a prolactin-​releasing factor under normal conditions.
Abnormal prolactin levels
The main role of prolactin in mammalian physiology is
to stimulate the proliferation and differentiation of the
mammary cells required for lactation. Prolactin exerts
minor effects on morphological changes occurring in the
mammary gland during fetal, neonatal and peripubertal
life, but it is greatly involved in most stages of lactation,
including mammogenesis (lobuloalveolar differen­
tiation), lactogenesis (achievement of the capacity to pro-
duce milk), galactopoiesis (maintenance of milk secretion)
and involution (a return to a nonlactating state)4,93.
Prolactin deficiency. Unlike hyperprolactinaemia, pro-
lactin deficiency is a very rare condition, with approxi-
mately a few dozen cases reported in the literature since
1975 (refs94,95). The main causes of hypoprolactinaemia
are summarized (Box 2) . Clinical manifestations of
abnormal prolactin levels are also presented (Fig. 3).
Most described cases of severe prolactin deficiency have
been in women, and in the majority of reported cases
the condition was revealed by the absence of lactation
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Box 2 | Main causes of hypoprolactinaemia
• Abnormal lactotroph cell development (genetic causes)
-- POU1F1, PROP1, LHX3, LHX4, HESX1, OTX2 and
IGSF1 loss-​of-function mutations
• Destruction of pituitary tissue
-- Sheehan syndrome
-- Inflammation or hypophysitis (or autoimmune
lactotroph damage)
-- Tumour or surgery
-- Infection (tuberculosis)
• Pseudohypoparathyroidism
• Idiopathic prolactin deficiency
• Medications
-- Dopamine agonists (cabergoline, bromocriptine,
quinagolide and pergolide)
after delivery (puerperal alactogenesis)96. Alactogenesis
due to prolactin deficiency has been successfully treated
by the administration of recombinant human prolac-
tin97. Following treatment, circulating prolactin levels
increased and milk volume increased. Patients with pro­
lactin deficiency represent a good model for studying the
possible role of prolactin in ovulation and pregnancy.
Published data indicate that ovulation and pregnancy are
possible in women with severe prolactin deficiency,
which excludes a crucial role of prolactin in female phys-
iological ovulation, contrary to the situation described
in rodents98. In men, as in nonlactating and nonpreg-
nant women, prolactin deficiency has no reported clin-
ical consequence96. Some patients with lactation failure
caused by prolactin deficiency have very low or even
undetectable serum prolactin concentrations when
measured with the available immunoassays94,95. Some
authors have suggested that an increase in prolactin
secretion in response to infant suckling is compromised
in obese women and could explain a relative increased
risk of failure to initiate breastfeeding and a delayed
onset of lactogenesis in this patient group99–102.
Prolactin deficiency has multiple causes (Box 2), but
all are associated with alteration of pituitary lactotroph
cells preventing the physiological secretion of prolactin,
particularly during pregnancy and lactation, or medica-
tions such as dopamine agonists that inhibit secretion
of prolactin95. Some prolactin deficiencies are the con-
sequence of genetic abnormalities (POU1F1, PROP1,
LHX3, LHX4, HESX1, OTX2 and IGSF1 loss-​of-function
mutations) that prevent the normal development of the
pituitary lactotroph cell line and other anterior pituitary
cell lineages such as somatotrophs or thyrotrophs103,104,
which explains the deficiency in other pituitary hor-
mones that commonly occurs with prolactin deficiency.
In patients with a genetic cause of prolactin deficiency, no
specific clinical complaint related to low prolactin levels
has been reported during childhood. Prolactin defi-
ciency can be clearly detectable in women only when
pregnancy occurs. In pregnant women with a PROP1
loss-​of-function mutation, serum prolactin levels are
much lower than the elevated levels observed in pregnant
women without this mutation105. As with other causes of
prolactin deficiency, puerperal alactogenesis occurs after
delivery in women with PROP1 mutations105.
volume 15 | JUNE 2019 | 361
 Reviews
Hypoprolactinaemia Hyperprolactinaemia
TIDA neuron KNDy neuron GnRH neuron
Prolactin
PRL-R
Hypothalamus
↓ Kisspeptin ↓ GnRH
Pituitary gland
↓ LH and FSH
Failure of lactation Anovulatory infertility
Fig. 3 | Consequences of abnormal prolactin levels in humans. Prolactin release is
controlled by tuberoinfundibular dopaminergic (TIDA) neurons. Prolactin deficiency
can result from alterations in pituitary lactotroph cells preventing the physiological
secretion of prolactin or from medications that activate the dopamine receptor and
inhibit prolactin release. The consequence of hypoprolactinaemia in women is a failure
of lactation. Increased serum prolactin levels (right) result in decreased kisspeptin
expression in KNDy neurons (that is, kisspeptin, neurokinin and dynorphin neurons)
in hypothalamic nuclei, mediated by the prolactin receptor (PRL-​R). Consequently,
gonadotropin-​releasing hormone (GnRH) release is reduced and leads to low pituitary
gonadotropin (luteinizing hormone (LH) and follicle-​stimulating hormone (FSH))
secretion and loss of ovarian stimulation, which results in anovulatory infertility.
Low circulating prolactin levels have been described
in patients with pseudohypoparathyroidism, a rare
clinical condition resulting from resistance to parathy-
roid hormone caused by GNAS genetic alterations106,107.
In these patients, serum prolactin secretion is not stim-
ulated by either TRH or by insulin hypoglycaemia106,107.
However, in these few reports published more than
30 years ago, the clinical consequences of low prolactin
levels were not specified.
In addition to the genetic causes, many cases of
acquired prolactin deficiency secondary to pituitary
lesions have been reported, in which physical damage
of lactotroph cells is caused by processes such as ischae-
mic pituitary necrosis (Sheehan syndrome)108, pituitary
tumours, surgical lesions, inflammatory or autoimmune
pituitary disorders (hypophysitis and sarcoidosis) and
tuberculosis infection94. In these cases, prolactin deficiency
most often occurs alongside other pituitary deficiencies.
The incidence of severe prolactin deficiency in patients
with acquired prolactin deficiency increases alongside
an increase in the number of other anterior pituitary
hormone defects; therefore, acquired severe prolactin
deficiency can be considered a marker of extensive pitu-
itary damage94. Reports of isolated prolactin deficiency
secondary to autoimmune disorders selectively affecting
lactotroph cells have also been published95. Dopamine
agonist drugs activating D2Rs are commonly used in
clinical practice for the treatment of tumour-​induced
362 | JUNE 2019 | volume 15
hyperprolactinaemia (prolactinomas), and in some
patients the chronic administration of these molecules
(cabergoline, bromocriptine, quinagolide or pergolide)
can lead to a dramatic decrease in circulating prolactin
levels109. This hypoprolactinaemic effect can prevent
breastfeeding when these therapies are administered in
pregnant women or in the postpartum period110.
Lobuloalveolar development of the mammary gland
is impaired in the Prlr−/− mouse model98,111. In 2018, the
first case of biallelic PRLR loss-​of-function mutation
leading to complete prolactin resistance and puerperal
alactogenesis was reported112. In this woman, an increase
in circulating prolactin levels was associated with the
absence of postpartum breastfeeding consistent with
findings in the mouse model.
Hyperprolactinaemia. Hyperprolactinaemia is the most
common pathological state associated with high circu-
lating prolactin levels. Hyperprolactinaemia is caused by
prolactinoma in approximately 50% of cases113, and many
other causes have been reported (Box 3). The association
between hyperprolactinaemia and adverse health out-
comes has been studied, and no excess in morbidity or
all-​cause mortality was reported in patients with hyperpro-
lactinaemia related to pituitary tumours114. In particular,
no increased risk of diabetes, cardiovascular disease, all-​
cause cancer or breast cancer was observed. These results
are in accordance with those obtained by the Framingham
Heart Study, revealing no association between prolactin
measurements and cardiovascular risk factors115.
Novel findings have emerged regarding the neuro­
endocrine impact of hyperprolactinaemia. Hyperpro­
lactinaemia is the most common cause of amenorrhoea
caused by hypogonadotropic anovulation and is one
of the most prevalent endocrine causes of infertility
in premenopausal women5. Evidence indicates that
hyperprolactinaemia-​induced pituitary gonadotropin
deficiency is indirect and results from suppression of
hypothalamic GnRH release by prolactin116,117. In agree-
ment with this idea, pulsatile GnRH administration
has been shown to stimulate gonadotropin secretion in
patients with hyperprolactinaemia and is sufficient to
restore ovarian endocrine function and fertility116–118.
Until recently, an unresolved question was whether
hyperprolactinaemia directly affects GnRH neurons
via the PRL-​R or indirectly affects GnRH neurons by
acting upstream on other intermediate neurons that
regulate GnRH secretion. GnRH neurons have now been
shown to be stimulated by kisspeptin neurons, which
are known to express PRL-​R119,120. A study showed that
hypothalamic kisspeptin expression was diminished in
a female hyperprolactinaemic mouse model with hypo-
gonadotropic anovulation and that kisspeptin adminis­
tration restored GnRH, gonadotropin secretion and
ovarian cyclicity121. The question that was immediately
raised by these findings was whether the same mecha­
nism might be responsible for hyperprolactinaemia-​
induced hypogonadotropic hypogonadism in humans
and whether kisspeptin administration could restore
gonadotropin levels and ovarian activity. Another study
showed that administration of kisspeptin 10 reacti-
vated gonadotropin secretion and increased ovarian
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 Reviews

Box 3 | Main causes of hyperprolactinaemia
• Physiological
-- Pregnancy
-- Lactation
-- Nipple stimulation
• Analytical
-- Macroprolactinaemia (hyperprolactinaemia with a
predominance of macroprolactin)
• Pathological
-- Prolactinomas and mixed secreting adenomas
-- Hypothalamic and pituitary stalk disorders
(compressive macroadenoma, hypophysitis,
granulomatous disease, Rathke cleft cyst, irradiation
and/or trauma, and tumours including cranio­
pharyngiomas, germinomas and metastases)
• Medications
-- Dopamine antagonists (antipsychotics, anti-​emetics
and α-​methyldopa antihypertensives)
-- Other (antidepressants, oestrogens and opiates)
• Chronic renal failure
• Ectopic prolactin secretion
-- Ovarian dermoids
-- Hypernephroma
-- Bronchogenic carcinoma
• Genetic
-- PRLR loss-​of-function mutation
• Idiopathic
-- Unknown
Reproduced from ref.5, Springer Nature Limited.
activity in women with hyperprolactinaemia caused by
cabergoline-​resistant prolactin microadenomas122. These
data suggest that, as in rodents, GnRH deficiency and
hypogonadotropic hypogonadism in women with hyper-
prolactinaemia could also be mediated by impairments
in hypothalamic kisspeptin secretion122.
In agreement with the idea that prolactin has an
inhibitory effect on hypothalamic kisspeptin secretion,
a study reported a particular pattern of gonadotropin
secretion in men and women with hyperprolactinae-
mia caused by microprolactinoma or antidopaminer-
gic drugs123. In these patients, rising prolactin level was
associated with a relative increase in circulating levels
of follicle-​stimulating hormone (FSH) and a relative
decrease in luteinizing hormone (LH) levels, a finding
that could be related to a reduction in hypothalamic
GnRH secretion, which would itself be caused by the
hyperprolactinaemia-​induced decrease in hypotha-
lamic kisspeptin secretion. This specific gonadotropic
profile was different from that observed in patients with
prolactin macroadenomas, in whom both FSH and LH
levels were decreased. The different endocrine profile in
the two patient groups could be caused by the fact that
large prolactinomas induce direct effects on secretion
from pituitary gonadotropic cells. From these findings,
the pattern of gonadotropin secretion in patients with
hyperprolactinaemia might be useful for predicting the
aetiology of hyperprolactinaemia123.
Another interesting area of investigation emerging is
the relationship between hyperprolactinaemia and hot
flushes. Most prolactinomas in females are diagnosed
during the reproductive age124. Prolactinomas can also be
detected in the postmenopausal period, although this sce-
nario is less common125. In menopausal women, hyperpro-
lactinaemia might also inhibit the secretion of kisspeptin
and GnRH and explain the observed blunting of pituitary
LH and FSH levels. Correction of hyperprolactinaemia
with dopamine agonists restores normal high gonadotro-
pin levels, possibly by restoring endogenous kisspeptin
and GnRH levels126. An interesting clinical observation is
that normalization of prolactin levels in postmenopausal
women with hyperprolactinaemia is accompanied by a
recurrence of hot flushes126. A growing body of evidence
implicates the hypothalamic neuropeptide neurokinin B
(secreted by kisspeptin, neurokinin and dynorphin neu-
rons, the so-​called KNDy neurons) together with its recep-
tor signalling in the aetiology of menopausal hot flushes127.
An interesting hypothesis proposed by the authors could
be that hyperprolactinaemia might reduce hot flushes by
inhibiting neurokinin secretion through KNDy neurons.
The correction of hyperprolactinaemia by restoring the
exaggerated secretion of neurokinin B in postmenopausal
women might explain the reappearance of hot flushes in
these women. Validation of this hypothesis would require
intervention studies using human recombinant prolactin
in postmenopausal women95.
Conclusions
In the past 10 years, major progress in our knowledge
of the mechanisms of action of prolactin and in its roles
in human health and disease has emerged. Our under-
standing of the role of prolactin in metabolic homeo-
stasis has improved. The newly described effects of
prolactin in bone remodelling and in long-​term devel-
opmental programming affecting the expression of
maternal behaviour extend the functional scope of this
hormone. In addition, prolactin has now been shown to
exert autocrine or paracrine actions on lactotroph cells
in vivo, and novel findings have emerged concerning
the neuroendocrine regulation of prolactin secretion.
Finally, major advances have emerged concerning our
understanding of the impact of hyperprolactinaemia on
the gonadotroph axis.
Published online 21 March 2019

1. Bole-​Feysot, C., Goffin, V., Edery, M., Binart, N. &
Kelly, P. A. Prolactin (PRL) and its receptor: actions,
signal transduction pathways and phenotypes
observed in PRL receptor knockout mice. Endocr. Rev.
19, 225–268 (1998).
2. Bugge, K. et al. A combined computational and
structural model of the full-​length human prolactin
receptor. Nat. Commun. 7, 11578 (2016).
3. Goffin, V., Binart, N., Touraine, P. & Kelly, P. A. Prolactin:
the new biology of an old hormone. Annu. Rev. Physiol.
64, 47–67 (2002).
4. Ben-​Jonathan, N., LaPensee, C. R. & LaPensee, E. W.
What can we learn from rodents about prolactin in
humans? Endocr. Rev. 29, 1–41 (2008).
5. Bernard, V., Young, J., Chanson, P. & Binart, N.
New insights in prolactin: pathological implications.
Nat. Rev. Endocrinol. 11, 265–275 (2015).
6. Halmi, N. S., Parsons, J. A., Erlandsen, S. L. & Duello, T.
Prolactin and growth hormone cells in the human
hypophysis: a study with immunoenzyme histochemistry
and differential staining. Cell Tissue Res. 158, 497–507
(1975).
7. Shingo, T. et al. Pregnancy-​stimulated neurogenesis
in the adult female forebrain mediated by prolactin.
Science 299, 117–120 (2003).
8. Bridges, R. S. Neuroendocrine regulation of maternal
behavior. Front. Neuroendocrinol. 36, 178–196
(2015).
9. Rizzoti, K., Akiyama, H. & Lovell-​Badge, R.
Mobilized adult pituitary stem cells contribute
to endocrine regeneration in response to
physiological demand. Cell Stem Cell 13, 419–432
(2013).

NATURE REvIEwS | ENDoCRiNoLogy volume 15 | JUNE 2019 | 363

Reviews
10. Hodson, D. J. et al. Existence of long-​lasting
experience-​dependent plasticity in endocrine cell
networks. Nat. Commun. 3, 605 (2012).
11. Gleiberman, A. S. et al. Genetic approaches identify
adult pituitary stem cells. Proc. Natl Acad. Sci. USA
105, 6332–6337 (2008).
12. Karaca, Z., Tanriverdi, F., Unluhizarci, K. & Kelestimur, F.
Pregnancy and pituitary disorders. Eur. J. Endocrinol.
162, 453–475 (2010).
13. Kline, J. B., Roehrs, H. & Clevenger, C. V. Functional
characterization of the intermediate isoform of the
human prolactin receptor. J. Biol. Chem. 274,
35461–35468 (1999).
14. Hu, Z. Z., Meng, J. & Dufau, M. L. Isolation and
characterization of two novel forms of the human
prolactin receptor generated by alternative splicing
of a newly identified exon 11. J. Biol. Chem. 276,
41086–41094 (2001).
15. Trott, J. F., Hovey, R. C., Koduri, S. & Vonderhaar, B. K.
Multiple new isoforms of the human prolactin receptor
gene. Adv. Exp. Med. Biol. 554, 495–499 (2004).
16. Goffin, V., Shiverick, K. T., Kelly, P. A. & Martial, J. A.
Sequence-​function relationships within the expanding
family of prolactin, growth hormone, placental lactogen,
and related proteins in mammals. Endocr. Rev. 17,
385–410 (1996).
17. Brooks, C. L. Molecular mechanisms of prolactin and
its receptor. Endocr. Rev. 33, 504–525 (2012).
18. Qazi, A. M., Tsai-​Morris, C.-H. & Dufau, M. L. Ligand-​
independent homo- and heterodimerization of human
prolactin receptor variants: inhibitory action of the
short forms by heterodimerization. Mol. Endocrinol.
20, 1912–1923 (2006).
19. Brooks, A. J. & Waters, M. J. The growth hormone
receptor: mechanism of activation and clinical
implications. Nat. Rev. Endocrinol. 6, 515–525
(2010).
20. Goffin, V., Martial, J. A. & Summers, N. L. Use of a
model to understand prolactin and growth hormone
specificities. Protein Eng. 8, 1215–1231 (1995).
21. Haxholm, G. W. et al. Intrinsically disordered
cytoplasmic domains of two cytokine receptors mediate
conserved interactions with membranes. Biochem. J.
468, 495–506 (2015).
22. Brooks, A. J. et al. Mechanism of activation of protein
kinase JAK2 by the growth hormone receptor. Science
344, 1249783 (2014).
23. Freemark, M. et al. Targeted deletion of the PRL
receptor: effects on islet development, insulin
production, and glucose tolerance. Endocrinology 143,
1378–1385 (2002).
24. Vasavada, R. C. et al. Growth factors and beta cell
replication. Int. J. Biochem. Cell Biol. 38, 931–950
(2006).
25. Ben-​Jonathan, N., Hugo, E. R., Brandebourg, T. D.
& LaPensee, C. R. Focus on prolactin as a metabolic
hormone. Trends Endocrinol. Metab. 17, 110–116
(2006).
26. Sauvé, D. & Woodside, B. Neuroanatomical specificity
of prolactin-​induced hyperphagia in virgin female rats.
Brain Res. 868, 306–314 (2000).
27. Arumugam, R., Fleenor, D. & Freemark, M. Lactogenic
and somatogenic hormones regulate the expression
of neuropeptide Y and cocaine- and amphetamine-​
regulated transcript in rat insulinoma (INS-1) cells:
interactions with glucose and glucocorticoids.
Endocrinology 148, 258–267 (2007).
28. Perez Millan, M. I. et al. Selective disruption of
dopamine D2 receptors in pituitary lactotropes
increases body weight and adiposity in female mice.
Endocrinology 155, 829–839 (2014).
29. Luque, G. M. et al. Chronic hyperprolactinemia evoked
by disruption of lactotrope dopamine D2 receptors
impacts on liver and adipocyte genes related to
glucose and insulin balance. Am. J. Physiol.
Endocrinol. Metab. 311, E974–E988 (2016).
30. Ling, C. et al. Prolactin (PRL) receptor gene expression
in mouse adipose tissue: increases during lactation
and in PRL-​transgenic mice. Endocrinology 141,
3564–3572 (2000).
31. Auffret, J. et al. Beige differentiation of adipose depots
in mice lacking prolactin receptor protects against high-​
fat-diet-​induced obesity. FASEB J. 26, 3728–3737
(2012).
32. Brelje, T. C. et al. Effect of homologous placental
lactogens, prolactins, and growth hormones on islet
B cell division and insulin secretion in rat, mouse, and
human islets: implication for placental lactogen
regulation of islet function during pregnancy.
Endocrinology 132, 879–887 (1993).
33. Auffret, J. et al. Defective prolactin signaling impairs
pancreatic β-​cell development during the perinatal
364 | JUNE 2019 | volume 15
period. Am. J. Physiol. Endocrinol. Metab. 305,
E1309–E1318 (2013).
34. Benner, C. et al. The transcriptional landscape of
mouse beta cells compared to human beta cells reveals
notable species differences in long non-​coding RNA
and protein-​coding gene expression. BMC Genomics
15, 620 (2014).
35. Chen, H. et al. Augmented Stat5 signaling bypasses
multiple impediments to lactogen-​mediated proliferation
in human β-​Cells. Diabetes 64, 3784–3797 (2015).
36. Nielsen, J. H. Beta cell adaptation in pregnancy: a
tribute to Claes Hellerström. Ups. J. Med. Sci. 121,
151–154 (2016).
37. Huang, C. Wild-​type offspring of heterozygous
prolactin receptor-​null female mice have maladaptive
β-​cell responses during pregnancy. J. Physiol. 591,
1325–1338 (2013).
38. Banerjee, R. R. et al. Gestational diabetes mellitus
from inactivation of prolactin receptor and MafB in
islet β-​Cells. Diabetes 65, 2331–2341 (2016).
39. Langan, E. A., Foitzik-​Lau, K., Goffin, V., Ramot, Y.
& Paus, R. Prolactin: an emerging force along the
cutaneous-​endocrine axis. Trends Endocrinol. Metab.
21, 569–577 (2010).
40. Craven, A. J. et al. Prolactin signaling influences the
timing mechanism of the hair follicle: analysis of hair
growth cycles in prolactin receptor knockout mice.
Endocrinology 142, 2533–2539 (2001).
41. Manzon, L. A. The role of prolactin in fish
osmoregulation: a review. Gen. Comp. Endocrinol.
125, 291–310 (2002).
42. Foitzik, K. et al. Prolactin and its receptor are expressed
in murine hair follicle epithelium, show hair cycle-​
dependent expression, and induce catagen. Am. J.
Pathol. 162, 1611–1621 (2003).
43. Littlejohn, M. D. et al. Functionally reciprocal
mutations of the prolactin signalling pathway define
hairy and slick cattle. Nat. Commun. 5, 5861 (2014).
44. Mills, D. E. & Robertshaw, D. Response of plasma
prolactin to changes in ambient temperature and
humidity in man. J. Clin. Endocrinol. Metab. 52,
279–283 (1981).
45. Porto-​Neto, L. R. et al. Convergent evolution of slick
coat in cattle through truncation mutations in the
prolactin receptor. Front. Genet. 9, 57 (2018).
46. Giustina, A., Mazziotti, G. & Canalis, E. Growth
hormone, insulin-​like growth factors, and the skeleton.
Endocr. Rev. 29, 535–559 (2008).
47. Clément-​Lacroix, P. et al. Osteoblasts are a new target
for prolactin: analysis of bone formation in prolactin
receptor knockout mice. Endocrinology 140, 96–105
(1999).
48. Macari, S. et al. Lactation induces increases in the
RANK/RANKL/OPG system in maxillary bone. Bone
110, 160–169 (2018).
49. Klibanski, A. et al. Decreased bone density in
hyperprolactinemic women. N. Engl. J. Med. 303,
1511–1514 (1980).
50. Schlechte, J. A., Sherman, B. & Martin, R. Bone
density in amenorrheic women with and without
hyperprolactinemia. J. Clin. Endocrinol. Metab. 56,
1120–1123 (1983).
51. Mazziotti, G. et al. High prevalence of radiological
vertebral fractures in women with prolactin-​secreting
pituitary adenomas. Pituitary 14, 299–306 (2011).
52. Mazziotti, G. et al. Vertebral fractures in males with
prolactinoma. Endocrine 39, 288–293 (2011).
53. Klibanski, A. & Greenspan, S. L. Increase in bone mass
after treatment of hyperprolactinemic amenorrhea.
N. Engl. J. Med. 315, 542–546 (1986).
54. Klibanski, A., Biller, B. M., Rosenthal, D. I.,
Schoenfeld, D. A. & Saxe, V. Effects of prolactin and
estrogen deficiency in amenorrheic bone loss. J. Clin.
Endocrinol. Metab. 67, 124–130 (1988).
55. Winter, E. M. & Appelman-​Dijkstra, N. M. Parathyroid
hormone-​related protein-​induced hypercalcemia of
pregnancy successfully reversed by a dopamine
agonist. J. Clin. Endocrinol. Metab. 102, 4417–4420
(2017).
56. Bridges, R. S., DiBiase, R., Loundes, D. D.
& Doherty, P. C. Prolactin stimulation of maternal
behavior in female rats. Science 227, 782–784 (1985).
57. Shyr, S. W., Crowley, W. R. & Grosvenor, C. E.
Effect of neonatal prolactin deficiency on prepubertal
tuberoinfundibular and tuberohypophyseal
dopaminergic neuronal activity. Endocrinology 119,
1217–1221 (1986).
58. Grosvenor, C. E., Shyr, S. W. & Crowley, W. R.
Effect of neonatal prolactin deficiency on prepubertal
tuberoinfundibular and tuberohypophyseal
dopaminergic neuronal activity. Endocrinol. Exp. 20,
223–228 (1986).
59. Lucas, B. K., Ormandy, C. J., Binart, N., Bridges, R. S.
& Kelly, P. A. Null mutation of the prolactin receptor
gene produces a defect in maternal behavior.
Endocrinology 139, 4102–4107 (1998).
60. Bridges, R. S. et al. Endocrine communication between
conceptus and mother: placental lactogen stimulation
of maternal behavior. Neuroendocrinology 64, 57–64
(1996).
61. Freeman, M. E., Kanyicska, B., Lerant, A. & Nagy, G.
Prolactin: structure, function, and regulation of
secretion. Physiol. Rev. 80, 1523–1631 (2000).
62. Brown, R. S. E. et al. Prolactin transport into mouse
brain is independent of prolactin receptor. FASEB J.
30, 1002–1010 (2016).
63. Brown, R. S. E. et al. Prolactin action in the medial
preoptic area is necessary for postpartum maternal
nursing behavior. Proc. Natl Acad. Sci. USA 114,
10779–10784 (2017).
64. Melo, A. I. et al. Effects of prolactin deficiency during
the early postnatal period on the development of
maternal behavior in female rats: mother’s milk makes
the difference. Horm. Behav. 56, 281–291 (2009).
65. Mann, P. E. & Bridges, R. S. Lactogenic hormone
regulation of maternal behavior. Prog. Brain Res. 133,
251–262 (2001).
66. Salais-​López, H., Lanuza, E., Agustín-​Pavón, C. &
Martínez-​García, F. Tuning the brain for motherhood:
prolactin-​like central signalling in virgin, pregnant, and
lactating female mice. Brain Struct. Funct. 222,
895–921 (2017).
67. Grattan, D. R. 60 YEARS OF NEUROENDOCRINOLOGY:
the hypothalamo-​prolactin axis. J. Endocrinol. 226,
T101–122 (2015).
68. Armario, A., Marti, O., Molina, T., de Pablo, J. &
Valdes, M. Acute stress markers in humans: response
of plasma glucose, cortisol and prolactin to two
examinations differing in the anxiety they provoke.
Psychoneuroendocrinology 21, 17–24 (1996).
69. Kirk, S. E., Xie, T. Y., Steyn, F. J., Grattan, D. R.
& Bunn, S. J. Restraint stress increases prolactin-​
mediated phosphorylation of signal transducer and
activator of transcription 5 in the hypothalamus and
adrenal cortex in the male mouse. J. Neuroendocrinol.
https://doi.org/10.1111/jne.12477 (2017).
70. Sobrinho, L. G. Prolactin, psychological stress and
environment in humans: adaptation and maladaptation.
Pituitary 6, 35–39 (2003).
71. Carter, J. N. et al. Adrenocortical function in
hyperprolactinemic women. J. Clin. Endocrinol. Metab.
45, 973–980 (1977).
72. Schiebinger, R. J., Chrousos, G. P., Cutler, G. B. &
Loriaux, D. L. The effect of serum prolactin on plasma
adrenal androgens and the production and metabolic
clearance rate of dehydroepiandrosterone sulfate in
normal and hyperprolactinemic subjects. J. Clin.
Endocrinol. Metab. 62, 202–209 (1986).
73. Belisle, S. & Menard, J. Adrenal androgen production
in hyperprolactinemic states. Fertil. Steril. 33,
396–400 (1980).
74. Parker, L. N., Chang, S. & Odell, W. D. Adrenal
androgens in patients with chronic marked elevation
of prolactin. Clin. Endocrinol. 8, 1–5 (1978).
75. Tritos, N. & Klibanski, A. in Yen & Jaffe’s
Reproductive Endocrinology E-​Book: Physiology,
Pathophysiology, and Clinical Management
(eds Strauss, J. F., Barbieri, R. L. & Gargiulo, A. R.)
8th edn 58–75 (Elsevier, 2018).
76. Grattan, D. R. & Kokay, I. C. Prolactin: a pleiotropic
neuroendocrine hormone. J. Neuroendocrinol. 20,
752–763 (2008).
77. Kelly, M. A. et al. Pituitary lactotroph hyperplasia and
chronic hyperprolactinemia in dopamine D2 receptor-​
deficient mice. Neuron 19, 103–113 (1997).
78. Asa, S. L., Kelly, M. A., Grandy, D. K. & Low, M. J.
Pituitary lactotroph adenomas develop after prolonged
lactotroph hyperplasia in dopamine D2 receptor-​
deficient mice. Endocrinology 140, 5348–5355
(1999).
79. Schuff, K. G. et al. Lack of prolactin receptor
signaling in mice results in lactotroph proliferation
and prolactinomas by dopamine-​dependent and
-independent mechanisms. J. Clin. Invest. 110,
973–981 (2002).
80. Bernard, V. et al. Natural and molecular history of
prolactinoma: insights from a Prlr−/− mouse model.
Oncotarget 9, 6144–6155 (2018).
81. Krause, D. S. & Van Etten, R. A. Tyrosine kinases as
targets for cancer therapy. N. Engl. J. Med. 353,
172–187 (2005).
82. Liu, X. et al. ErbB receptor-​driven prolactinomas
respond to targeted lapatinib treatment in female
transgenic mice. Endocrinology 156, 71–79 (2015).
www.nature.com/nrendo

83. Fielitz, K. et al. Characterization of pancreatic
glucagon-​producing tumors and pituitary gland
tumors in transgenic mice overexpressing MYCN in
hGFAP-​positive cells. Oncotarget 7, 74415–74426
(2016).
84. Bernard, V. et al. Autocrine actions of prolactin
contribute to the regulation of lactotroph function
in vivo. FASEB J. 9, 4791–4797 (2018).
85. MohanKumar, P. S., MohanKumar, S. M., Quadri, S. K.
& Voogt, J. L. Effects of chronic bromocriptine treatment
on tyrosine hydroxylase (TH) mRNA expression, TH
activity and median eminence dopamine concentrations
in ageing rats. J. Neuroendocrinol. 13, 261–269
(2001).
86. Le Tissier, P. et al. An updated view of hypothalamic-​
vascular-pituitary unit function and plasticity. Nat. Rev.
Endocrinol. 13, 257–267 (2017).
87. Nikolics, K., Mason, A. J., Szönyi, E., Ramachandran, J.
& Seeburg, P. H. A prolactin-​inhibiting factor within the
precursor for human gonadotropin-​releasing hormone.
Nature 316, 511–517 (1985).
88. Bouligand, J. et al. Isolated familial hypogonadotropic
hypogonadism and a GNRH1 mutation. N. Engl. J. Med.
360, 2742–2748 (2009).
89. Cattanach, B. M., Iddon, C. A., Charlton, H. M.,
Chiappa, S. A. & Fink, G. Gonadotrophin-​releasing
hormone deficiency in a mutant mouse with
hypogonadism. Nature 269, 338–340 (1977).
90. Charlton, H. M. et al. Prolactin measurements in
normal and hypogonadal (hpg) mice: developmental
and experimental studies. Endocrinology 113,
545–548 (1983).
91. Bonomi, M. et al. A family with complete resistance to
thyrotropin-​releasing hormone. N. Engl. J. Med. 360,
731–734 (2009).
92. Yamada, M. et al. Tertiary hypothyroidism and
hyperglycemia in mice with targeted disruption of the
thyrotropin-​releasing hormone gene. Proc. Natl Acad.
Sci. USA 94, 10862–10867 (1997).
93. Hennighausen, L. & Robinson, G. W. Information
networks in the mammary gland. Nat. Rev. Mol.
Cell Biol. 6, 715–725 (2005).
94. Toledano, Y., Lubetsky, A. & Shimon, I. Acquired
prolactin deficiency in patients with disorders of the
hypothalamic-​pituitary axis. J. Endocrinol. Invest. 30,
268–273 (2007).
95. Iwama, S., Welt, C. K., Romero, C. J., Radovick, S. &
Caturegli, P. Isolated prolactin deficiency associated with
serum autoantibodies against prolactin-​secreting cells.
J. Clin. Endocrinol. Metab. 98, 3920–3925 (2013).
96. Kauppila, A., Chatelain, P., Kirkinen, P., Kivinen, S.
& Ruokonen, A. Isolated prolactin deficiency in a
woman with puerperal alactogenesis. J. Clin. Endocrinol.
Metab. 64, 309–312 (1987).
97. Powe, C. E. et al. Recombinant human prolactin for the
treatment of lactation insufficiency. Clin. Endocrinol.
73, 645–653 (2010).
98. Ormandy, C. J. et al. Null mutation of the prolactin
receptor gene produces multiple reproductive defects
in the mouse. Genes Dev. 11, 167–178 (1997).
99. Rasmussen, K. M., Hilson, J. A. & Kjolhede, C. L.
Obesity may impair lactogenesis II. J. Nutr. 131,
3009S–3011S (2001).
100. Rasmussen, K. M., Hilson, J. A. & Kjolhede, C. L.
Obesity as a risk factor for failure to initiate and sustain
lactation. Adv. Exp. Med. Biol. 503, 217–222 (2002).
NATURE REvIEwS | ENDoCRiNoLogy
101. Rasmussen, K. M. & Kjolhede, C. L. Prepregnant
overweight and obesity diminish the prolactin
response to suckling in the first week postpartum.
Pediatrics 113, e465–e471 (2004).
102. Garcia, A. H. et al. Maternal weight status, diet, and
supplement use as determinants of breastfeeding
and complementary feeding: a systematic review and
meta-​analysis. Nutr. Rev. 74, 490–516 (2016).
103. Pfäffle, R. & Klammt, J. Pituitary transcription factors
in the aetiology of combined pituitary hormone
deficiency. Best Pract. Res. Clin. Endocrinol. Metab.
25, 43–60 (2011).
104. Nakamura, A. et al. Three novel IGSF1 mutations in
four Japanese patients with X-​linked congenital central
hypothyroidism. J. Clin. Endocrinol. Metab. 98,
E1682–E1691 (2013).
105. Voutetakis, A. et al. Ovulation induction and
successful pregnancy outcome in two patients with
Prop1 gene mutations. Fertil. Steril. 82, 454–457
(2004).
106. Carlson, H. E., Brickman, A. S. & Bottazzo, G. F.
Prolactin deficiency in pseudohypoparathyroidism.
N. Engl. J. Med. 296, 140–144 (1977).
107. Shapiro, M. S., Bernheim, J., Gutman, A., Arber, I.
& Spitz, I. M. Multiple abnormalities of anterior
pituitary hormone secretion in association with
pseudohypoparathyroidism. J. Clin. Endocrinol. Metab.
51, 483–487 (1980).
108. Karaca, Z., Laway, B. A., Dokmetas, H. S., Atmaca, H.
& Kelestimur, F. Sheehan syndrome. Nat. Rev. Dis.
Primers 2, 16092 (2016).
109. Webster, J. A comparative review of the tolerability
profiles of dopamine agonists in the treatment of
hyperprolactinaemia and inhibition of lactation.
Drug Saf. 14, 228–238 (1996).
110. Rains, C. P., Bryson, H. M. & Fitton, A. Cabergoline.
A review of its pharmacological properties and
therapeutic potential in the treatment of
hyperprolactinaemia and inhibition of lactation. Drugs
49, 255–279 (1995).
111. Gallego, M. I. et al. Prolactin, growth hormone, and
epidermal growth factor activate Stat5 in different
compartments of mammary tissue and exert different
and overlapping developmental effects. Dev. Biol.
229, 163–175 (2001).
112. Kobayashi, T., Usui, H., Tanaka, H. & Shozu, M. Variant
prolactin receptor in agalactia and hyperprolactinemia.
N. Engl. J. Med. 379, 2230–2236 (2018).
113. Vilar, L. et al. Diagnosis and management of
hyperprolactinemia: results of a Brazilian multicenter
study with 1234 patients. J. Endocrinol. Invest. 31,
436–444 (2008).
114. Soto-​Pedre, E., Newey, P. J., Bevan, J. S. & Leese, G. P.
Morbidity and mortality in patients with
hyperprolactinaemia: the PROLEARS study. Endocr.
Connect. 6, 580–588 (2017).
115. Therkelsen, K. E. et al. Association between prolactin
and incidence of cardiovascular risk factors in the
Framingham Heart Study. J. Am. Heart Assoc. 5,
e002640 (2016).
116. Bouchard, P., Lagoguey, M., Brailly, S. & Schaison, G.
Gonadotropin-​releasing hormone pulsatile
administration restores luteinizing hormone pulsatility
and normal testosterone levels in males with
hyperprolactinemia. J. Clin. Endocrinol. Metab. 60,
258–262 (1985).
Reviews
117. Lecomte, P. et al. Pregnancy after intravenous
pulsatile gonadotropin-​releasing hormone in a
hyperprolactinaemic woman resistant to treatment
with dopamine agonists. Eur. J. Obstet. Gynecol.
Reprod. Biol. 74, 219–221 (1997).
118. Sauder, S. E., Frager, M., Case, G. D., Kelch, R. P.
& Marshall, J. C. Abnormal patterns of pulsatile
luteinizing hormone secretion in women with
hyperprolactinemia and amenorrhea: responses to
bromocriptine. J. Clin. Endocrinol. Metab. 59,
941–948 (1984).
119. Li, Q., Rao, A., Pereira, A., Clarke, I. J. & Smith, J. T.
Kisspeptin cells in the ovine arcuate nucleus express
prolactin receptor but not melatonin receptor.
J. Neuroendocrinol. 23, 871–882 (2011).
120. Smith, J. T. et al. Kisspeptin is essential for the full
preovulatory LH surge and stimulates GnRH release
from the isolated ovine median eminence.
Endocrinology 152, 1001–1012 (2011).
121. Sonigo, C. et al. Hyperprolactinemia-​induced ovarian
acyclicity is reversed by kisspeptin administration.
J. Clin. Invest. 122, 3791–3795 (2012).
122. Millar, R. P. et al. Hypothalamic-​pituitary-ovarian axis
reactivation by kisspeptin-10 in hyperprolactinemic
women with chronic amenorrhea. J. Endocr. Soc. 1,
1362–1371 (2017).
123. Abbara, A. et al. Interpretation of serum gonadotropin
levels in hyperprolactinemia. Neuroendocrinology
107, 105–113 (2018).
124. Raappana, A., Koivukangas, J., Ebeling, T. & Pirilä, T.
Incidence of pituitary adenomas in Northern Finland
in 1992–2007. J. Clin. Endocrinol. Metab. 95,
4268–4275 (2010).
125. Santharam, S. et al. Prolactinomas diagnosed in
the postmenopausal period: clinical phenotype
and outcomes. Clin. Endocrinol. 87, 508–514
(2017).
126. Scoccia, B., Schneider, A. B., Marut, E. L. &
Scommegna, A. Pathological hyperprolactinemia
suppresses hot flashes in menopausal women. J. Clin.
Endocrinol. Metab. 66, 868–871 (1988).
127. Rance, N. E., Dacks, P. A., Mittelman-​Smith, M. A.,
Romanovsky, A. A. & Krajewski-​Hall, S. J. Modulation
of body temperature and LH secretion by hypothalamic
KNDy (kisspeptin, neurokinin B and dynorphin)
neurons: a novel hypothesis on the mechanism of
hot flushes. Front. Neuroendocrinol. 34, 211–227
(2013).
Author contributions
All authors provided a substantial contribution to the discus-
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article and the review and editing of the manuscript before
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Competing interests
The authors declare no competing interests.
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Reviewer information
Nature Reviews Endocrinology thanks D. Grattan, and other
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review of this work.
volume 15 | JUNE 2019 | 365