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.

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

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 Reviews

Key points steps in which conformational changes within the

receptor dimer ultimately lead to receptor activation22.
• Prolactin exerts its actions via a transmembrane prolactin receptor (PRL-​R),
the structure of which has now been elucidated. Physiological roles of prolactin
• Prolactin signalling is essential for the ontogenesis of pancreatic stem cells for Prolactin has many different targets and pleiotropic
the establishment of a functional β-​cell reserve. functions in health and disease. In addition to its cru-
• In addition to its role in increasing dopaminergic inhibitory tone, prolactin exerts cial role in lactation, many other functions have been
autocrine and paracrine feedback on lactotroph cells. attributed to prolactin in multiple species, including
• Prolactin deficiency is rare and causes failure of lactation. roles in metabolism, skin and hair follicles, bone homeo­
• Hyperprolactinaemia can be caused by medications or pituitary disease, can have stasis, maternal care and adrenal function (Fig. 2). Most
systemic causes or can be idiopathic; this condition frequently leads to hypogonadism current knowledge on prolactin has been obtained from
and infertility. studies of animal phenotypes in particular conditional
or complete Prlr−/− mouse models. Although this infor-
mation is indispensable for understanding prolactin in
intracellular portion, which can be short, intermediate human health and disease, sufficient disparity exists
or long1,13–15. in the control of the production, distribution and physio­
The main isoform of PRL-​R found in humans is a logical functions of prolactin between these species to
long protein made up of 598 amino acids. Human PRL-R warrant careful and judicial extrapolation of findings
can bind at least three ligands (prolactin, placental to humans.
lactogen and growth hormone), which could make it
difficult to determine the specific effects of prolactin Prolactin and metabolic homeostasis. A large body of
in vivo16,17. Human PRL-​R dimers are constitutively literature in rodents reported that prolactin has pivotal
expressed on the cell surface, associated via the trans- roles in glucose metabolism through effects on pancre-
membrane domains18,19. Signalling is initiated by the atic β-​cell mass and insulin production23,24. Prolactin also
binding of a single ligand molecule (prolactin) to two has a role in peripheral insulin sensitivity25 and has orexi-
extracellular interaction sites of different affinities called genic actions on the central nervous system, promoting
binding domain 1 and binding domain 2, which triggers positive energy balance26–29. In addition, prolactin might
a change in the conformation of the receptor dimer20. also affect energy homeostasis through modulation of
PRL-​R does not have intrinsic tyrosine kinase activity lipid metabolism30. Direct evidence is now available that
but transmits a signal through associated cytoplasmic prolactin has a pivotal role in energy balance through
proteins. Determination of the architecture of human control of adipocyte differentiation and fate. Prlr−/−
PRL-​R revealed the existence of multiple short motifs mutant mice displayed reduced fat mass associated with
in its intracellular domain, providing a structural basis the appearance of massive brown-​like adipocyte foci
for the idea that it can interact with several kinases or in perirenal fat deposits under conditions of a high-​fat
signal partners at the same time2. The activation of diet31. Lack of PRL-​R causes resistance to high-​fat-diet-​
downstream signalling pathways can produce different induced obesity owing to enhanced energy expenditure
cell responses, which partly explains the versatility of the and increased metabolic rate. These results provide
actions of prolactin reported in some tissues. direct genetic evidence that the PRL-​R affects energy
The first comprehensive structural characteriza- balance and metabolic adaptation in rodents via effects
tion of the PRL-​R intracellular domain shows that it is on brown adipose tissue differentiation and function.
intrinsically disordered through its entire length and Prolactin and placental lactogens also stimulate β-​cell
interacts specifically with hallmark lipids of the inner replication as well as insulin production in pancreatic
plasma membrane through conserved basic clusters21. islets and insulinoma cells32. However, the contribution
The full receptor structure was generated a few years ago of PRL-​R signalling to β-​cell ontogeny and function in
by combining experimental and computational find- perinatal life is poorly understood. The effects of lacto-
ings with previously published data, including solution gens on adaptive islet growth are also not well under-
nuclear magnetic resonance spectroscopy, small-​angle stood. Recent data provide evidence that expansion of
X-ray scattering, native mass spectrometry and molecu­ β-​cell mass during both embryogenesis and the post-
lar modelling2. The results provided the first full view natal period is impaired in the Prlr−/− mouse model33.
of a class 1 cytokine receptor, which exemplifies the Thus, prolactin signalling is essential for the ontogene-
architecture of more than 40 different receptors. sis of pancreatic stem cells during the critical perinatal
The intracellular domain of the receptor is now window responsible for the establishment of a functional
known to be more than twice as extended in the direction β-​cell reserve.
of the normal membrane compared with the extracellu- The reduced β-​cell pool in the perinatal period in
lar and the transmembrane domains together2. The cyto- Prlr−/− newborn mice might lead to inadequate responses
plasmic domain can reach and interact with numerous to metabolic stresses in later life (for example, obesity,
interaction partners owing to its structural flexibility. pregnancy, glucocorticoid therapy and ageing) and
This innovative view of the receptor reveals that the could lead to failure of β-​cell function, insufficient insu-
extracellular domain is merely the tip of an enormous lin production and glucose intolerance, which could
molecular iceberg2 (Fig. 1). The molecular mechanism of predispose to diabetes. To date, some data suggest that
PRL-​R activation is similar to that of growth hormone the human β-​cells are less responsive than mouse β-​cells
receptor activation and involves multiple scissor-​like 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 both the loss of ions and the excessive uptake of water41.
reported34–36. Further studies are needed to clarify the Therefore, prolactin seems to mediate epidermal
potential role of prolactin in human metabolism. adaptation to environmental stress, at least in fish.
Maternal adaptations to pregnancy include changes Interestingly, prolactin has been shown to have a
in glucose metabolism and development of insulin direct effect on thermoregulation and hair morphology
resistance as a physiological response shunting nutrients phenotypes in dairy cattle42,43. A truncated autosomal
to the fetus. Both human and animal studies have shown dominant mutation, located in the tenth exon of PRLR,
that the presence of gestational diabetes increases the was shown to contribute to heat tolerance adaptation
risk of abnormal glucose homeostasis in the offspring37. in Senepol cattle and resulted in short hair known as
A 2016 study showed that mice lacking PRL-​R in pan- slick43. Some associations between prolactin and ther-
creatic β-​cells developed hallmark features of gestational mal stress have been observed in humans43, but a direct
diabetes mellitus38. The results of these studies contri­bute modulatory role for prolactin in human thermoregu-
to establish the important role of the PRL-R in β-cells lation has remained unproven44. Given the key role of
for modulating the expression of genes necessary for prolactin signalling in hair follicle growth and cycling
proliferation of β-​cells during pregnancy. in mice40, the identification of the mutation shown to
contribute to heat tolerance in cattle was in agreement
Prolactin in skin and hair follicles. Prolactin is produced with its impact on hair development and homeothermy.
in both human skin and hair follicles and is now known This mutation might have been increased through natu­
to have an important role in human cutaneous bio­l­ ral selection because of the advantage conferred in hot
ogy, ranging from the regulation of keratin expression tropical environments45.
via hair growth modulation to the control of epithelial
stem cell function39. Specifically, prolactin promotes hair Osteoporosis, phosphocalcic metabolism and prolactin.
growth in human hair follicle organ culture, upregulates Numerous lines of evidence suggest that abnormalities
expression of keratin 15 in adult human epithelial stem in prolactin levels are frequently associated with abnor-
cells ex vivo and stimulates epidermal keratinocyte pro- mal bone metabolism46. Although no particular growth
liferation in cell culture39. In mice, prolactin has been phenotype was observed in Prlr−/− animals, examina-
shown to modulate the seasonally independent hair tion of the calvariae of Prlr−/− mouse embryos indicates
follicle cycling40. Indeed, analysis of Prlr−/− mice showed lower ossification than in controls47. Histomorphometric
a striking hair phenotype characterized by longer and analysis showed that Prlr−/− adult mice had decreased
coarser hair, premature fur moulting and premature bone formation rate and reduced BMD47. A direct effect
entry of hair follicles into the next hair40. of prolactin on osteoblasts might be required for nor-
Sweat glands have an important role in thermoregula- mal bone formation and maintenance of bone mass in
tion and osmoregulation. Ideas about the possible role of mice47. However, low sex steroid levels in these animals
prolactin in human sweat gland regulation can be drawn also account for low BMD. A 2018 paper highlights the
from nonmammals. In fish skin, for example, prolactin role of both cytokines and prolactin as key regulators of
has an important role in osmoregulation by preventing bone resorption during lactation and as local receptor

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 Reviews

In summary, prolactin exerts direct and indirect effects

on bone remodelling by modulating sex hormone levels.

Hair cycle
Pituitary Maternal nursing behaviour. A role for prolactin in
regulation
gland 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,
Behaviour resulted in rapid induction of maternal care towards fos-
• Food intake Prolactin ter young56. Prolactin is present in the milk of lactating
• Maternal nursing
rodents, and when ingested by the pups, the prolactin
Lactotroph goes into their systemic circulation57. Prolactin defi-
homeostasis ciency during the early postpartum period can affect the
normal activity of the tuberoinfundibular dopaminergic
Stress and
adrenal function (TIDA) system58.
Metabolism Studies in mice further support a role for prolac-
• β-Cells
• White and brown tin and the PRL-​R in maternal behaviour59. Over the
adipocytes 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
Bone homeostasis 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
Fig. 2 | New acceptance of prolactin physiological roles. In addition to its crucial role wild-type controls59.
in lactation, many other functions have been attributed to prolactin in multiple species,
Prolactin helps establish a nurturing link between
including implications in metabolism, hair cycle regulation, bone homeostasis, behaviour,
adrenal response to stress and lactotroph homeostasis.
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
activators of the nuclear factor-​κB ligand (RANKL)– establishes and maintains the normal parental care that
osteoprotegerin (OPG; also known as TNFRSF11B) ensures offspring survival63. Indeed, these female mice
system in mice48. were able to become pregnant and give birth normally
Several clinical studies indicate that hyperprolactin­ but abandoned their litters 1 day after birth. The develop-
aemia (Box 1) is associated with deleterious effects on ment of maternal behaviour in female rats is also depend-
bone in humans. Women and men with hyperprolactin­ ent on prolactin64. When prolactin secretion is reduced
aemia and hypogonadism have decreased BMD and in lactating rats, their offspring later display deficits in
increased risk of vertebral fractures49–52. Dopaminergic their latencies to respond to foster pups. The exposure to
agonist therapy suppresses prolactin excess and leads to prolactin in the mother’s milk might facilitate maternal
improvements in BMD53. Of note, women with hyper- care when the young reach adulthood64. This study sup-
prolactinaemia who have regular menstrual cycles ports the hypothesis that prolactin is able to influence the
also have normal BMD54. These data are most con- development of the neuronal system of the offspring that
sistent with the hypothesis that sex steroid deficiency underlies the control of maternal behaviour.
induced by prolactin, but not prolactin excess per se, The effect of prolactin exposure after and perhaps
causes the development of low BMD in patients with before birth might result in long-​term developmen-
hyperprolactinaemia54. tal programming affecting the expression of maternal
A case of hypercalcaemia has been described sec- behaviour. Unfortunately, less is known on the potential
ondary to prolactin-​induced mammary gland produc- role of the prolactin system in maternal care in primates
tion of parathyroid hormone-​related protein (PTHrP) and humans, although the possibility that the situation
during pregnancy, a physiological state of hyperpro­ is similar certainly deserves consideration. For instance,
lactinaemia55. In this very rare context, treatment with studying the maternal behaviour of women presenting
dopamine agonists to decrease prolactin levels led to with a deficit of pituitary prolactin after Sheehan syn-
complete remission of hypercalcaemia and resulted in a drome (postpartum hypopituitarism) could be interest-
pregnancy carried to full term without complications55. ing. To date, no consequence on maternal care has been

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Box 1 | Definition of hyperprolactinaemia hyperprolactinaemia71, but these data are not concordant
with other study findings72,73. Increases in testosterone
• Hyperprolactinaemia is defined as any situation in levels can also occur in some patients as a consequence
which circulating prolactin levels are higher than those of conversion from androgenic precursors. Hirsutism
in the reference population arises in some women with high prolactin levels, but
• In clinical practice, the term hyperprolactinaemia is it is not clear whether increased DHEA-​S concentra-
typically used when the prolactin level is chronically tion is also associated with hirsutism74. Treatment with
increased
bromocriptine, which is able to suppress prolactin
• Values >20–25 ng per ml (420–500 mIU per L) are excess, can lead to a decrease in DHEA-​S levels75.
considered pathological, but the threshold value
depends on the type of assay used
Regulation of prolactin secretion
Role of prolactin in lactotroph homeostasis. As noted
reported in this patient population. It is possible that above, lactotroph cell secretion and proliferation are under
the defects in pituitary prolactin in these women could the control of dopamine, which is synthesized by hypotha-
be compensated by lactogenic actions in the brain pro- lamic TIDA neurons and secreted into the pituitary portal
vided by placental lactogens, as these are a major ligand blood76. The inhibitory effects of dopamine on prolactin
for PRL-​R during the peripartum period65. A study has secretion are exerted via dopamine D2 receptors (D2Rs)
tested this hypothesis in female mice66. Prolactin activity located on the surface of lacto­troph cells. Conversely, pro-
patterns in female mice and their variation throughout lactin stimulates hypothalamic dopamine secretion via
pregnancy and lactation were characterized by analysing PRL-​Rs located on TIDA membranes, exerting a negative
the brain immunoreactivity of a key molecule in the sig- feedback effect on its own secretion. Both Drd2−/− mice
nalling cascade of PRL-​R66. Nonhypophyseal lactogenic and Prlr−/− mice develop hyperprolactinaemia and lacto­
activity during pregnancy was also evaluated by admin- troph adenomas, also called prolactinomas, confirm­
istering bromocriptine, which suppresses pituitary pro­ ing the importance of hypothalamic dopaminergic
lactin release. Late-​pregnant and lactating females showed tone in the regulation of lactotroph homeostasis77–80.
significantly increased brain immunoreactivity compared The molecular mechanisms and signalling pathways
with nonpregnant mice. During late pregnancy, this pat- involved in the development of pituitary lactotroph
tern was not affected by the administration of bromocrip- tumours and prolactin hypersecretion in Prlr−/− mice
tine, suggesting that it is elicited mostly by circulating have now been studied80. Gene-​set enrichment analy-
PRL-​R ligands such as placental lactogens66. sis suggested that dysregulation of several signalling
pathways results in the late development of lactotroph
Stress and adrenal function. Prolactin secretion is pri- adenomas in mice80. Gene-​set enrichment analysis aims
marily regulated by a negative feedback loop. Prolactin to identify candidate genes that could be involved in
activates TIDA neurons, increasing their release of prolactin pituitary tumour initiation. Examples of can-
dopamine, which accesses the pituitary via the median didate genes that remain to be evaluated in human pro­
eminence and the hypothalamic–pituitary blood system lactinoma pathophysiology include Brd4, which encodes
to suppress further prolactin secretion67. Circulating a member of the BET family of nuclear proteins carrying
prolactin is secreted in response to stress, although the bromodomains that are implicated in chromatin interac-
mechanism by which this is achieved, or its cellular tions, and Erbb4, which encodes a member of the ERBB/
targets, remains unknown68. EGFR tyrosine kinase receptor family. These candidate
A brief period of restraint stress in male mice has genes could constitute interesting therapeutic targets for
been shown to cause an increase in circulating prolactin lactotroph tumours resistant to dopaminergic agonists.
concentration69. This stress-​induced increase in prolac- Indeed, tyrosine kinase inhibitors (TKIs) have already
tin interacts with both central targets (the arcuate nucleus demonstrated their efficacy in the targeted treatment
and median eminence) and peripheral targets (the zona of various tumours81. In particular, lapatinib, a TKI that
fasciculata of the adrenal cortex). On the other hand, inhibits both EGFR and HER2 signalling, demonstrated
restraint stress resulted in reduced prolactin signalling in its efficacy in vivo in the treatment of ERBB receptor-​
the TIDA neurons, which suggests that there might be a driven prolactinomas in female transgenic mice82. JQ1,
decline in their inhibitory influence on prolactin secretion a BRD4 inhibitor, has been shown in vivo to reduce
under these conditions, suggesting a potential mechanism pituitary tumour growth in mice83. To our knowledge,
by which stress can elevate prolactin secretion69. no study has yet evaluated the effect of JQ1 in human
In humans, numerous links have been reported dopamine-​agonist-resistant prolactinoma.
between prolactin, the environment and psychologi- In addition to its role in increasing dopaminergic
cal stress (including diseases, pharmacological hypo- tone, prolactin has also been shown to exert auto-
glycaemia, acute experimental prolactin responses to crine or paracrine actions on lactotroph cells in vivo84.
psychological stress and chronic hyperprolactinaemia Conditional deletion of the Prlr in lactotroph cells was
associated with states, traits or coping strategies)70. described in mice: females exhibited normal prolactin
The effect of prolactin on the secretion of andro- levels and did not develop pituitary lactotroph adeno-
gens by the human adrenal gland is highly debated. mas, even at 20 months of age. Nevertheless, they showed
Hyperandrogenism of adrenal origin (measured by increased dopaminergic inhibitory tone compared with
elevated dehydroepiandrosterone sulfate (DHEA-​S) control mice, confirming the presence of autocrine or
concentrations) has been reported in women with paracrine feedback of prolactin in lacto­troph cells in vivo

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that can be fully compensated by an intact hypothalamic Box 2 | Main causes of hypoprolactinaemia
feedback system84. In physiological situations in which
dopamine output is impaired, such as during lactation or • Abnormal lactotroph cell development (genetic causes)
ageing10,85,86, pituitary autoregulation might be important -- POU1F1, PROP1, LHX3, LHX4, HESX1, OTX2 and
for minimizing the occurrence of adenomas. IGSF1 loss-​of-function mutations
• Destruction of pituitary tissue
Human models of neuroendocrine regulation of pro­ -- Sheehan syndrome
-- Inflammation or hypophysitis (or autoimmune
lactin secretion. Prolactin is the sole pituitary hormone
lactotroph damage)
for which release is controlled by hypothalamic inhibi- -- Tumour or surgery
tory tone. Classically, other factors such as oestrogens, -- Infection (tuberculosis)
TSH-​releasing hormone (TRH) or vasoactive intestinal • Pseudohypoparathyroidism
peptide might have some role in stimulating prolactin
• Idiopathic prolactin deficiency
secretion75. Under physiological conditions, dopamine
• Medications
is the most important inhibitor of prolactin secretion,
-- Dopamine agonists (cabergoline, bromocriptine,
but other inhibitors of prolactin secretion have been quinagolide and pergolide)
proposed, including gonadotropin-​releasing hormone
(GnRH)-associated peptide (GAP) in experimental para­
digms75, but the relevance of the findings in rodents and after delivery (puerperal alactogenesis)96. Alactogenesis
humans is unclear. Indeed, GAP, encoded by GNRH1, due to prolactin deficiency has been successfully treated
was reported to be a potent inhibitor of prolactin secre- by the administration of recombinant human prolac-
tion in cultures of rat pituitary cells87. Notably, humans tin97. Following treatment, circulating prolactin levels
carrying GNRH1 homozygous frameshift mutations increased and milk volume increased. Patients with pro­
have been shown to have normal or even low plasma lactin deficiency represent a good model for studying the
prolactin levels, although these patients lack the GAP possible role of prolactin in ovulation and pregnancy.
peptide sequence, indicating that in the physiological Published data indicate that ovulation and pregnancy are
state, GAP does not act on the pituitary gland to regu­ possible in women with severe prolactin deficiency,
late prolactin secretion in humans88. By contrast, in the which excludes a crucial role of prolactin in female phys-
Hpg mouse model lacking the Gnrh1 gene, the absence iological ovulation, contrary to the situation described
of GAP is associated with a sharp decrease in pituitary in rodents98. In men, as in nonlactating and nonpreg-
prolactin content in Hpg females89,90, a finding that argues nant women, prolactin deficiency has no reported clin-
against a major physiological role for GnRH and GAP in ical consequence96. Some patients with lactation failure
regulating prolactin secretion. In the same way, we can caused by prolactin deficiency have very low or even
say that the TRH receptor does not have a relevant stimu­ undetectable serum prolactin concentrations when
latory physiological role in prolactin secretion, given that measured with the available immunoassays94,95. Some
the TRHR loss-​of-function mutation in humans and authors have suggested that an increase in prolactin
mice is associated with normal (not decreased) prolactin secretion in response to infant suckling is compromised
levels91,92. Therefore, TRH action is not required for pitu- in obese women and could explain a relative increased
itary development, nor is it required for expression of the risk of failure to initiate breastfeeding and a delayed
PRL gene, meaning that TRH does not have a major role onset of lactogenesis in this patient group99–102.
as a prolactin-​releasing factor under normal conditions. Prolactin deficiency has multiple causes (Box 2), but
all are associated with alteration of pituitary lactotroph
Abnormal prolactin levels cells preventing the physiological secretion of prolactin,
The main role of prolactin in mammalian physiology is particularly during pregnancy and lactation, or medica-
to stimulate the proliferation and differentiation of the tions such as dopamine agonists that inhibit secretion
mammary cells required for lactation. Prolactin exerts of prolactin95. Some prolactin deficiencies are the con-
minor effects on morphological changes occurring in the sequence of genetic abnormalities (POU1F1, PROP1,
mammary gland during fetal, neonatal and peripubertal LHX3, LHX4, HESX1, OTX2 and IGSF1 loss-​of-function
life, but it is greatly involved in most stages of lactation, mutations) that prevent the normal development of the
including mammogenesis (lobuloalveolar differen­ pituitary lactotroph cell line and other anterior pituitary
tiation), lactogenesis (achievement of the capacity to pro- cell lineages such as somatotrophs or thyrotrophs103,104,
duce milk), galactopoiesis (maintenance of milk secretion) which explains the deficiency in other pituitary hor-
and involution (a return to a nonlactating state)4,93. mones that commonly occurs with prolactin deficiency.
In patients with a genetic cause of prolactin deficiency, no
Prolactin deficiency. Unlike hyperprolactinaemia, pro- specific clinical complaint related to low prolactin levels
lactin deficiency is a very rare condition, with approxi- has been reported during childhood. Prolactin defi-
mately a few dozen cases reported in the literature since ciency can be clearly detectable in women only when
1975 (refs94,95). The main causes of hypoprolactinaemia pregnancy occurs. In pregnant women with a PROP1
are summarized (Box 2) . Clinical manifestations of loss-​of-function mutation, serum prolactin levels are
abnormal prolactin levels are also presented (Fig. 3). much lower than the elevated levels observed in pregnant
Most described cases of severe prolactin deficiency have women without this mutation105. As with other causes of
been in women, and in the majority of reported cases prolactin deficiency, puerperal alactogenesis occurs after
the condition was revealed by the absence of lactation delivery in women with PROP1 mutations105.

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Hypoprolactinaemia Hyperprolactinaemia hyperprolactinaemia (prolactinomas), and in some

patients the chronic administration of these molecules
TIDA neuron KNDy neuron GnRH neuron
(cabergoline, bromocriptine, quinagolide or pergolide)
Prolactin can lead to a dramatic decrease in circulating prolactin
levels109. This hypoprolactinaemic effect can prevent
PRL-R breastfeeding when these therapies are administered in
Hypothalamus

pregnant women or in the postpartum period110.

↓ Kisspeptin ↓ GnRH 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
Pituitary gland

findings in the mouse model.

↓ LH and FSH 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
Failure of lactation Anovulatory infertility 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
Fig. 3 | Consequences of abnormal prolactin levels in humans. Prolactin release is
controlled by tuberoinfundibular dopaminergic (TIDA) neurons. Prolactin deficiency all-​cause mortality was reported in patients with hyperpro-
can result from alterations in pituitary lactotroph cells preventing the physiological lactinaemia related to pituitary tumours114. In particular,
secretion of prolactin or from medications that activate the dopamine receptor and no increased risk of diabetes, cardiovascular disease, all-​
inhibit prolactin release. The consequence of hypoprolactinaemia in women is a failure cause cancer or breast cancer was observed. These results
of lactation. Increased serum prolactin levels (right) result in decreased kisspeptin are in accordance with those obtained by the Framingham
expression in KNDy neurons (that is, kisspeptin, neurokinin and dynorphin neurons) Heart Study, revealing no association between prolactin
in hypothalamic nuclei, mediated by the prolactin receptor (PRL-​R). Consequently, measurements and cardiovascular risk factors115.
gonadotropin-​releasing hormone (GnRH) release is reduced and leads to low pituitary Novel findings have emerged regarding the neuro­
gonadotropin (luteinizing hormone (LH) and follicle-​stimulating hormone (FSH)) endocrine impact of hyperprolactinaemia. Hyperpro­
secretion and loss of ovarian stimulation, which results in anovulatory infertility.
lactinaemia is the most common cause of amenorrhoea
caused by hypogonadotropic anovulation and is one
Low circulating prolactin levels have been described of the most prevalent endocrine causes of infertility
in patients with pseudohypoparathyroidism, a rare in premenopausal women5. Evidence indicates that
clinical condition resulting from resistance to parathy- hyperprolactinaemia-​induced pituitary gonadotropin
roid hormone caused by GNAS genetic alterations106,107. deficiency is indirect and results from suppression of
In these patients, serum prolactin secretion is not stim- hypothalamic GnRH release by prolactin116,117. In agree-
ulated by either TRH or by insulin hypoglycaemia106,107. ment with this idea, pulsatile GnRH administration
However, in these few reports published more than has been shown to stimulate gonadotropin secretion in
30 years ago, the clinical consequences of low prolactin patients with hyperprolactinaemia and is sufficient to
levels were not specified. restore ovarian endocrine function and fertility116–118.
In addition to the genetic causes, many cases of Until recently, an unresolved question was whether
acquired prolactin deficiency secondary to pituitary hyperprolactinaemia directly affects GnRH neurons
lesions have been reported, in which physical damage via the PRL-​R or indirectly affects GnRH neurons by
of lactotroph cells is caused by processes such as ischae- acting upstream on other intermediate neurons that
mic pituitary necrosis (Sheehan syndrome)108, pituitary regulate GnRH secretion. GnRH neurons have now been
tumours, surgical lesions, inflammatory or autoimmune shown to be stimulated by kisspeptin neurons, which
pituitary disorders (hypophysitis and sarcoidosis) and are known to express PRL-​R119,120. A study showed that
tuberculosis infection94. In these cases, prolactin deficiency hypothalamic kisspeptin expression was diminished in
most often occurs alongside other pituitary deficiencies. a female hyperprolactinaemic mouse model with hypo-
The incidence of severe prolactin deficiency in patients gonadotropic anovulation and that kisspeptin adminis­
with acquired prolactin deficiency increases alongside tration restored GnRH, gonadotropin secretion and
an increase in the number of other anterior pituitary ovarian cyclicity121. The question that was immediately
hormone defects; therefore, acquired severe prolactin raised by these findings was whether the same mecha­
deficiency can be considered a marker of extensive pitu- nism might be responsible for hyperprolactinaemia-​
itary damage94. Reports of isolated prolactin deficiency induced hypogonadotropic hypogonadism in humans
secondary to autoimmune disorders selectively affecting and whether kisspeptin administration could restore
lactotroph cells have also been published95. Dopamine gonadotropin levels and ovarian activity. Another study
agonist drugs activating D2Rs are commonly used in showed that administration of kisspeptin 10 reacti-
clinical practice for the treatment of tumour-​induced vated gonadotropin secretion and increased ovarian

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 Reviews

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

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