Download Drug-induced hypo- and hyperprolactinemia: mechanisms, clinical

Review
1.
Introduction
2.
Physiological function and
control of prolactin secretion
3.
Prolactin receptors,
mechanisms of activation and
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consequences
4.
Hyperprolactinemia
5.
Pharmacokinetic and
pharmacodynamic
particularities of antipsychotics
and consequences on prolactin
secretion
6.
Expert opinion
Drug-induced hypo- and
hyperprolactinemia: mechanisms,
clinical and therapeutic
consequences
Victor Voicu†, Andrei Medvedovici, Aurelian Emil Ranetti &
Flavian Ştefan Rădulescu
†
University of Medicine and Pharmacy Carol Davila, Faculty of Medicine, Department of Clinical
Pharmacology, Toxicology and Psychopharmacology, Bucharest, Romania
Introduction: The altered profiles of prolactin secretion in the anterior
hypophysis, generated by pathological, pharmacological or toxicological
causes, have special consequences on multiple functions in both genders.
Areas covered: This selective review presents the main mechanisms controlling prolactin secretion, focusing on the interplay of various neurotransmitters or xenobiotics, but also on the role of psychic or posttraumatic stress. A
detailed analysis of several pharmacotherapeutic groups with hyperprolactinemic effects emphasize on the relevance of the pharmacokinetic/pharmacodynamic mechanisms and the clinical significance of the long term
administration.
Expert opinion: Accurate monitoring and evaluation of the hyperprolactinemia induced by xenobiotics is strongly recommended. The typical antipsychotics and some of the atypical agents (amisulpride, risperidone,
paliperidone), as well as some antidepressants, antihypertensives and prokinetics, are the most important groups inducing hyperprolactinemia. The
hyperprolactinemic effects are correlated with their affinity for dopamine
D2 receptors, their blood--brain barrier penetration and, implicitly, the
requested dose for adequate occupancy of cerebral D2 receptors. Consequently, integration of available pharmacokinetic and pharmacodynamic
data supports the idea of therapeutic switch to non-hyperprolactinemic
agents (especially aripiprazole) or their association, for an optimal management of antipsychotic-induced hyperprolactinemia. Possible alternative
strategies for counteracting the xenobiotics-induced hyperprolactinemia
are also mentioned.
Keywords: anterior hypophysis, antidepressants, antipsychotics, blood--brain barrier,
dopamine D2 receptors, hyperprolactinemia, logBB, therapeutic switching
Expert Opin. Drug Metab. Toxicol. [Early Online]
1.
Introduction
Prolactin, a polypeptide hormone, is secreted in the anterior hypophysis by the specialized lactotroph cells. Most of the prolactin existing in the hypophysis has a
molecular weight of 23 kDa, but there are also molecular variants generated by proteolytic cleavage, posttranslational changes, etc. Prolactin circulates under various
molecular forms, with different molecular weights, the usual one being composed
of 199 amino acids. Approximately 80 -- 90% of the circulant prolactin is monomeric, but dimeric or polymeric forms, with high molecular weights, could also
be observed [1]. Macroprolactin, the high molecular weight circulating form, has a
reduced biological activity, a low clearance and can be identified by analytical tests;
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1
V. Voicu et al.
Article highlights.
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Prolactin is secreted by the anterior hypophysis, passes
in the systemic circulation and acts on the target
structures by the specialized receptors, further
generating effects on growth factors, neurotransmission
and immunomodulation.
Hyperprolactinemia is described as a consequence of
specific physiological (pregnancy, lactation) or
pathological states (tumors of the lactotroph cells,
prolactinomas) or as consequence of action of various
exogenous factors, including antidopaminergic drugs
and other xenobiotics.
The affinity for dopamine D2 receptors, the occupancy
half-life and the values of molecular descriptors which
are determinants for BBB penetration could be used as
predictors of xenobiotics potential to induce
hyperprolactinemia.
For antipsychotics, switching or association of
non-hyperprolactinemic agents could be the optimal
approach, in case of clinical significant
hyperprolactinemia.
The use of hypoprolactinemiant dopaminergic drugs is
mainly reserved for hyperprolactinemia associated with
prolactinomas and essential hyperprolactinemia.
This box summarizes key points contained in the article.
therefore it could generate errors in the clinical diagnostic.
The use of laboratory methods that specifically identify the
various forms of circulating prolactin has been suggested [1].
The posttranslational changes of prolactin alter its biological
activity [2,3]. For example, glycosylation decreases the biological activity of prolactin; phosphorylation generates antagonists
of prolactin in some species, while the cleavage of the 16K
molecule cancels its binding capacity [2]. It is admitted that
prolactin has almost 300 functions in different organs and
species, but their relevance in humans still needs to be
established [4].
Prolactin is also produced in the central nervous system
(CNS), being identified in cortex, hypothalamus, amygdala,
septum, bulbus, cerebellum, spinal cord, choroid plexus and
circumventricular organs. In hypothalamus, the secretion of
prolactin is independent from the one in the hypophysis,
although the exact function of prolactin produced at this level
or elsewhere has not been identified. It must be noted that, for
delivery at the CNS level, the circulant prolactin must
penetrate the blood--brain barrier (BBB) at the level of the
choroid plexus, where an increased density of prolactin
receptors has been described [5].
Prolactin or prolactin-like molecules have been identified
in placenta, amnion, uterus, mammary glands and milk,
with more or less identified functions, subject to numerous
studies. A series of other cells, including lymphocytes and
immunocompetent thymic cells, contain prolactin. Extensive
evaluations have been dedicated to the assessment of the physiological control of prolactin secretion, at the level of the
2
hypophysis lactotroph cells, and to the consequences of the
action on these mechanisms during therapy with different
drugs and other xenobiotics (Figure 1).
Physiological function and control of
prolactin secretion
2.
Prolactin has a circadian rhythm of secretion, similar to other
hormones with major functions, for example, corticosteroids.
Its secretion is increased during the sleeping period and
decreases in the wakeful state. In the case of corticosteroids,
the pattern is reversed, increasing from the first hours in the
morning. Extensive proofs emphasize that the dopaminergic
tonus controlled by the hypothalamus exerts inhibitory effects
on prolactin secretion, correlated with different periods of the
day, under the control of the dopaminergic tonus of the
tuberoinfundibular neurons. If the first, fundamental aspect
of the control of the prolactin secretion refers to its dependence on the prevalent inhibitory tonus of the hypothalamus,
the second aspect focuses on dopamine, as the main inhibitory
factor of prolactin secretion. Dopamine D2 receptors are
located in the membrane of the lactotroph cells. The tuberoinfundibular neurons release dopamine through the portal
system in the sinusoidal capillaries of the anterior lobe of
hypophysis, being considered as the major physiological
regulator of prolactin secretion.
The anatomical support of the dopamine system controlling the prolactin release is the tuberoinfundibular and
tuberohypophiseal dopaminergic tract. The first dopaminergic projections, the tuberoinfundibular ones, represent
the main dopaminergic control of the anterior hypophysis [6]. An important particularity results from the fact that
the released dopamine does not interact with the postsynaptic receptors, but reaches the perivascular space, is uptaken by the port circulation and transported to the anterior
hypophysis. This generates the neuroselective function
characteristic for such neurons [6]. However, it is a rough
simplification to consider that the dopamine pathways control the prolactin release, including the dopamine--prolactin
interaction. The interference of other multiple factors with
positive or negative effects on the control of prolactin
release should be considered, as it results from the further
succinct presentation.
It is admitted that the lactotroph cells have as unique characteristic an intense basal secretory activity of prolactin. The
inhibitory tonus of dopamine on this process implicitly
requests increased secretion and release of dopamine, induced
among other factors, by the high activity of hypothalamic
tyrosine hydroxylase (conversion of tyrosine to DOPA and
furthermore, to dopamine), which is constitutive active, as
an adaptive consequence to the increased request of dopamine. Moreover, the consensus with the phenomenon
described previously, the maintenance of a high concentration
of dopamine, is achieved also by the absence of dopaminergic
auto-receptors at the level of tuberoinfundibular projections,
Expert Opin. Drug Metab. Toxicol. [Early Online]
Drug-induced hypo- and hyperprolactinemia: mechanisms, clinical and therapeutic consequences
Endobiotics
Endobiotics
Inhibitors of dopamine
activity
Stimulators of dopamine
activity
- Serotonin;
- Acetylcholine;
- Noradrenalin;
- TRH (tirotropin releasing
hormone);
- Histamine;
- Oxytocin;
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- Endogenous opioids;
- Angiotensin II;
- Somatostatin;
- Natriuretic atrial peptide;
Xenobiotics
Xenobiotics
Stimulators of prolactin
secretion
Inhibitors of prolactin
secretion
- Antidopaminergic
(antipsychotics, digestive
prokinetics);
- Dopamine agonists;
TIDA
- Cholinergics;
- Serotonin antagonists.
- Selective serotonin
reuptake inhibitors and
other antidepressants;
- Opioids, cocaine;
DA
- Amphetamine-like
compounds;
- Calcium channels
blockers (verapamil);
- Simpatholytics
(reserpine, α-methyl-dopa).
PRL
Figure 1. Direct effects of various endobiotics (neurotransmitters, neuromodulators, hormones) and xenobiotics on
tuberoinfundibular dopaminergic system (TIDA) and consequently, on prolactin secretion [1,5,37,48,105,106].
therefore removing the negative feedback on the tyrosine
hydroxylase activity [6].
The description of dopamine effects on lactotroph cells and of
their time dependence is relevant for illustration of their consequences on prolactin secretion. Consecutive to the interaction
with D2 receptors at the level of the membrane of lactotroph
cells, it determines in few seconds the increase of conductance
in potassium channels, inactivating the voltage-sensitive calcium
channels. Consequently, a hyperpolarization of the membrane
arises, followed by a decrease of intracellular calcium concentration below the threshold of activation of the secretion processes
and a consecutive inhibition of prolactin secretion. In the following sequences, after minutes or hours, dopamine generates the
inhibition of the adenylylcyclase activity, of the metabolism of
inositol phosphate and of the release of arachidonic acid,
processes followed by down-regulation of the prolactin gene [7].
The secretion of prolactin acts as a feedback mechanism on
the dopamine endocrine neurons, the increase in hormone
secretion leading to the increase of hypothalamic synthesis
of dopamine. The action of dopamine at the level of specific
receptors ends after the neuronal reuptake, by active transport
in the dopaminergic nerve endings. The pharmacodynamic
(PD) interference to this transport mechanism has, implicitly,
consequences on the dopaminergic tonus and, consequently,
on prolactin secretion. Other segments of the transduction
pathways of the signal at the level of dopamine D2 receptors
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V. Voicu et al.
from the membrane of the lactotroph cells which might be
influenced pharmacodynamically are the activity of adenylate
cyclase, the metabolism of inositol-phosphate, the ionic
channels for potassium and voltage-sensitive calcium channels.
For example, the net secretion of prolactin can be altered by
inhibition of calcium channels and stimulation of potassium
channels. There are proofs of the stimulatory action of a component of the serotoninergic center for the secretion of prolactin.
The central adrenergic system is involved in the regulation of
the prolactin secretion, by modulation of the activity of the
tuberoinfundibular neurons. This action is relevant especially
in the stress-induced prolactin secretion. Histamine, through
H2 receptors, has a stimulatory effect on the prolactin secretion,
the process being blocked by the H2 receptors antagonists.
The endogenous opioid system of CNS produces the
increase of prolactin secretion by inhibiting the dopaminergic
neurons in hypothalamus, in various physiological conditions,
most probably by activation of µ and k receptors. Their
antagonists, for example, naloxone, reduce the stress-induced
secretion of prolactin. It is considered that this type of effect
of the endogenous opioids is integrated into the neurohumoral
adaptive mechanisms [5].
Angiotensin II as principal effector of the renin--angiotensin-aldosterone system, based on its tissue distribution, at the level
of CNS, cardiovascular and renal system, has connections and
control/regulation functions on the prolactin secretion, in
hypothalamus and hypophysis [5]. It seems like the endogenous
angiotensin system produces a decrease of the hypothalamus-hypophysis response on increasing prolactin secretion,
consecutive to the action of several endogenous and
exogenous factors.
Calcitonin, a polypeptide secreted by the thyroid, with
effects of reduction of the plasma calcium concentration, generates a decrease of prolactin secretion, according to some
authors, by activation of the tuberoinfundibular dopaminergic system [8]. A series of experimental proofs emphasize that
endothelin and endothelin-like compounds are involved in
the control of prolactin secretion, correlated with environmental factors, having variable consequences [9]. These proofs,
beside the distribution of endothelin and of its precursors,
implicitly of its specific receptors at the level of hypothalamus
and hypophysis, suggest that they act as neurotransmitters and
neuromodulators of prolactin secretion [5].
The system of amino acids and their specific receptors in
the CNS, with important functions in the excitatory (glutamatergic) or inhibitory (GABA-ergic) neurotransmission, is
involved also in the control and regulation of prolactin secretion. Essentially, the excitatory amino acids produce effects on
prolactin secretion by acting on the hypothalamic receptors,
modulating the prolactin releasing or inhibitory factors. The
inhibitory amino acids display also either stimulatory or
inhibitory activity on prolactin secretion. It is admitted that
the main function of the GABA-ergic system is the negative
feedback regulation of the prolactin secretion under the influence of several physiological factors [5,10].
4
Prolactin itself exists in an interrelationship of feedback
control with its own secretion/concentration in the biophase.
The inhibition of secretion is triggered by activation of
hypothalamic dopamine neurons or directly, by acting on
the lactotroph cells [5].
The cholinergic system in the hypophysis, by activation of
the muscarinic receptors, exerts a tonic inhibitory action on
the prolactin secretion [5,11]. Atropine, the competitive antagonist of muscarinic receptors, induces a dose-dependent
increase of the prolactin secretion [12]. In a broad review,
Freeman et al. [5] pointed out that prolactin secretion and its
complex control, correlated with the reproduction and survival
of individuals, is a complex, homeostatic process. The control
and regulation of prolactin secretion by various endogenous
factors is achieved by acting at the level of different effector
structures involved in this process, that is, hypothalamus or
hypophysis. The impact is variable, according to the physiological status of the organism. Finally, the prolactin reaching
the biophase interacts with the prolactin receptors of lactotroph cells, launching the activation of a cascade of events leading to the activation of effector structures. The receptors,
having specific membrane disposition, belong to the superfamily of cytokine receptors. The prolactin receptors are present in
almost all tissues, with a net expression in liver, mammary
glands, suprarenal glands and choroid plexus [13]. These receptors have a single membrane crossing, generating an extracellular domain on which the ligand binds and an intracellular one,
coupling the receptors with the signaling molecules [13].
Noteworthy, the prolactin receptors interact with three
types of ligands: prolactin, placental lactogen (PL) and growth
hormone (GH), resulting in the difficulty in understanding
the biological effects [2] and potentially pathological consequences, correlated with the prolactin variations. The first
stage of interaction, the binding of prolactin to the receptors,
initiates the activation and dimerization, triggering the cascade of intracellular signaling by means of associated kinases
which activate the subsequent effectors [2].
This concise summary of the complex functional interrelationships of various systems involved in the homeostasis of
prolactin secretion should be considered as a background, the
functional basis and potential links and targets, on which
various groups of biologically active substances, either drugs or
toxicants act and determine changes of the prolactin levels. The
complexity of the control and regulation of secretion, beside
the considerable number of functions and targets assigned to
prolactin (approximately 300) suggest the need to accurately
evaluate the relevance and impact of the changes induced by
the exposure of human organism to various xenobiotics [4].
Prolactin receptors, mechanisms of
activation and consequences
3.
Prolactin acts as a hormone. It is secreted by the anterior
hypophysis, passes in the systemic circulation and acts on
the target structures by the specialized receptors, further
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Drug-induced hypo- and hyperprolactinemia: mechanisms, clinical and therapeutic consequences
generating effects such as growth factors, neurotransmission
and immunomodulation. The prolactin receptors are produced in various types of cells, with several isoforms and
transported at the level of the cell membrane. The interaction
with prolactin determines a series of structural changes of the
extracellular domain of the receptor, changes transmitted to
the intracellular domain which, by its activity controls different signaling pathways [14]. The life cycle of the receptor ends
by its removal from the plasma membrane. The critical analysis of the literature reports in the field emphasizes, on one
hand, on the protein system by which human prolactin induces its effects on several cellular systems, but also the scarce
data explaining their mechanism of action [14]. Obviously,
the physiological agonists of the receptor are the lactotroph
hormones (GHs, placental lactotroph and prolactin), with
prolactin having the central role. Noteworthy, it is considered
that prolactin binds and activates the prolactin receptors by a
unique mechanism, completely different compared with other
lactogens [14]. It is interesting that prolactin receptors are
largely distributed in highly different tissues. The 85 identified
functions have been standardized into five categories: reproduction, osmoregulation, growth, integument and synergism
with corticosteroids [15]. Bole-Feysot et al. added water and
electrolytes balance, growth and development, endocrinology
and metabolism, brain and behavior, immunoregulation and
protection [16].
4.
Hyperprolactinemia
Hyperprolactinemia, due to increased secretion of the hormone
at the level of the lactotroph cells of the hypophysis, with a
plasma concentration above the physiological level, is described
as a consequence of specific physiological (pregnancy, lactation)
or pathological states (tumors of the lactotroph cells, prolactinomas) or as consequence of action of various exogenous factors, including antidopaminergic drugs and other xenobiotics.
Currently, one can state that the single characterized pathological state correlated with prolactin is hyperprolactinemia [2],
generated by different mechanisms described briefly herein. It
is considered that hyperprolactinemia is involved in approximately 25% of the menstrual disturbances in women [2]. It is
to be pointed out that there are proofs linking the high levels
of circulating prolactin with the increased risk of mammary
cancer in pre- or postmenopausal women [4], without identification of a clear mechanism. A study performed on human
mammary cancer cell cultures emphasized that prolactin acts
as a potent survival factor for tumor cells, preventing their entry
into apoptosis [17]. Moreover, prolactin might contribute to
the increased viability of tumor cells, to their resistance to
chemotherapy and metastatic processes [18]. Table 1 presents
the consequences of hyperprolactinemia in males and females.
In female subjects, hyperprolactinemia can induce a series
of neuroendocrine disorders, notably breast augmentation,
galactorrhea, ovarian dysfunction, decrease of libido, atrophy
of urethra and vaginal mucosa, dyspareunia. In addition,
hostility, anxiety and depression have been reported [19].
A series of data correlate hyperprolactinemia with breast cancer in male subjects. The experimental proofs, although not
clearly confirmed in humans, underline the role of prolactin
as initiator and promoter of cancer [20]. On the other hand,
available data are contradictory. Moreover, there are concerns
regarding the relationship between schizophrenia and various
types of cancer. The screening of female schizophrenia
patients for breast cancer has been recommended [21]. Moreover, hyperprolactinemia induced by several antipsychotics is
not clearly correlated with an increased risk of breast cancer [22]. Therefore, it is rather difficult to clearly state if
antipsychotic-induced hyperprolactinemia or schizophrenia
determines a high risk of breast cancer.
It is beyond doubt that typical antipsychotic (phenothiazine, haloperidol and thioxanthens) produce side effects on
the sexual function in 30 -- 60% of schizophrenic patients [23].
In male subjects, hyperprolactinemia induces effects such as
reduced libido, erectile and ejaculatory dysfunction, gynecomastia, galactorrhea, reduction of semen volume, priapism.
In females, the effects are more intense and of high risk:
reduced libido, amenorrhea, dysmenorrhea, gynecomastia,
galactorrhea, painful breasts, obesity, risk of osteoporosis, risk
of breast cancer. On the whole, it can be concluded that female
subjects are more susceptible to drug hyperprolactinemic
effects as compared with males [24]. However, the role of prolactin in regulating metabolism or body weight is not clear.
Insulin resistance has been correlated with hyperprolactinemia
and prolactin inhibits the secretion of adiponectin [25,26].
Effects of psychic and posttraumatic stress on
prolactin secretion
4.1.
It is admitted that prolactin, its secretion and control, represent a complex process, correlated with the functional status
of the organism (adaptative, pathological status, psychic stress,
posttraumatic stress) [27-29]. The hormonal response to psychic
stress is correlated with the individual particularities, but can
generate an effect on prolactin or cortisol secretion. There is
a negative correlation between peak secretion of prolactin
and cortisol, resulting that the two hormonal components
are two distinct and alternative strategies to stress [29]. Posttraumatic stress disorder (PTSD) is associated with disturbances of the hypothalamus--pituitary--adrenal (HPA) axis, but
also of hypothalamus--pituitary--thyroid pathway [28]. The
studies conducted in PTSD patients indicate that a series of
plasmatic hormones, including cortisol, prolactin, thyrotropin
and free thyrotoxin have significantly decreased levels,
compared with healthy subjects [28].
Recently, another group of researchers has evaluated the
predictive factors resulting from the reactivity of HPA axis
in PTSD patients and healthy subjects. The results of dexamethasone test demonstrated a hypersuppression of cortisol
concentration and a significant decrease of plasma prolactin
in patients [27].
Expert Opin. Drug Metab. Toxicol. [Early Online]
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V. Voicu et al.
Table 1. Clinical consequences of hyperprolactinemia.
Gender
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General characteristics
Consequences
Male
Female
Hypogonadism
Erectile dysfunction
Diminished ejaculate volume
Oligospermia
Delayed puberty
Decreased libido
Decreased bone mineral density [107]
Rarely: gynecomastia, galactorrhea (approx. 20%)
Possible increased incidence of breast cancer
Hypogonadism
Breast volume increase
Galactorrhea
Increased risk of breast cancer
Ovarian dysfunction
Infertility
Decreased libido
Atrophy of the urethral and vaginal mucosa
Decreased bone mineral density [107]
Decreased vaginal lubrication and dyspareunia
Acne and possible hirsutism
Possible consequences: hostility, anxiety,
depression, all of medium intensity [19]
In subjects with a diagnostic of first episode of psychoses
(bipolar or depressive), the pituitary volume is increased,
according to the MRI scans [30]. The increase was obvious in
the case of first episode of schizophrenia. The explanation
resides on the hyperactivity of the HPA axis, as the answer
of the main neurohormonal system to stress. The authors
mentioned that the subjects without antipsychotic treatment
or under treatment with atypical antipsychotics have a similar
increase of the pituitary volume, whereas typical antipsychotics seem to induce a more pronounced increase. They
concluded that, on one hand, this increase of pituitary volume
is independent on the antipsychotic effect; on the other hand,
the typical antipsychotics induce an adjacent increase,
consecutive to the activation of lactotroph cells.
Hyperprolactinemic effects of drugs
The analysis of the effects of some drugs and/or xenobiotics
on prolactin secretion needs a description of their pattern,
pharmacokinetic (PK) and PD mechanism and consequences
on the therapeutic strategy for selected drugs used in the treatment of chronic diseases, for example, schizophrenia or
depressive syndrome. Tables 2 and 3 illustrate a synthesis of
the available data, classifying the compounds generating
hypo- and hyperprolactinemia according to their pharmacotherapeutic class, mechanism of action and therapeutic indication. Some general characteristics correlated with clinical and
therapeutic consequences must be emphasized. Thus, the
hyperprolactinemic domain is obviously important and relevant for the clinical consequences and, implicitly, the measures for prevention of major effects of hyperprolactinemia,
especially since long-term administration is needed in several
instances (antipsychotics, antidepressants, antihypertensives,
prokinetics).
It results that the main therapeutic group producing hyperprolactinemia is represented by the typical (first-generation)
antipsychotics, but also by some atypical antipsychotics (especially risperidone, paliperidone and amisulpride). Olanzapine
can generate hyperprolactinemia at high doses. The firstgeneration antidepressants are considered hyperprolactinemic
4.2.
6
agents of short duration. All selective serotonin reuptake inhibitor (SSRI) antidepressant drugs have been associated with
hyperprolactinemic effects [31]. Beside the risk of breast cancer,
the long-term complication of hyperprolactinemia is the
decrease of bone density, reported especially in women, but
also in men. Noteworthy, even after correction of hyperprolactinemia or transitory hyperprolactinemia, the osteopenia persists [32]. The drug-induced hyperprolactinemia and its
consequences impose both clinical and laboratory diagnostic,
especially in schizophrenic patients under treatment with antipsychotics. In this context, either the decrease of the dose, the
therapy switching to aripiprazole (as an example, due to its partial antagonist effect on dopamine D2 receptors) or adjuvant
therapy for correction of sexual dysfunction (phosphodiesterase
inhibitors) should be initiated [33].
Although several authors suggest that hyperprolactinemia is
an important adverse effect of the antipsychotic treatment,
this is generally neglected [34]. Recent data indicate that hyperprolactinemia represents a risk factor not only for the breast
cancer, but also for prostate cancer [35]. Experimental, clinical
and epidemiological studies suggest that hyperprolactinemia
is associated with breast cancer [35]. Emerging proofs also support a relationship between hyperprolactinemia and prostate
carcinogenesis. Currently, there are recommendations for
evaluation of these aspects, as part of both regulatory and clinical toxicology, in high-risk patients under treatment with
hyperprolactinemic drugs [35].
The increase of prolactin secretion induced by SSRI drugs
is correlated with the serotoninergic mechanisms involved in
the generation of specific antidepressant effects. These drugs
have as common mechanism the inhibition of serotonin reuptake, therefore increasing the availability of the neurotransmitter at the level of the corresponding synapses (Figure 1
and Table 3) [31].
Antipsychotic-induced hyperprolactinemia
A series of clinical data suggest that the hyperprolactinemic
effects in patients treated with antipsychotic drugs could be
at least underestimated, if not neglected, for several reasons
4.3.
Expert Opin. Drug Metab. Toxicol. [Early Online]
Drug-induced hypo- and hyperprolactinemia: mechanisms, clinical and therapeutic consequences
Table 2. Drugs with inhibitory activity on the prolactin secretion.
PD class
Dopamine antagonists
Bromocriptine
Pergolide
Cabergoline
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L-DOPA
Effect on prolactin
Mechanism of action
Intense decrease,
short duration
Intense decrease,
medium duration
Intense decrease,
long duration
Decrease, short
duration
D2 R agonist
Therapeutic use
D2 R agonist
Antiparkinsonian, treatment of
hyperprolactinemia
Antiparkinsonian, off-label treatment
of hyperprolactinemia
Treatment of hyperprolactinemia
Dopamine precursor
Antiparkinsonian
D1 R and D2 R agonist
Parasympathomimetics
Pilocarpine
Physostigmine
Cocaine
Increase
Stimulation of muscarinic R
Obsolete
Decrease
Release of catechol amines,
blocking of reuptake
Local anesthetic
Serotonin antagonists
Cyproheptadine
Decrease
5-HT2A R antagonist,
H1 R antagonist, antimuscarinic
Antihistamine, serotonin syndrome, etc.
Opioid antagonists
Naloxone
Decrease
PD: Pharmacodynamic.
Data from [84,105,106,108].
linked to patient, physician, associated medication, psychopathological aspects or environmental factors [36]. The atypical
antipsychotics generate much reduced or no effects, excepting
risperidone and amisulpride. In a recent review, the authors
have emphasized on the similar profile of the 9-hydroxy metabolite of risperidone (paliperidone) [37,38]. Among other secondgeneration antipsychotics, amisulpride, risperidone and
paliperidone have hyperprolactinemic effects comparable with
those reported for the first generation [39]. It is estimated that risperidone, paliperidone and amisulpride have superior hyperprolactinemic effects compared with haloperidol [40-42]. By contrast,
quetiapine and clozapine do not induce hyperprolactinemic
effects, whereas aripiprazole can induce a decrease of prolactin
levels, also at high doses [43]. The hyperprolactinemic effects of
risperidone are dose-dependent [42,44,45]. In case of amisulpride
administered in doses of 630 -- 910 mg [46], the decline of
initially high prolactin levels during a long-term treatment, was
explained by an up-regulation of dopamine D2 receptors, following a prolonged blockade. The decreasing levels of prolactin
on the time course of treatment and their normalization after
discontinuation has been considered a proof of lack of persistent
modification of neuroendocrine mechanisms, but additional,
adaptive changes could also be involved [46].
Pharmacokinetic and pharmacodynamic
particularities of antipsychotics and
consequences on prolactin secretion
5.
A recent analysis of the consequences of antidopaminergic
activity in case of antipsychotics on the prolactin secretion
underlines, beside the differences between the two types (typical and atypical), a series of other determinants of
antipsychotics and other drugs with antidopaminergic action
on the considered hormone [47]. The affinity ratio for serotonin (5-HT2) and dopamine (D2) receptors is discussed.
Another determinant factor, focusing on the distinct effects
within the atypical antipsychotic drugs, is correlated with differences in the transport (permeability) through the BBB.
Obviously, the entities not penetrating BBB or not reaching a
sufficient concentration at the level of target structures in the
CNS do not generate effects on the cerebral function. The relative low penetration by some compounds requests high doses
in order to generate an occupancy of central D2 receptors,
therefore leading to an increased occupancy in periphery (anterior hypophysis) and an increase in prolactin secretion [37,48,47].
The biotransformation of several neuropsychotropic generates
more hydrophilic metabolites with decreased BBB penetration
and, in some instances, distinct PD properties [37], which can
be better evaluated by PK--PD correlations, including both
parent drugs and active metabolites. In this direction, it is relevant, for example, that the ratio of affinities for serotonin
5-HT2 and dopamine D2 receptors is highly different for
active metabolites, compared with the parent drug [37,49].
It is the case of 9-hydroxy risperidone which, as a new
pharmacologically active entity, has been subject to extensive
analysis of molecular descriptors defining the ‘physico-chemical properties space’ [37,50,51]. It results that the mentioned
active metabolite is characterized by a decreased lipophilicity
(as estimated by the partition coefficient in n-octanol/
water binary systems, logKow), implicitly increased hydrophilicity, decreased DlogP (difference in logP evaluated in
n-octanol and cyclohexane/water binary systems), increased
hydrogen bonding ability (HBD), increased polar surface
area (PSA), decreased membrane permeability.
Expert Opin. Drug Metab. Toxicol. [Early Online]
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Table 3. Drugs with stimulatory activity on the prolactin secretion.
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by 188.27.9.12 on 04/22/13
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PD class
Antipsychotics (typical and atypical)
phenothiazines
butyrophenones (haloperidol)
risperidone, paliperidone
amisulpride
molindone
zotepine
Antidepressants
imipramine
desimipramine
amitriptyline
clomipramine
paroxetine, fluoxetine, citalopram,
fluvoxamine (SSRI)
MAO inhibitors
(pergoline, tranylcypromine)
Digestive prokinetics
metoclopramide
domperidone
Opiates and opioids
morphine
spiradoline
methadone
Amphetamines (amphetamine-like)
fenfluramine
Antihypertensive
calcium channel blockers (verapamil)
methyldopa
neurosympatholytic (reserpine)
Effect on prolactin
Mechanism
of action
Therapeutic use
Chronic increase
D2 R antagonist
D2 R and 5-HT2 R antagonist
Treatment of
schizophrenia
Increase, short duration
Increased availability of
serotonin, by blocking
the reuptake
Treatment of
depressive syndrome
Stimulation, short duration
moderate stimulation
D2 R antagonist
D2 R peripheral antagonist
Antiemetic, prokinetic
prokinetic
Stimulation, short duration
moderate stimulation
chronic moderate stimulation
µ R agonist
k R agonist
µ R agonist
Central anesthetic and
treatment of substitution
Intense, short stimulation
Increased release and
inhibition of serotonin
reuptake
Recreational drugs,
drugs of abuse
Chronic stimulation
chronic, moderate stimulation
Calcium channel blockers
decrease of sympathetic
tonus by false mediator
(a-methyldopa)
catecholamine depletion
Antihypertensive,
antiarrhythmic
antihypertensive
antihypertensive (obsolete)
PD: Pharmacodynamic; SSRI: Selective serotonin reuptake inhibitor.
Data from [105,106,108,84].
The brain/plasma ratio for 9-hydroxy risperidone drops
five times compared with the parent drug, generating a logBB
value (logarithm of the brain/plasma ratio) of - 0.67 and
- 0.02, respectively [52-54]. The comparison with domperidone, unanimously considered to act outside CNS, could be
suggestive, since logBB is - 0.78, static and dynamic PSA are
68 and 57 Å2, respectively [55]. Noteworthy, the logP for domperidone is 3.9, indicating an optimal value for BBB penetration [56]. Domperidone is a dopamine antagonist of peripheral
D2 receptors, having digestive prokinetic effects (acceleration
of gastric emptying, increase of the motor activity of esophagus, increase of antral-duodenal contractions). It is assumed
that, although in very small concentrations, domperidone
penetrates BBB. The antiemetic effects, generated by acting
at the level of the chemoreceptor trigger zone in the IV ventricle, although manifested on some cerebral mechanisms, are
placed outside BBB. Most probably, the antiemetic and prokinetic effects contribute synergistically to the central one (at
the level of the trigger zone) in generating the specific
8
effect [57-59]. On the other hand, risperidone has dynamic
and static PSA of 57 and 74 Å2, respectively, while the
9-hydroxy metabolite, 45 and 62 Å2. The optimal interval
of PSA for CNS activity is 60 -- 70 Å2. The drop in PSA is
reflected by the decreased logBB value for the metabolite.
An important aspect which must be considered is the
unbound fraction of the considered compound. The binding
profile to plasma protein is correlated with the lipophilicity,
which is decreased for the metabolite, if considering risperidone and its 9-hydroxy-derivative. Finally, as a consequence
of hydroxylation, the 9-hydroxy metabolite has a lower affinity for both serotonin 5-HT2 and dopamine D2 receptors,
compared with the parent drug [60,61]. On human cloned
D2 receptors, the dissociation half-life for 9-hydroxy
risperidone is 1 min, while for risperidone is 27 min.
The hyperprolactinemic effects of the antipsychotic drugs
become relevant approximately 10 h after the initiation of
treatment, with levels of prolactin almost 10 times higher,
compared with the basal level [19]. After intravenous
Expert Opin. Drug Metab. Toxicol. [Early Online]
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Drug-induced hypo- and hyperprolactinemia: mechanisms, clinical and therapeutic consequences
administration of amisulpride of two dose strengths, 20 and
100 mg, respectively, comparable maximum concentrations
of prolactin were reached in 15 -- 30 min, detectable levels
being maintained for 7 h [62]. Two aspects are essential. On
one hand, the hyperprolactinemia induced by several antipsychotics is correlated with their concentration. For risperidone,
this correlation is valid in adults, since age-specific patterns
have been described for children and adolescents, as a result
of difference in neurotransmitter systems, number of lactotroph cells or sensitivity to hyperprolactinemiants [63]. On
the other hand, the concentration level is determined by the
dose necessary to induce the central antipsychotic effect.
The plasma concentration generates a gradient controlling
the BBB penetration (if only the passive diffusion processes
are considered) and achievement of the active concentration
at the level of cerebral receptors (dopaminergic D2, serotoninergic 5-HT2, cholinergic, etc.). The relationship between the
mentioned determinants and BBB permeability is characterized by the ratio of the concentrations in brain and blood,
that is, logBB. Finally, the necessary concentration of the antipsychotic in the biophase of the cerebral receptors is determined by its affinity. For amisulpride, the hydrophilic
character and low fraction unbound to plasma protein were
mentioned as the main determinants for preferential distribution outside BBB [64]. Therefore, this specific PK profile,
combined with the high affinity for dopamine D2 receptors,
could account for the marked hyperprolactinemic effect.
In fact, the mean efficient dose and the occupancy
half-life for each antipsychotic and receptor reveal the affinity
for the considered type of receptor. It is a very well-known
fact that, beside partition coefficient (logP), a series of molecular descriptors, that is, PSA, molecular volume, plasma
protein binding or distribution coefficient (logD), determine
the penetration of BBB (logBB), but implicitly, the resulting
hyperprolactinemic effects. Although molecular determinants
mentioned above have been correlated with passive diffusion
processes, the interplay of P-glycoprotein (P-gp) alters considerably ratio of brain to blood concentration, some reports
suggesting a possible influence on the rate of non-responders
to antipsychotic therapy [65]. Noteworthy, lipophilicity, the
presence of at least one nitrogen atom ionized at the physiological pH and a rather narrow interval of variation for the
molecular weight seems to describe the modulators of
P-gp [66]. Several antipsychotic drugs, for example, haloperidol, quetiapine, olanzapine and clozapine are weak or no
substrate for P-gp, but display inhibitory activity on this efflux
transporters [66,67]. Of particular importance is the fact that,
while several antipsychotics are inhibitors of P-gp (risperidone,
clozapine), their active metabolites generated in vivo by different
biotransformation pathways are substrates of P-gp, that is, paliperidone [37,68] and N-desmethyl-clozapine [67]. It concerns the
switching to prolactin-sparing antipsychotics, it should be mentioned that both aripiprazole and its active metabolite dehydro
metabolite are substrates of P-gp [69]. Potential clinically relevant
drug--drug interaction should be considered in case of
hyperprolactinemic agents such as haloperidol, risperidone or
amisulpride, the later one being both inhibitor and substrate of
P-gp [70].
In the authors’ opinion, a useful approach should consider
three distinct parameters that, according to available data, are
correlated with the hyperprolactinemic effect of antipsychotic
drugs: the affinity for dopamine D2 receptors, the half-life of
occupancy and the distribution through BBB, estimated by
logBB. Decreased affinities and shorter occupancy (1/ED50) are
correlated with a lower incidence of hyperprolactinemic effects
(decreasing from risperidone to aripiprazole) [71-73]. As mentioned previously, amisulpride and risperidone induce the most
intense effects. Based on estimated or experimental data, a reverse
correlation has been suggested between logBB of some
antipsychotics and their induced hyperprolactinemic effect.
The affinity of antipsychotics for dopamine D2 receptors,
compared with the affinity for dopamine, is relevant for the
incidence of hyperprolactinemic effects, but also of the
extrapyramidal effects, although generated in another cerebral
area [74].
Moreover, there is a continuous search of the psychiatrists
and psychopharmacologists for criteria that distinguish between
the ability to induce not only the specific clinical efficacy, but
also the presence or absence of some adverse effects, including
the extrapyramidal or hyperprolactinemic effects [75]. Notable
hyperprolactinemic effects with significant clinical consequences impose the switch to another antipsychotic therapy which
reduces or exhibits no hyperprolactinemic effects.
Another key aspect should be discussed, which correlates
well with the previously presented facts, the tardive dyskinesia.
It is assumed that tardive dyskinesia is just an indicator of
an ample dysfunction, the dopaminergic neurotransmission,
a pandopaminergic dysfunctional state which may appear in
patients with or without antipsychotic treatment [76].
Nevertheless, it seems like there is a correlation between
tardive dyskinesia and deviation of the neuroendocrine answer
to hyperprolactinemia. The minority at risk to develop tardive
dyskinesia has also a high risk to develop sexual dysfunctions
correlated with the hypersecretion of prolactin (prolactinrelated sexual disturbances). Notably, the hyperprolactinemic
effects are consecutive to the interaction of antipsychotics
with dopamine D2 receptors at the level of the lactotroph
cells, outside BBB, while tardive dyskinesia is a consequence
of the interaction at the central level. Possibly, tardive dyskinesia and sexual disturbances are two distinct manifestations,
with a common support, that is the pandopaminergic
dysfunction characteristic of schizophrenia [76-78].
In the past, the secondary motor effects of antipsychotics
were correlated with the hyperprolactinemic effects, both
being generated by the interaction with dopamine D2
receptors. The significant difference resides on the fact
that the extrapyramidal effects are consequences of blocking of striatal dopamine D2 receptors, whereas hyperprolactinemia is consecutive to the blockage in the anterior
hypophysis [49].
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9
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V. Voicu et al.
The ratio of brain to plasma concentrations of antipsychotics is a determinant for hyperprolactinemia. There is a
reverse dependence, the highest the ratio, the lowest the level
of prolactin, in relation with the targeted antipsychotic
effect. The authors have demonstrated a reverse dependence
between the hyperprolactinemic effect of some antipsychotics and logBB value [37,79]. In order to obtain a specific
effect for a compound with low BBB permeability, an
increased plasma level is required, generating an increased
incidence of the hyperprolactinemic effects, correlated with
the occupancy of dopamine D2 receptors in the anterior
hypophysis (1/ED50) and with the affinity (1/Ki) and the
dissociation rate (t1/2).
The analysis of the model for agonist--antagonist interaction and release of prolactin after the administration of
risperidone and paliperidone emphasize a similar potency
for the two antipsychotics for the release of prolactin [38]. It
is interesting to note that the metabolite has a distinct profile
of affinities for serotonin 5-HT2 versus dopamine D2
receptors [49], but also distinct half-life of dissociation.
6.
Expert opinion
As it results from the analysis of the clinical consequences of
hyperprolactinemia in humans, a key aspect is the accurate
monitoring of the treatment with hyperprolactinemic drugs.
Depending on the causal agent (pharmacological, toxicological or pathological), a strategy of hyperprolactinemia management is to be defined. In the case of an antipsychotic
treatment, with relevant hyperprolactinemic effects on plasma
levels (higher than 100 ng/ml) and symptoms, several issues
must be discussed. The most important aspect is the switching
between the hyperprolactinemic agent (amisulpride, risperidone) and olanzapine, quetiapine, clozapine or aripiprazole.
Apparently, the switching is a simple procedure. In reality,
this is not easy to be accomplished if an adequate antipsychotic outcome has been obtained. The switching to another
antipsychotic can generate an unsatisfactory outcome or
another type of adverse effects [80]. It is considered that
matching a specific antipsychotic medication for a specific
patient is a substantial challenge [81,82].
In this context, adjunctive treatment with aripiprazole for
antipsychotic-induced hyperprolactinemia represents an adequate therapeutic solution, with restoration of normal values
for prolactin and reversal of consequent clinical symptoms [83].
There were some attempts to associate risperidone and
aripiprazole, with significant results on the hyperprolactinemia
generated by the first antipsychotic [84,85]. Reversal of
paliperidone-induced hyperprolactinemia was also reported [86].
The PK particularities of amisulpride, especially the
hydrophilicity-driven distribution outside BBB, administered
in high doses (1000 mg) could explain why addition of aripiprazole, a highly lipophilic, high affinity agonist/antagonist of
dopamine D2 receptors doesn’t seem to lower the prolactin
levels [64]. The dose of hyperprolactinemic agent could be the
10
key factor, since there is a report of association between
200 -- 300 mg amisulpride and 10 -- 15 mg aripiprazole leading
to decreased prolactin concentration [87].
In the case of hyperprolactinemia in patients with antidepressant treatment, the switch with another agent is recommended. The treatment with other hypoprolactinemiant
(dopaminergic) drugs, for example, cabergoline, bromocriptine, etc. is generally not recommended, the outcome being
controversial. The main reason is the worsening of psychotic
symptoms [88]. The single, partial agonist of dopamine with
significant results in both switching of the hyperprolactinemic
antipsychotic or temporary association is aripiprazole [34,89]. In
the previously mentioned context or for normalization of prolactin levels, one could admit that the effects of the association
of the hyperprolactinemic antipsychotic and aripiprazole are
consequences of their PD antagonism at the level of dopamine
D2 receptors [81], but this approach requests a broader
discussion. The above-mentioned dopaminergic compounds
preserve the therapeutic significance in prolactinomas and idiopathic hyperprolactinemia, that is, they normalize the plasma
prolactin level, improve the clinical symptomatology and reduce
the volume of prolactinomas [90,91]. In this context, cabergoline
is preferred to bromocriptine, based on the higher rate of success
and on the reduced incidence of adverse effects [90,91].
The hyperprolactinemia induced by different classes of drugs,
particularly those administered chronically, has clinically
significant consequences, such as sexual dysfunction in both
genders, breast or prostate cancer and low bone mineral density.
Therefore, accurate monitoring and evaluation of the hyperprolactinemia induced by some drugs appears as a necessity, imposing a strategy for the management of this type of disturbance.
The typical antipsychotics and some of the atypical agents
(amisulpride, risperidone, paliperidone), but also some antidepressants, antihypertensives and prokinetics, are the most
important classes of drugs that generate hyperprolactinemia.
Based on available recommendation [92,93], regular assessment of possible sexual dysfunction must be performed.
Whenever available, prolactin levels should be determined at
baseline. The level and duration of hyperprolactinemic effects
are of particular importance. Mild elevation, persisting
for > 3 months should determine either a dose reduction of
incriminated hyperprolactinemc agent or switching to a
prolactin-spearing one. The switching is usually recommended by persistent prolactin levels above the threshold of
50 ng/ml [92]. Particularly for men experiencing sexual
dysfunction induced by hyperprolactinemia, levels higher
than 17 ng/ml has been proposed for identification of patients
benefiting from switching to prolactin-spearing antipsychotics [94]. In case of prolactin levels above 200 ng/ml or if
lateral visual deficits are concluded [92], screening of prolactinoma should be performed [95]. Evaluation of bone mineral
density must be implemented if hypogonadism associated
with hyperprolactinemia was identified.
Specifically for the procedures involving the switching to
aripiprazole, there are several case reports of worsening
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Drug-induced hypo- and hyperprolactinemia: mechanisms, clinical and therapeutic consequences
psychosis [96-99]. It has been suggested that this particular
feature may be related to the previously described, unique
receptor binding profile of aripiprazole, that is, partial agonist
of dopamine D2/D3 receptors, partial agonist of serotonin
5-HT1A receptors [100]. The agonistic/antagonistic profile of
aripiprazole is receptor reserve-dependent [101]. An up-regulation
of dopamine receptors in the areas of intense and prolonged
blockage has been correlated with increased sensitivity to
dopamine, phenomenon described as the ‘neuroleptic-induced
supersensitivity psychosis’ [102,103].
The hyperprolactinemic effects of antipsychotics and other
drugs are correlated with their affinity for dopamine
D2 receptors, their BBB penetration and, implicitly, the necessary dose for an adequate occupancy of cerebral D2 receptors.
The penetrability is a complex resultant of several molecular
descriptors (partition or distribution coefficient, PSA, molecular
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Affiliation
Victor Voicu†1, Andrei Medvedovici2,
Aurelian Emil Ranetti3 &
Flavian Ştefan Rădulescu4
†
Author for correspondence
1
Professor,
University of Medicine and Pharmacy Carol
Davila, Faculty of Medicine,
Department of Clinical Pharmacology,
Toxicology and Psychopharmacology,
Scoala Floreasca Street #8,
Bucharest 011643, Romania
E-mail: [email protected]
2
Professor,
University of Bucharest,
Faculty of Chemistry,
Department of Analytical Chemistry,
Panduri Avenue # 90,
Bucharest 050663, Romania
3
Doctor,
Central Universitary Emergency Military
Hospital, Department of Endocrinology,
Mircea Vulcănescu Street #88,
Bucharest 010825, Romania
4
Doctor,
University of Medicine and Pharmacy Carol
Davila, Faculty of Pharmacy,
Department of Drug Industry and
Pharmaceutical Biotechnology,
Traian Vuia Street # 6,
Bucharest 020956, Romania