Psychoneuroendocrinology 28 (2003) 53–67
www.elsevier.com/locate/psyneuen
Elevated prolactin levels in patients with
schizophrenia: mechanisms and related
adverse effects
U. Halbreich a,∗, B.J. Kinon b, J.A. Gilmore b, L.S. Kahn a
a
BioBehavioral Program, School of Medicine and Biomedical Sciences, State University of New York
at Buffalo, Hayes C Ste. 1, 3435 Main St., Building 5, Buffalo, NY 14214-3016, USA
b
Eli Lilly and Company, Indianapolis, IN, USA
Abstract
The neurologic processes involved in schizophrenia are complex and diverse and the mechanisms through which antipsychotic agents exert their effects have been only partly elucidated.
Hyperprolactinemia is a common side effect of treatment with many antipsychotics and is
particularly associated with conventional (‘typical’) agents as well as the atypical antipsychotic
risperidone. In contrast, other atypical agents introduced over the last decade do not elevate
prolactin levels. This article discusses the regulatory mechanisms involved in prolactin
secretion, the physiologic role of prolactin, and the etiology of hyperprolactinemia. Elevated
prolactin levels may play important roles, both direct and indirect, in various pathologic states,
including breast cancer, osteoporosis, cardiovascular disorders, and sexual disturbances. Antipsychotic-induced hyperprolactinemia may be associated with similar clinical manifestations;
these are examined with particular reference to patients with schizophrenia.
 2002 Elsevier Science Ltd. All rights reserved.
Keywords: Hyperprolactinemia; Schizophrenia; Prolactin; Antipsychotics; Osteoporosis
∗
Corresponding author. Tel.: +716-829-3808; fax: +716-829-3812.
E-mail address: [email protected] (U. Halbreich).
0306-4530/02/$ - see front matter  2002 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0306-4530(02)00112-9
54
U. Halbreich et al. / Psychoneuroendocrinology 28 (2003) 53–67
1. Introduction
Prolactin is a polypeptide hormone secreted by the lactotroph cells of the anterior
pituitary gland. Prolactin release is pulsatory with approximately 13–14 pulses a day
and displays a significant diurnal rhythm. Levels increase shortly after sleep onset,
peak during the night, and start to decline shortly after waking, reaching a nadir
around noon (Yen and Jaffe, 1991). Food, especially a midday meal, increases prolactin levels (Ishizuka et al., 1983). Levels among individuals also tend to fluctuate
over time and this is particularly evident in post-menopausal women (Hankinson et
al., 1995). The predominant form of prolactin is a monomer molecule (23 kDa) but
the 16 kDa and 40–50 kDa dimers as well as the 70–80 kDa variant also occur
(Davis et al., 1991). It has been suggested that the various prolactin molecules may
have different bioavailability and some differential clinical effects. For the most part,
these effects are related to reproductive endocrinology (Rogol et al., 1975; Sinha,
1995); we are not aware of differential effects in the context of central nervous
system (CNS) disorders.
2. Regulation of prolactin secretion
The primary physiologic role of prolactin is the induction of lactation. However,
prolactin interacts with other CNS and peripheral processes and its secretion is influenced by both stimulatory and inhibitory endogenous substances (Table 1) (Melmed,
2000). Prolactin release is also indirectly influenced by the effects of exogenous
substances on endogenous ones (Melmed, 1995).
Prolactin secretion is regulated via tonic secretion of dopamine in the tuberoinfundibular tract and the hypothalamo-hypophyseal vessels. Dopamine acts as a
prolactin-inhibiting factor on D2 receptors located on the surface of the pituitary
lactotroph cells, whereas serotonin stimulates prolactin secretion. The serotoninmediated increase is probably via stimulation of prolactin-releasing factors, in particular thyrotropin-releasing hormone, vasoactive intestinal polypeptide, and peptide
histidine methionine (Fig. 1). Prolactin is also released in response to strong stimulatory effects on the nipple, such as breastfeeding, and in response to stress. In the
context of CNS mechanisms and disorders, it is important to note that estrogen,
opioids, substance P, and many other endogenous substances increase prolactin
secretion while major neurotransmitters such as gamma aminobutyric acid (GABA)
and acetylcholine inhibit prolactin secretion (Table 1) (Melmed, 2000). Therefore,
medications that interfere with the main regulatory mechanisms of prolactin or with
specific endogenous substances may cause an increase or decrease in prolactin levels
with downstream effects on other systems. As conventional (typical) antipsychotic
agents inhibit dopamine action at D2 receptors, this may be one explanation for the
hyperprolactinemia that can occur during treatment with these agents.
U. Halbreich et al. / Psychoneuroendocrinology 28 (2003) 53–67
55
Table 1
Endogenous substances affecting prolactin release
Stimulatory
Serotonin (5-HT)
Thyrotropin-releasing hormone
Estrogen
Vasoactive intestinal
polypeptide
Peptide histidine isoleucine
Opioid peptides
Growth hormone-releasing
hormone
GnRH
Oxytocin
Vasopressin
Histamine (H1)
Bradykinin
Angiotensin II
Inhibitory
Cholecystokinin (CCK)
Bombesin
Secretin
Gastrin
Dopamine
GABA
Somatostatin
Acetylcholine
Galanin
Calcitonin
Calcitonin gene-related peptide
Glucocorticosteroids
Gonadotropin-associated peptide
Tymosin factor 5
Melatonin
Other posterior pituitary factors (?)
Platelet activating factor
Epidermal growth factor
α-Melanocyte-stimulating
hormone
Neurotensin
Substance P
Corticotropin-releasing
hormone?
Adapted from the work of Melmed (2000).
3. The differential diagnosis of hyperprolactinemia
The causes of hyperprolactinemia are wide-ranging, with CNS disorders, various
systemic conditions, pituitary disorders, and antidepressive and antipsychotic medications all implicated (Table 2). As such, even in patients who receive prolactininducing medications, other possible causes of hyperprolactinemia should be considered.
3.1. Systemic conditions
The most prevalent systemic condition associated with hyperprolactinemia is stress
in response to psychologic, environmental, or internal stimuli. Together with cortisol
and growth hormones, prolactin is recognized as a major stress-induced hormone
but its role in the normal and abnormal stress responses has been less widely studied
than that of cortisol. Physical stress, whether brought about from normal exercise,
medical conditions such as hypoglycemia (Nathan et al., 1980), or induced by
surgery, may also cause hyperprolactinemia. In addition, any impairment in prolactin
metabolism, including advanced liver dysfunction, cirrhosis, or chronic renal failure,
may result in elevated prolactin levels.
The increase in estrogen that occurs during pregnancy can lead to elevated levels
56
U. Halbreich et al. / Psychoneuroendocrinology 28 (2003) 53–67
Fig. 1. Regulatory mechanisms involved in prolactin secretion (SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant).
of prolactin but hormonal levels are also increased in pseudocyesis. The interrelationship between prolactin and estrogen is quite complex. As will be discussed
in more detail below, hyperprolactinemia-induced hypogonadism and its consequences are important but estrogen itself increases levels of prolactin. This elevation is effected through estrogen’s multiple influences on CNS functions
(Halbreich et al., 1981; McEwen et al., 1997), as well as through a direct influence
on lactotrophs (Melmed, 1995; Petty, 1999). Estrogen increases lactotroph mRNA
levels, influences prolactin gene transcription and expression, and affects mitotic
activity and DNA synthesis (Petty, 1999). It elevates levels of prolactin, thereby
increasing the amplitude of prolactin bursts as well as prolactin release and storage
(Veldhuis et al., 1989). Estrogen also has an indirect effect on prolactin via synthesis
of protein intermediates, modulation of the inhibiting effect of dopamine or prolactin
gene transcription, and a decrease in cellular cAMP. Any increase in levels of estrogen, whether from endogenous or exogenous sources, may result in increased levels
of prolactin. These levels are usually not high enough to cause prolactin-induced
hypoestrogenism.
3.2. CNS and pituitary disorders
Any space-occupying lesions or processes in the CNS that are also located in or
influence the hypothalmus may cause hyperprolactinemia. Meningiomas, craniopharingiomas, sarcoidosis, disseminated autoimmune disorders, and vascular impairments
are all potential causes.
U. Halbreich et al. / Psychoneuroendocrinology 28 (2003) 53–67
57
Table 2
Differential diagnosis of hyperprolactionemia
Systemic conditions
Medications
Stress
Pregnancy
Pseudocyesis
Hypothyroidism
Cushing’s disease
Cirrhosis
Chronic renal failure
Breast stimulation
First generation neuroleptics
Phenothiazines
Haloperidol
Second generation neuroleptics
Risperidone
CNS disorders
Meningiomas
Craniopharingiomas
Sarcoidosis
Disseminated autoimmune disorders
Vascular disorders
Hypothalamic tumors and metastases
Cranial irradiation
Antidepressants
Some tricyclic antidepressants
Specific serotonin reuptake inhibitors
Monoamine-oxidase inhibitors
d-fenfluramine
Reserpine
α-methyldopa
Cocaine and other opiates
Verapamil
Cimethidine
Estrogens
Oral contraceptives
Pituitary disorders
Prolactinomas (micro and macro adenomas)
Empty sella syndrome
Acromegaly
Pituitary stalk section (tumors)
Tumors in the anterior pituitary, particularly prolactinomas, are one of the most
common causes of hyperprolactinemia. Other pituitary disorders, such as empty sella
syndrome and acromegaly, may also elevate prolactin. Magnetic resonance imaging
and computed tomography scans that focus on the sella turica are therefore essential
in diagnosing hyperprolactinemia.
3.3. Schizophrenia and antipsychotic-induced hyperprolactinemia
Prolactin secretion in patients with schizophrenia is important, even though schizophrenia affects only 1% of the total world population. This is because the chronicity
of schizophrenia and associated long-term disability means that it is one of the
10 most common disorders documented by the World Bank and World Health
Organization causing cumulative disability and lost productive years.
The influence of schizophrenia per se on prolactin secretion is not completely
clear. The current broad boundaries of the clinical definition of schizophrenia,
together with the diversified CNS processes involved in the pathobiology of psychotic disorders, which can increase or decrease levels of prolactin, makes a coherent
explanation difficult. As the diversity of clinically effective atypical antipsychotics
and functional imaging studies have shown, schizophrenic patients may display a
58
U. Halbreich et al. / Psychoneuroendocrinology 28 (2003) 53–67
range of receptor abnormalities. These include, but are not limited to, D1, D2 and
other dopamine receptors, serotonin receptors, α1 and α2 adrenoceptors, muscarinic
cholinergic receptors, histamine, GABA, sigma opioid receptors, and glutamate
systems (NMDA receptors) (Goldstein, 1999a). Therefore, prolactin levels in a given
untreated schizophrenic individual are the result of the balance between multiple
internal regulatory processes and external stimuli (e.g. stressful events).
Most of our knowledge concerning prolactin levels in schizophrenic patients has
been gained from studies of patients treated with antipsychotic medications. The
dopaminergic hypothesis for the pathobiology of schizophrenia was developed
mainly because the efficacious conventional (typical) antipsychotics were all dopamine-blocking agents. Their clinical efficacy was attributed to blockade of the mesolimbic and mesocortical dopaminergic pathways, while the extrapyramidal adverse
effects associated with conventional antipsychotics were due to blockade of the
nigrostriatal dopamine pathway.
The tubero-infundibular system regulates prolactin secretion via dopamine
neurones. Dopamine from the tubero-infundibular system is secreted from the median
eminence of the hypothalamus, via the portal veins of the pituitary stalk, to the
lactotrophs in the anterior pituitary where it exerts its tonic-inhibitory effect. (There
is a short feedback mechanism between prolactin and dopamine released from the
hypothalamus.) Therefore, any blockade of dopamine receptors in the tubero-infundibular system would reverse prolactin inhibitory effects and lead to hyperprolactinemia. Typical antipsychotic agents are nonselective, blocking all dopamine pathways
including the tubero-infundibular pathway. Indeed, it has been suggested that the
magnitude of hyperprolactinemia may be a biological marker for the therapeutic
effects of an antipsychotic, and a very high correlation between hyperprolactinemic
effect and ‘therapeutic potency’ has been demonstrated across a group of conventional antipsychotic drugs (Gruen et al., 1978). While antipsychotic-induced hyperprolactinemia is almost universal with typical agents, most atypical antipsychotics
do not cause a sustained elevation in prolactin levels. Conversely, risperidone induces
hyperprolactinemia at least to a similar level to that of the conventional neuroleptics
(Goldstein, 1999b). In addition, there is some evidence that zotepine (von Bardeleben
et al., 1987) and amisulpride (Wetzel et al., 1994) also induce hyperprolactinemia.
3.4. Antidepressants and other medications
Some tricyclic antidepressants cause hyperprolactinemia, as do selective serotonin
reuptake inhibitors, due to their increased serotonergic stimulatory effects. Similarly,
d-fenfluramine, an ingredient in some weight-reduction products, increases serotonin
activity and can produce elevated prolactin levels (Asnis et al., 1988). Monoamine
oxidase inhibitors, which increase activity of dopamine but also norepinephrine and
serotonin, have also been shown to induce hyperprolactinemia. We reported that
depletion of dopamine with reserpine has been shown to increase levels of prolactin
(Asnis et al., 1980).
Several opioids, including morphine, cocaine, and β-endorphin, have been reported
to increase prolactin secretion through dopamine interaction (Gold et al., 1978). The
U. Halbreich et al. / Psychoneuroendocrinology 28 (2003) 53–67
59
opioid antagonist naloxone and its long-acting counterpart naltrexone block increase
in prolactin, which might be caused by other stimuli such as stress and surgery.
However, it is not yet clear whether these opioids actually decrease prolactin levels
if they are not already elevated.
4. Clinical effects of hyperprolactinemia
For clinical purposes, hyperprolactinemia can be defined as a plasma prolactin
level of ⬎20 ng/ml for men and ⬎25 ng/ml for women. The diurnal rhythm of
prolactin levels makes it preferable to obtain a fasting blood sample at least 2 h
after waking.
Most of the clinical adverse effects of hyperprolactinemia (Table 3) may be attributed to prolactin interference with the hypothalamic–pituitary–gonadal system. This
interference takes place on multiple levels (Malarkey et al., 1980; O’Dell et al.,
1990). Prolactin suppresses gonadotropin-releasing hormone (GnRH) pulsatile
secretion from the hypothalamus and directly interferes with the pituitary action of
the gonadotropin luteinizing hormones (LH) and follicle-stimulating hormone (FSH)
on the gonads. Additionally, prolactin interferes with steroid feedback mechanisms
at all levels, from the pituitary up to the hypothalamus, and with the extra hypothalamus CNS processes which regulate the hypothalamus. It also inhibits aromatase
activity and causes blockade of 5α-reductase. These interactions produce a major
dysregulation of the hypothalamic–pituitary–gonadal system, as well as of the
systems and processes affected by the pituitary and gonadal hormones.
Table 3
Clinical adverse effects of hyperprolatinemia
Decreased BMD and osteoporosis
Infertility
Disturbed menstrual cycles
Anovulation
Amenorrhea
Irregular cycles
Decreased testosterone levels and sperm mobility
Sexual dysfunction
Decreased libido and arousal
Un- or hypo-orgasmia
Increased risk of CV disorders
Galactorrhea
Breast engorgement
Increased risk of tardive dyskinesia?
Increased risk of breast cancer
Abnormal function of the immune system?
Anxiety, depression, hostility
60
U. Halbreich et al. / Psychoneuroendocrinology 28 (2003) 53–67
4.1. Decreased bone mineral density (BMD) and osteoporosis
The consequences of hyperprolactinemia-induced decreases in estrogen and testosterone levels may lead to debilitating and long-term disease. Probably the least
obvious in the short term, but one of the most serious in the long term, is osteoporosis. This prevalent bone disorder is characterized by a decrease in BMD or bone
mass and is associated with significant morbidity, particularly in the elderly. Several
studies (Rojansky et al., 1990; Schweiger et al., 1993; Abraham et al., 1995; Halbreich et al., 1995; Michelson et al., 1996; Keeley et al., 1997) have reported a decrease
in BMD in psychiatric patients treated with neuroleptics and/or antidepressants. In
patients with schizophrenia, osteoporosis does not follow the usual pattern of agerelated decreases in BMD. The magnitude of decreased BMD and the ensuing
increased susceptibility to osteoporosis and bone fractures is higher in men with
schizophrenia than women with schizophrenia.
Osteoporosis is a disease of impaired homeostatic regulation (Riggs, 1981). The
bone normally undergoes constant change and remodeling and is vulnerable to multiple influences (Steele, 1985), many of which might occur in patients with schizophrenia (Halbreich and Palter, 1996). Hyperprolactinemia has been linked to hypoestrogenism secondary to disruption of the hypothalamic–pituitary–gonadal axis
(Dickson and Glazer, 1999). However, the relative contribution of hypogonadism or
of prolactin elevation itself to the development of osteoporosis is not entirely clear.
For instance, a preclinical study found that estrogen deficiency was more important
in determining BMD than prolactin excess and concluded that osteoporosis was probably due to prolactin-induced hypogonadism rather than a direct effect of prolactin
on calcium homeostatis (Adler et al., 1998). Support for this finding was provided
in a clinical study of women with hyperprolactinemia and amenorrhea. Those with
the most severe reduction in BMD had the lowest levels of estradiol, indicating that
the bone loss was caused by reduced estrogen not directly by elevated prolactin
(Klibanski et al., 1980).
Patients with schizophrenia, especially those who are treated with conventional
antipsychotics, appear particularly susceptible to decreases in BMD (Lacro and Jeste,
1994). Chronic psychotropic-induced hyperprolactinemia is associated with hypogonadism in both men and women (Levinson and Simpson, 1987). For instance, a
study examining antipsychotic-induced body-weight gain in pre-menopausal women
found that the atypical agent sulpiride significantly increased prolactin levels and
significantly reduced estradiol levels, surmizing that the decreased serum estradiol
level was secondary to hyperprolactinemia (Baptista et al., 1997). This in turn may
lead to osteoporosis in both genders (Klibanski et al., 1980; Ataya et al., 1988).
It is suggested that the neuroleptic-induced decrease in gonadal hormones may be
responsible for a decrease in 1α hydroxylate in the kidney, in 1,25 dihydroxy
vitamin-D synthesis, and reduced calcium absorption in the intestine, all of which may
contribute to decreases in BMD. Low levels of estrogen also influence interleukin
activity, which, following a complex process (Halbreich and Palter, 1996), leads to
increased bone resorption and decreased bone formation, resulting in decreased BMD.
Indeed, in patients with schizophrenia, pathways other than hyperprolactinemia-induced
U. Halbreich et al. / Psychoneuroendocrinology 28 (2003) 53–67
61
bone processes may be involved in the development of osteoporosis. Polydipsia
and impaired fluid and electrolyte balance (mostly calcium), smoking, dietary
and vitamin deficiencies, as well as a lack of exercise and limited exposure to
sunlight may all contribute. Nevertheless, hypogonadism remains a major contributing factor.
4.2. Prolactin and the immune system
As discussed previously, prolactin influences several interleukins and in turn is
influenced by changes in interleukin-2 and other interleukins. Prolactin receptors
have been identified on several blood cells, notably B-cells, T-cells, and monocytes.
Prolactin synthesis by normal lymphocyte cells has also been confirmed. It has been
suggested that prolactin is secreted from mononuclear cells and has an
autocrine/paracrine effect on immune-cell function (Pellegrini et al., 1992). Though
it is clear that pituitary prolactin and mononuclear-secreted prolactin modulate the
immune system, the hormonal effects are multifaceted and diverse. It is still unclear
whether antipsychotic-induced hyperprolactinemia per se influences the immune
system and if so in what way, because several immune-related processes are impaired
in untreated patients with schizophrenia.
4.3. Prolactin and the cardiovascular (CV) system
It is well documented that women of reproductive age suffer less from CV disorders and cardiac infarction than men. However, following menopause this gender
difference disappears. It has been suggested that the decreased prevalence of CV
disorders in pre-menopausal women is attributable to the protective effects of estrogen against arteriosclerosis, hypertension, and raised cholesterol and triglyceride levels (Schenck-Gustafsson, 1996). As such, the low estrogen levels that commonly
occur with hyperprolactinemia may increase the rate of CV disorders in this group.
Shaarawy et al. (1997) reported high blood pressure and decreased nitric oxide in
women with hyperprolactinemia and low estrogen, which were normalized following
treatment with bromocriptine. We are not aware of any similar studies in treated
patients with schizophrenia, or whether a hypo-estrogenic state resulting from antipsychotic-induced hyperprolactinemia increases the prevalence of CV disorders and
accelerates vulnerability to myocardial infarcts in female patients.
4.4. Prolactin and breast cancer
Increased levels of prolactin have been identified as a risk factor for breast cancer
(Adams, 1992), which is the most common malignant disorder among women and
is a major cause of death (Kelsey and Horn-Ross, 1993). Once the link between
conventional antipsychotics and hyperprolactinemia was established, the publication
of several reports focusing on breast cancer followed (Katz et al., 1967; Oriana et
al., 1991). However, the results from these studies were inconclusive and did not
confirm either an increased prevalence of breast cancer in psychiatric patients or any
62
U. Halbreich et al. / Psychoneuroendocrinology 28 (2003) 53–67
connection with hyperprolactinemia. These inconclusive findings were in contrast to
those from our own study. We reviewed the mammograms, psychiatric history, and
treatment of 275 women patients aged ⬎40 years in a psychiatric state hospital and
compared these to 928 women of similar age at a general hospital radiology clinic
(Halbreich et al., 1996). The incidence of breast cancer documented by pathology
was ⬎3.5 times higher among psychiatric patients than among patients in the specialized radiology clinic and 9.5 times higher than the reported incidence in the general
population. While this increased incidence may be attributed to antipsychotic-induced
hyperprolactinemia, cigarette smoking and alcohol consumption may also play a role.
The study drew criticism, which was amplified due to the sensitivity of the issue.
However, the hyperprolactinemia connection is supported by a large prospective
study of ⬎30,000 post-menopausal women (Hankinson et al., 1999). Blood sampling
resulted in 306 of the women being diagnosed with breast cancer and this group
was compared with 448 matched control individuals. The prospective data suggests
that higher plasma prolactin levels are associated with an increased risk of breast
cancer in post-menopausal women. This increased risk also held after controlling for
plasma estrogen and androgens and IGF-1.
Several putative mechanisms have been put forward to explain the role of prolactin
in breast cancer. These include expression of prolactin in both normal and malignant
breast tissue, the existence of receptors for prolactin in ⬎50% of breast tumors, and
a prolactin-induced increase in DNA synthesis of breast cancer cells in vivo
(Hankinson et al., 1999). It is of interest that prolactin administration has been shown
to increase the rate of mammary tumors in mice (Welsch and Nagasawa, 1977). As
the magnitude of a positive relationship between plasma prolactin levels and the risk
of breast cancer has been reported to be similar to that observed between estrogen
levels and breast cancer, this association should not be ignored. In younger women,
increased prolactin and decreased estrogen levels may counteract each other to some
extent but this is not the case in post-menopausal women who have been exposed
to long-term treatment with typical antipsychotics. It is not yet known whether
women who were administered conventional neuroleptics for a long time and then
switch to those atypical agents that do not induce prolactin elevation, reduce their
risk of breast cancer. In any case, regular mammograms are a necessary minimum
precaution in women receiving antipsychotic treatment for schizophrenia.
4.5. Galactorrhea
Galactorrhea has been reported in 30–80% of women with hyperprolactinemia
associated with pituitary tumors (Franks and Nabarro, 1977) but the reported prevalence of galactorrhea in patients with schizophrenia taking antipsychotics is much
lower (Wesselmann and Windgassen, 1995; Windgassen et al., 1996). One explanation for this apparent difference might be that, as breast milk is not spontaneously
secreted (nipple stimulation is necessary), galactorrhea goes unnoticed and is therefore under-reported. Not all women with hyperprolactinemia suffer from galactorrhea
and, conversely, the symptom may be present in women with normal levels of prolactin. Galactorrhea also occurs in men although to a lesser degree. Even though
U. Halbreich et al. / Psychoneuroendocrinology 28 (2003) 53–67
63
galactorrhea is a mild and harmless side effect of some antipsychotics, its confirmation is simple (diagnosis can be made by squeezing the nipple) and its occurrence
could point to other, more serious, adverse effects.
4.6. Influence of hyperprolactinemia on the menstrual cycle and fertility
As hyperprolactinemia is associated with suppressed estrogen levels, initial evidence of elevated prolactin is often identified by reproductive-related symptoms,
particularly in women. Symptoms include menstrual irregularities, anovulation and
its sequelae, and amenorrhea. These symptoms are often accompanied by galactorrhea, breast enlargement, or a feeling of engorgement (Knegtering et al., 2000).
However, the percentage of women on antipsychotics who report amenorrhea
(ⱖ33%) is approximately twice the proportion who report galactorrhea (Santoni and
Saubadu, 1995). This may be attributed to reports that galactorrhea depends on the
duration of hyperprolactinemia and hypogonadism. Women with long-standing
amenorrhea are less likely to have galactorrhea (Thorner et al., 1998) even though
self-reports of the latter are few even when it exists. Amenorrhea is accompanied
by infertility so antipsychotic-induced hyperprolactinemia can, indirectly, serve as a
contraceptive for women with schizophrenia. Our own experience is that not all
women consider drug-induced amenorrhea to be an undesirable adverse effect. However, they might be more concerned about sexual dysfunction, which has been linked
to elevated levels of prolactin.
A similar situation exists for men with hyperprolactinemia. The prolactin-induced
decrease in GnRH levels, pulsativity, and activity causes decreases in LH, FSH,
and testosterone. Prolactin is actively concentrated in the testes and decreases sperm
production and motility (Rogol et al., 1975), therefore decreasing male fertility even
when sexual function is maintained. It is of note that, when examined, up to 33% of
men with hyperprolactinemia had galactorrhea. This suggests that breast examination
should be part of routine clinical examination of both women and men on antipsychotics and should not be left to self report.
4.7. Sexual dysfunction
Normal sexual function comprises a combination and culmination of several
components: libido, arousal, and orgasm. All three are regulated by complex multiple
processes, only some of which will be discussed here. Increased dopamine and
decreased prolactin are associated with increased libido. Increased nitric oxide and
increased cAMP, as well as increased acetylcholine, are needed for arousal and
orgasm is associated with a decrease in serotonin and an increase in norepinephrine
levels. Thus, it is apparent that hyperprolactinemia is only part of the sexual dysfunction equation.
In patients undergoing dialysis for renal dysfunction, those reporting sexual function disturbances had significantly higher serum prolactin levels than patients with
normal sexual function. Treatment with the dopamine agonist bromocriptine nor-
64
U. Halbreich et al. / Psychoneuroendocrinology 28 (2003) 53–67
malized prolactin levels and improved libido and the frequency of sexual activity
(Weizman et al., 1983).
In men, neuroleptic-induced hyperprolactinemia has been reported to cause
impaired sexual function on several levels: reduced libido, erectile dysfunction,
partial to complete impotence, delayed orgasm, retrograde ejaculation, painful ejaculation, and anorgasmia (Keks et al., 1987; Knegtering et al., 2000). These symptoms
have been reported by up to 50% of patients on typical antipsychotics (Ghadirian et
al., 1982). Reduced libido has also been noted in women. Among the atypical agents,
clozapine has been reported to be associated with fewer sexual side effects than
conventional antipsychotics (Peacock et al., 1994) and sexual side effects from olanzapine were reported infrequently during clinical trials. Risperidone, on the other
hand, is associated with a higher incidence of sexual dysfunction (Claus et al., 1992;
Marder and Meibach, 1994). This may be a reflection of risperidone-induced hyperprolactinemia (Goldstein, 1999b). It is also of interest that female reports of
decreased ability to reach orgasm are high with risperidone when compared with
typical neuroleptics (Knegtering et al., 2000). The few spontaneous reports of sexual
problems from patients in the quetiapine clinical trials program are consistent with
evidence that quetiapine does not elevate prolactin levels (Borison et al., 1996;
Arvanitis and Miller, 1997; Small et al., 1997).
4.8. Mood and behavioral effects of hyperprolactinemia
Hostility, depression, and anxiety were reported to be more frequent in
amenorrheic women with hyperprolactinemia than in both amenorrheic women with
normal levels of prolactin and in women with regular menstrual cycles (Fava et al.,
1983, 1988). Similar mood symptoms have also been reported in response to elevated
prolactin in healthy women (Buckman, 1985). However in men, the direct impact
of increased prolactin on mood and behavior is still unclear. Furthermore, prolactin
has been suggested to induce dysphoric states in its own right (Kellner et al., 1984).
The issue is further complicated because the influence of increased prolactin on
estrogen and testosterone means that some of the long-term hormonal effects of
hyperprolactinemia are difficult to distinguish from those related to hypogonadism
and to the effects of decreased estrogen and testosterone on the CNS.
5. Conclusions
In recent years, increased prescribing of atypical antipsychotics would suggest
that the prevalence of hyperprolactinemia in patients with schizophrenia is probably
declining, at least in developed countries, although this assumption needs to be confirmed. Whether a switch to those atypical antipsychotics that do not induce hyperprolactinemia will completely rectify the long-term hyperprolactinemic effects of the
typical antipsychotics, or just prevent further deterioration, has not yet been determined. Long-term follow-up studies are required to answer this question.
From a public-health and cost-effectiveness perspective, the disability and pro-
U. Halbreich et al. / Psychoneuroendocrinology 28 (2003) 53–67
65
jected costs associated with the long-term effects of hyperprolactinemia, as well as
with other drug-induced adverse effects, should be taken into account when selecting
antipsychotic medications. This is particularly true for the treatment of schizophrenia
in developing countries and for patients elsewhere whose treatment is paid for from
public or institutional funds.
References
Abraham, G., Friedman, R.H., Verghese, C., de Leon, J., 1995. Osteoporosis and schizophrenia: can we
limit known risk factors? Biol. Psychiatry 38, 131–132.
Adams, J.B., 1992. Human breast cancer: concerted role of diet, prolactin and adrenal C19-delta 5-steroids
in tumorigenesis. Int. J. Cancer 50, 854–858.
Adler, R.A., Evani, R., Mansouri, A., Krieg, R.J. Jr., 1998. Relative effects of prolactin excess and
estrogen deficiency on bone in rats. Metabolism 47, 425–428.
Arvanitis, L.A., Miller, B.G., 1997. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute
exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13
Study Group, Biol. Psychiatry 42, 233–246.
Asnis, G.M., Nathan, R.S., Halbreich, U., Halpern, F.S., Sachar, E.J., 1980. Prolactin changes in major
depressive disorders. Am. J. Psychiatry 137, 1117–1118.
Asnis, G.M., Eisenberg, J., van Praag, H.M., Lemus, C.Z., Friedman, J.M., Miller, A.H., 1988. The
neuroendocrine response to fenfluramine in depressives and normal controls. Biol. Psychiatry 24,
117–120.
Ataya, K., Mercado, A., Kartaginer, J., Abbasi, A., Moghissi, K.S., 1988. Bone density and reproductive
hormones in patients with neuroleptic-induced hyperprolactinemia. Fertil. Steril. 50, 876–881.
Baptista, T., Molina, M.G., Martinez, J.L., de Quijada, M., Calanche de Cuesta, I., Acosta, A., Paez, X.,
Martinez, J.M., Hernandez, L., 1997. Effects of the antipsychotic drug sulpiride on reproductive hormones in healthy premenopausal women: relationship with body weight regulation. Pharmacopsychiatry 30, 256–262.
Borison, R.L., Arvanitis, L.A., Miller, B.G., 1996. ICI 204,636, an atypical antipsychotic: efficacy and
safety in a multicenter, placebo-controlled trial in patients with schizophrenia. U.S. SEROQUEL Study
Group. J. Clin. Psychopharmacol. 16, 158–169.
Buckman, M., 1985. Psychological distress in hyperprolactinemic women. In: Macleod, R., Thorner, M.,
Seapagnini, U. (Eds.), Prolactin: Basic and Clinical Correlates. Liviana Press, Padova, pp. 601–668.
Claus, A., Bollen, J., De Cuyper, H., Eneman, M., Malfroid, M., Peuskens, J., Heylen, S., 1992. Risperidone versus haloperidol in the treatment of chronic schizophrenic inpatients: a multicentre doubleblind comparative study. Acta Psychiatr. Scand. 85, 295–305.
Davis, K.L., Kahn, R.S., Ko, G., Davidson, M., 1991. Dopamine in schizophrenia: a review and reconceptualization. Am. J. Psychiatry 148, 1474–1486.
Dickson, R.A., Glazer, W.M., 1999. Neuroleptic-induced hyperprolactinemia. Schizophr. Res. 35 (Suppl.),
S75–S86.
Fava, G.A., Sonino, N., Wise, T.N., 1988. Management of depression in medical patients. Psychother.
Psychosom. 49, 81–102.
Fava, M., Fava, G.A., Kellner, R., Buckman, M.T., Lisansky, J., Serafini, E., DeBesi, L., Mastrogiacomo,
I., 1983. Psychosomatic aspects of hyperprolactinemia. Psychother. Psychosom. 40, 257–262.
Franks, S., Nabarro, J.D., 1977. Prevalence and presentation of hyperprolactinaemia in patients with
“functionless” pituitary tumours. Lancet 1, 778–780.
Ghadirian, A.M., Chouinard, G., Annable, L., 1982. Sexual dysfunction and plasma prolactin levels in
neuroleptic-treated schizophrenic outpatients. J. Nerv. Ment. Dis. 170, 463–467.
Gold, M.S., Redmond, D.E. Jr., Donabedian, R.K., Goodwin, F.K., Extein, I., 1978. Increase in serum
prolactin by exogenous and endogenous opiates: evidence for antidopamine and antipsychotic effects.
Am. J. Psychiatry 135, 1415–1416.
66
U. Halbreich et al. / Psychoneuroendocrinology 28 (2003) 53–67
Goldstein, S.R., 1999a. Selective estrogen receptor modulators: a new category of compounds to extend
postmenopausal women’s health. Int. J. Fertil. Womens Med. 44, 221–226.
Goldstein, J., 1999b. Seroquel (quetiapine fumerate): a new atypical antipsychotic. Drugs Today 35,
193–210.
Gruen, P.H., Sachar, E.J., Langer, G., Altman, N., Leifer, M., Frantz, A., Halpern, F.S., 1978. Prolactin
responses to neuroleptics in normal and schizophrenic subjects. Arch. Gen. Psychiatry 35, 108–116.
Halbreich, U., Sachar, E.J., Asnis, G.M., Nathan, R.S., Halpern, F.S., 1981. The prolactin response to
intravenous dextroamphetamine in normal young men and postmenopausal women. Life Sci. 28,
2337–2342.
Halbreich, U., Rojansky, N., Palter, S., Hreshchyshyn, M., Kreeger, J., Bakhai, Y., Rosan, R., 1995.
Decreased bone mineral density in medicated psychiatric patients. Psychosom. Med. 57, 485–491.
Halbreich, U., Palter, S., 1996. Accelerated osteoporosis in psychiatric patients: possible pathophysiological processes. Schizophr. Bull. 22, 447–454.
Halbreich, U., Shen, J., Panaro, V., 1996. Are chronic psychiatric patients at increased risk for developing
breast cancer? Am. J. Psychiatry 153, 559–560.
Hankinson, S.E., Manson, J.E., Spiegelman, D., Willett, W.C., Longcope, C., Speizer, F.E., 1995. Reproducibility of plasma hormone levels in postmenopausal women over a 2–3-year period. Cancer Epidemiol. Biomarkers Prev. 4, 649–654.
Hankinson, S.E., Willett, W.C., Michaud, D.S., Manson, J.E., Colditz, G.A., Longcope, C., Rosner, B.,
Speizer, F.E., 1999. Plasma prolactin levels and subsequent risk of breast cancer in postmenopausal
women. J. Natl. Cancer Inst. 91, 629–634.
Ishizuka, B., Quigley, M.E., Yen, S.S., 1983. Pituitary hormone release in response to food ingestion:
evidence for neuroendocrine signals from gut to brain. J. Clin. Endocrinol. Metab. 57, 1111–1116.
Katz, J., Kunofsky, S., Patton, R.E., Allaway, N.C., 1967. Cancer mortality among patients in New York
mental hospitals. Cancer 20, 2194–2199.
Keeley, E., Reis, J.P., Drinkwater, D., Faiman, C., 1997. Bone mineral density, sex hormones, and longterm use of neuroleptic agents in men. Endocr. Pract. 3, 209–213.
Keks, N.A., Copolov, D.L., Singh, B.S., 1987. Abnormal prolactin response to haloperidol challenge in
men with schizophrenia. Am. J. Psychiatry 144, 1335–1337.
Kellner, R., Buckman, M.T., Fava, G.A., Pathak, D., 1984. Hyperprolactinemia, distress and hostility.
Am. J. Psychiatry 141, 759–763.
Kelsey, J.L., Horn-Ross, P.L., 1993. Breast cancer: magnitude of the problem and descriptive epidemiology. Epidemiol. Rev. 15, 7–16.
Klibanski, A., Neer, R.M., Beitins, I.Z., Ridgway, E.C., Zervas, N.T., McArthur, J.W., 1980. Decreased
bone density in hyperprolactinemic women. N. Engl. J. Med. 303, 1511–1514.
Knegtering, H., Lambers, P.A., Prakken, G., Ten Brink, C., 2000. Serum prolactin levels and sexual
dysfunctions in antipsychotic medication, such as risperidone: a review. Acta Neuropsychiatr. 12,
19–26.
Lacro, J.P., Jeste, D.V., 1994. Physical comorbidity and polypharmacy in older psychiatric patients. Biol.
Psychiatry 36, 146–152.
Levinson, D.F., Simpson, G., 1987. Sequelae of neuroleptic malignant syndrome. Biol. Psychiatry 22,
237–238.
Malarkey, W.B., Goodenow, T.J., Lanese, R.R., 1980. Diurnal variation of prolactin secretion differentiates pituitary tumors from the primary empty sella syndrome. Am. J. Med. 69, 886–890.
Marder, S.R., Meibach, R.C., 1994. Risperidone in the treatment of schizophrenia. Am. J. Psychiatry 151,
825–835.
McEwen, B.S., Alves, S.E., Bulloch, K., Weiland, N.G., 1997. Ovarian steroids and the brain: implications
for cognition and aging. Neurology 48 (5 Suppl. 7), S8–S15.
Melmed, S., 1995. The Pituitary. Blackwell Science, Cambridge, Massachusetts.
Melmed, S., 2000. The Pituitary. Second ed. Blackwell Science, Cambridge, Massachusetts.
Michelson, D., Stratakis, C., Hill, L., Reynolds, J., Galliven, E., Chrousos, G., Gold, P., 1996. Bone
mineral density in women with depression. N. Engl. J. Med. 335, 1176–1181.
Nathan, R.S., Asnis, G.M., Dyrenfurth, I., Halpern, F.S., Halbreich, U., Ostrow, L.C., Sachar, E.J., 1980.
Plasma prolactin and testosterone during penfluridol treatment (letter). Lancet 2, 94.
U. Halbreich et al. / Psychoneuroendocrinology 28 (2003) 53–67
67
O’Dell, S.J., LaHoste, G.J., Widmark, D.B., Shapiro, R.M., Potkin, S.G., Marshall, J.F., 1990. Chronic
treatment with clozapine or haloperidol differentially regulates dopamine and serotonin receptors in
rat brain. Synapse 6, 146–153.
Oriana, S., Coradini, D., Sasso, G.M., Di Fronzo, G., 1991. Adjuvant hormone treatment and chemotherapy in postmenopausal women with operable breast cancer: a retrospective analysis. Anticancer
Res. 11, 2199–2205.
Peacock, L., Solgard, T., Lublin, H., Gerlach, J., 1994. Clozapine versus typical antipsychotics: effects
and side effects. Neuropsychopharmacology 10, 223–354.
Pellegrini, I., Lebrun, J.J., Ali, S., Kelly, P.A., 1992. Expression of prolactin and its receptor in human
lymphoid cells. Mol. Endocrinol. 6, 1023–1031.
Petty, R.G., 1999. Prolactin and antipsychotic medications: mechanism of action. Schizophr. Res. 35
(Suppl.), S67–S73.
Riggs, B.L., 1981. Osteoporosis—a disease of impaired homeostatic regulation. Miner. Electrolyte Metab.
5, 265–272.
Rogol, A.D., Ben-David, M., Sheats, R., Rodbard, D., Chrambach, A., 1975. Charge properties of human
pituitary and amniotic fluid prolactins. Endocr. Res. Commun. 2, 379–402.
Rojansky, N., Halbreich, U., Rosan, R., Wang, K., Hreshchyshyn, M., 1990. Hormonally related osteoporosis in chronic psychiatric patients. Neuroendocrinol. Lett. 12, 304.
Santoni, J.P., Saubadu, S., 1995. Adverse events associated with neuroleptic drugs: focus on neuroendocrine reactions. Acta Ther. 21, 193–204.
Schenck-Gustafsson, K., 1996. Risk factors for cardiovascular disease in women: assessment and management. Eur. Heart J. 17 (Suppl. D), 2–8.
Schweiger, U., Deuschle, M., Korner, A., Lammers, C.H., Schmider, J., Gotthardt, U., Holsboer, F.,
Heuser, I., 1993. Low lumbar bone mineral density in patients with major depression (abstract). Biol.
Psychiatry 33, 76.
Shaarawy, M., Nafei, S., Abul-Nasr, A., el-Sharkawy, S., Younis, A., 1997. Circulating nitric oxide levels
in galactorrheic, hyperprolactinemic, amenorrheic women. Fertil. Steril. 68, 454–459.
Sinha, Y.N., 1995. Structural variants of prolactin: occurrence and physiological significance. Endocr.
Rev. 16, 354–369.
Small, J.G., Hirsch, S.R., Arvanitis, L.A., Miller, B.G., Link, C.G., 1997. Quetiapine in patients with
schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group.
Arch. Gen. Psychiatry 54, 549–557.
Steele, F.R., 1985. Evolutions: bone remodeling. J. NIH Res. 7, 78–87.
Thorner, M., Vance, M., Laws, E., Horvath, E., Kovacs, K., 1998. The anterior pituitary. In: Williams
(Ed.), Textbook of Endocrinology, Ninth ed. WB Saunders, Philadelphia, pp. 249–340.
Veldhuis, J.D., Evans, W.S., Stumpf, P.G., 1989. Mechanisms that subserve estradiol’s induction of
increased prolactin concentrations: evidence of amplitude modulation of spontaneous prolactin
secretory bursts. Am. J. Obstet. Gynecol. 161, 1149–1158.
von Bardeleben, U., Benkert, O., Holsboer, F., 1987. Clinical and neuroendocrine effects of zotepine—
a new neuroleptic drug. Pharmacopsychiatry 20, 28–34.
Weizman, R., Weizman, A., Levi, J., Gura, V., Zevin, D., Maoz, B., Wijsenbeek, H., Ben David, M., 1983.
Sexual dysfunction associated with hyperprolactinemia in males and females undergoing hemodialysis.
Psychosom. Med. 45, 259–269.
Welsch, C.W., Nagasawa, H., 1977. Prolactin and murine mammary tumorigenesis: a review. Cancer Res.
37, 951–963.
Wesselmann, U., Windgassen, K., 1995. Galactorrhea: subjective response by schizophrenic patients. Acta
Psychiatr. Scand. 91, 152–155.
Wetzel, H., Wiesner, J., Hiemke, C., Benkert, O., 1994. Acute antagonism of dopamine D2-like receptors
by amisulpride: effects on hormone secretion in healthy volunteers. J. Psychiatr. Res. 28, 461–473.
Windgassen, K., Wesselmann, U., Schulze Monking, H., 1996. Galactorrhea and hyperprolactinemia in
schizophrenic patients on neuroleptics: frequency and etiology. Neuropsychobiology 33, 142–146.
Yen, S., Jaffe, R., 1991. Reproductive Endocrinology. Third ed. WB Saunders, Philadelphia.