During antipsychotic treatment, prolactin concentrations can rise to ten times normal levels or above.
Existing data indicate that 17-78% of female patients have amenorrhoea with or without galactorrhoea.
Survey data, however, suggest that clinicians underestimate the prevalence of these conditions.
Long-term consequences of antipsychotic-related hypo-oestrogenism require further research but are likely to include premature bone loss.
Antipsychotic-induced hyperprolactinaemia should become a focus of interest in the drug treatment of psychiatric patients.
3. Pharmacologic hyperprolactinemia is a
problem of underestimated prevalence.
This is due to:
◦ More attention to the original serious disease.
◦ Lack of externally visible symptoms.
◦ Patients’ reluctance for embarrassing disturbs.
◦ Clinicians’ lack of awareness.
4. Do we have to treat???
Are there real risks if left untreated???
What are the concerns???
Can we use Dopamin Agonist or it will
counteract the effect of the original drug &
promotes exacerbation of the disease???
8. In a pharmaco-epidemiological analysis
recording adverse drug reactions 1985-2000
in france, hyperprolactinaemia showed:
◦ female/male ratio was 5.9
◦ mean age was 40 (range 14–85) years.
◦ 31% were associated with neuroleptics,
◦ 28% with neuroleptic-like drugs
◦ 26% with antidepressants
◦ 5% with H2-receptor antagonists
French Pharmacovigilance Database 1985 to 2000,
Petit et al 2003
9. Prolactin is secreted in a pulsatile manner by
the anterior pituitary.
There are 13 or 14 peaks per day.
inter-pulse interval of about 95 min.
The mean pulse amplitude increase about
20-30% of the upper normal value
Veldhuis & Johnson, 1988
10. Breast enlargement during pregnancy .
Milk production during lactation.
The reductions in libido and fertility that are
associated with nursing may have
evolutionary advantages.(Benker et al 1990)
Possible metabolic effects.
Immune responsiveness stimulation.
(Halbreich et al 2003).
11. Accurate definition of normal prolactin level
can be difficult, because of :
◦ Daytime levels and peak amplitudes vary
considerably between individuals.
◦ Levels are higher at the middle and during the
second half of the cycle.
◦ Transient increases occur in response to meals,
stress and sexual activity.
◦ The frequent occurrence of “macroprolactinemia” .
Suliman et al 2003
12. Big variants of prolactin and prolactin-IgG
complexes , with high immunogenic properties
but poor biological effects, can circulate in large
amount (up to 85% of total prolactin).
The prevalence of macroprolactinemia is 10–25%
in patients with hyperprolactinemia and 3.7% in
general population.
It is characterized by high levels of prolactin and
lack of clinical symptoms .
can be revealed by polyethylene glycol
precipitation of serum samples .
Gibney et al 2005
13. Hyper-prolactinemia, usually defined as fasting
levels at least 2 hours after waking up:
◦ above 20 ng/ml in men and above 25 ng/ml in women
(Halbreich et al 2003)
◦ Or above 400 mU/L .
• Mildly elevated prolactin (400-1000mU/L)(25-
60ng/ml) may need to be repeated.
• Levels >5000mU/L (300 ng/ml) usually indicate true
prolactinoma.
• Drug-induced increases in serum prolactin do not
generally lead to levels above 2500 mU/L (150ng/ml);
however occasionally levels up to 6000 mU/L have
been observed
14. Dopamine
is the predominant
prolactin-inhibiting
factor:
Other prolactin-
inhibiting factors
Gonadotrophin-associated
protein
Gamma-aminobutyric acid
(GABA)
Acetylcholine
Somatostatin
Norepinephine
15. Serotonin (5-HT) has a
stimulatory role
Other stimulatory factors :
oxytocin
vasopressin
vasoactive intestinal
peptide (VIP)
thyreotropin releasing
hormone (TRH)
Oestrogens can
modulate prolactin
secretion using various
mechanisms;
18. Drugs impairing dopaminergic function:
◦ false dopamine precursors
◦ inhibitors of L-aromatic aminoacids decarboxylase
◦ dopamine receptor antagonists
Drugs enhancing serotoninergic
neurotransmission
◦ serotoninergic precursors
◦ direct and indirect serotonin agonists
◦ blockers of serotonin reuptake
◦ histamine H2 receptor antagonists
(Steiner et al 1976; Polleri et al 1980; Muller et al 1983;
Di Renzo et al 1989; Molitch 2005).
21. Meltzer &
Fang, 1976
Elevation of prolactin levels occurs within a few hours of
treatment initiation
Meltzer & Fang, 1976;
Gruen et al, 1978;
Oseko et al, 1988;
Kuruvilla et al, 1992;
Arvanitis et al, 1997;
Crawford et al, 1997
Medium-term treatment (3-9 weeks) with therapeutic
dosages increases mean baseline prolactin levels up to
ten-fold
Meltzer &
Fang, 1976
Low daily dosing regimens (e.g. 200 mg chlorpromazine)
can cause significant prolactin elevations
Meltzer et al,
1983; Green
& Brown,
1988
Levels increase in a dose-dependent manner
Brown &
Laughren,
1981
Although partial tolerance may occur during chronic
treatment
Rivera et al,
1976;
Zelaschi et
al, 1996
Still patients treated for several years have significantly
higher baseline prolactin levels than untreated healthy
controls
22. Wode-Helgodt
et al, 1977;
Kuruvilla et al,
1992; Smith et
al, 2002
Women have significantly greater prolactin elevations
than men
Kinon &
Gilmore, 2001
59% of women and 42% of men had a prolactin level
above the upper limit of normal
Turkington,
1972
When discontinued, baseline prolactin levels may take
up to 3 weeks to return to the normal
Wistedt et al,
1981
In the case of depot medication normalisation may take
as long as 6 months
23. Clozapine, quetiapine
and olanzapine
are reported either to
cause no increase in
prolactin secretion at all
or to increase it only
transiently and mildly
So, can be used in
switching protocols to
correct an antipsychotic-
induced
hyperprolactinemia (
Meltzer et al, 1979; Small et al,
1997; Tollefson & Kuntz, 1999).
risperidone and
amisulpride
cause a marked and
sustained increase in
serum prolactin levels
24. Sustained and symptomatic hyperprolactinemia
has been demonstrated with the TCAD
amitriptyline, desipramine, clomipramine and
amoxapine.
However, SSRIs have been reported to be the
most frequent cause of drug-induced
hyperprolactinemia.
Among those, sertraline appears to be the most
frequent cause of sustained hyperprolactinemia,
but also fluoxetine and paroxetine may induce
pathologic and symptomatic increases in
prolactin levels.
25. Breast enlargement
Galactorrhoea
Ovarian dysfunction
Menstrual irregularities: oligomenorrhoea, amenorrhoea
Infertility
Sexual dysfunction: decreased libido, impaired arousal, impaired
orgasm
Atrophic changes in the urethra and vaginal mucosa, reduced
vaginal lubrication and dyspareunia.
26. Acne and mild hirsutism, due to the relative increase of
androgenic compared with oestrogenic activity. Decreased
bone mineral density (BMD) which may lead to increased risk
of osteoporosis.
Probable link to tumour growth especially breast cancer.
Behavioural effects : hostility, anxiety and depression in
women, although the severity of these symptoms appears to
be mild ( Sobrinho, 1993; Reavley et al, 1997).
27. Inhibits the activity of the hypothalamic—pituitary—ovarian
axis at several levels:
◦ It suppresses the pulsatile release of gonadotrophin-
releasing hormone (GnRH) from the hypothalamus
◦ inhibits the effect of GnRH on the pituitary gland
◦ blocks the positive feedback effect of oestradiol on
luteinising hormone secretion.
28. Five cross-sectional studies investigated
menstrual irregularities in women with
severe psychiatric illnesses receiving
chronic treatment with various conventional
antipsychotic agents at therapeutic dosages
and found point prevalence rates of 26%,
40%, 45%, 55% and 78% respectively ( Polishuk
& Kulcsar, 1956; Ghadirian et al, 1982; Prentice & Deakin,
1992; Magharious et al, 1998; Smith et al, 2002).
29. In the study by Prentice & Deakin ( 1992) indicators of
illness severity were associated with menstrual dysfunction
independently of prolactin levels.
In two other studies ( Bergemann, 2001; Canuso et al, 2002)
some women with schizophrenia treated with prolactin-
sparing antipsychotic agents also showed evidence of
ovarian dysfunction.
Irrespective of the mechanisms, the data suggest that the
hypothalamic—pituitary system in women with
schizophrenia is particularly sensitive to further
disturbances such as hyperprolactinaemia.
30. In women treated with conventional
antipsychotic agents spontaneous
galactorrhoea prevalence was of 10-57% (
Wesselmann & Windgassen, 1995).
It is more likely to occur in women who have
had children and are of premenopausal age (
Windgassen et al, 1996).
31. Ghadirian et al (
1982)
with schizophrenia ,sexual dysfunction in 54% of men
and 30% of women.
Barnes &
Harvey, 1993
Medication might cause a worsening of sexual
functioning even if the medication is effective in
treating their illness
Lundberg &
Hulter ( 1991)
Among women with hyperprolactinaemia the
prevalence was 84% but in those with normal
prolactin levels the prevalence was only 32.6% (P <
0.001).
32. In premenopausal women with hyperprolactinaemic
oestrogen deficiency , radiological studies have
shown significant decreases in bone mineral
content, ranging from 5% to 25% depending on the
site measured ( Koppelman et al 1984; Schlechte et
al, 1987).
If prolactin levels and menstrual cycles normalise
with treatment, BMD values increase but remain
significantly lower than those of age-matched
normal women ( Klibanski & Greenspan, 1986;
Schlechte et al, 1987).
33. Psychiatric ttt often commenced in late teens
or early twenties leads to a reduced peak
bone mass & also premature acceleration of
bone loss.
In a female psychiatric patient, if the BMD at
the age of 50 years were to be reduced by 1
s.d. her future risk of fracture at these sites
might be doubled.
34. Ataya et al ( 1988) Bone density was reduced by
about 12% at three sites of the femur, but not in
the spine after10 years of antipsychotic use.
Halbreich et al ( 1995) found significantly reduced
BMD values in the lumbar spine in a group of
women treated with antipsychotic, antidepressant
and mood-stabilising medication, either alone or
in combination.
35. Several studies have linked hyperprolactinemia to an increased risk
of breast cancer in women (Halbreich U, Kinon BJ, Gilmore JA, et al) (
Hankinson SE, Willett WC, Michaud DS, et al)
The most recent and methodologically strong study, found that
antipsychotic dopamine receptor antagonists conferred a small but
significant risk of breast cancer. This study had a retrospective
cohort design and compared women who were exposed to
prolactin-raising antipsychotics with age-matched women who
were not (Wang P S, Walker A M, Tsuang M T, et al.)
36. High prolactin levels should not usually be a concern unless
symptoms develop.
Baseline prolactin levels should be obtained in symptomatic
patients.
37. women
Reproductive
age
Eumenorrheic
Prolactin measurement not
necessary unless clinically
significant galactorrhea
Amenorrheic
Check
prolactin
Prolactin normal
Assess for other
causes of
amenorrhea
Prolactin high
Check hCG
(rule out
pregnancy) ,
Check TSH (rule
out primary
hypothyroidism)
hCG negative , TSH normal
Decide whether to obtain
pituitary MRI
Postmenopausal
age
38. Decide whether to obtain pituitary MRI based on
◦ Temporal relationship between onset of signs/symptoms and initiation of
psychotropic medication
◦ Degree of elevation of prolactin (over 2500 mU/L)
◦ Clinical symptoms suggestive of tumor
◦ detailed physical examination (including visual fields)
Check mineral bone density
Consider estrogen/progestin therapy, if not contraindicated
(risk of thromboembolism and breast cancer).
Bisphosphonates and other drugs affecting bone metabolism
have been used to prevent osteoporosis.
Miller, KK. Effect of antipsychotic treatments on reproductive function.
Presented at: 2nd World Congress on Women’s Mental Health; March
19, 2004; Washington, D.C.
39. Discontinuing antipsychotic where appropriate .
Reducing the dose of the antipsychotic for stable patients.
If dose reduction fails, switching to a prolactin-sparing antipsychotic
should be considered.
When dose reduction has failed and switching agents is not an
option, patients who need to remain on a prolactin-elevating
antipsychotic may be treated with dopamine agonists.
Amantadine (200 to 300 mg/day in divided doses), cabergoline
(0.25 to 1mg once a week) and bromocriptine (2.5 to 15 mg/day
administered twice a day), have all been used but are associated
with side-effects and may provoke or worsen psychosis.
Cabergoline appears to have greater efficacy and fewer psychiatric
adverse effects than bromocriptine in patients with antipsychotic-
induced hyperprolactinaemia.
40. Miller 2004 dopamine agonist therapy is not generally advisable
Tollin 2000 though successful cases are reported of risperidone-
induced hyperprolactinemia treated with the addition
of either cabergoline or bromocriptine, without
worsening psychotic symptoms
Smith 1992 bromocriptine, confirmed to be effective in reducing
hyperprolactinemia and resolving
amenorrhea/oligomennorrhea in schizophrenic
women, should be cautiously considered as a drug
potentially exacerbating acute psychosis
Frye et al
1982
other treatment approaches should be suggested for
neuroleptic-induced hyperprolactinemia and
associated manifestations
41. During antipsychotic treatment, prolactin
concentrations can rise to ten times normal levels or
above.
Existing data indicate that 17-78% of female patients
have amenorrhoea with or without galactorrhoea.
Survey data, however, suggest that clinicians
underestimate the prevalence of these conditions.
Long-term consequences of antipsychotic-related
hypo-oestrogenism require further research but are
likely to include premature bone loss.
Antipsychotic-induced hyperprolactinaemia should
become a focus of interest in the drug treatment of
psychiatric patients.
