Therapeutic effects of
Lisuride in hyperprolactinemic infertile women
Dr. Kawa Dizaye *
Dr. Hemn O. AhmedAL-Qashqay
Dr. Emil N. Azzo
ABSTRACT
The study has been conducted on 50 hyperprolactinemic infertile women aged
between 19 and 40 years and 30 controls aged between 21 and 35 years. All patients
complained of infertility with or without galactorrhea, oligomenorrhoea and amenorrhea.
The effects of lisuride on serum prolactin concentration, luteinizing hormone (LH) and
follicle stimulating hormone (FSH) at day 2 of menstrual cycle, thyroid stimulating
hormone (TSH), and progesterone at day 21 of menstrual cycle and kidney function
parameters before and after four months were studied. All the patients were clinically
examined by a gynecologist and patient complaints including galactorrhea, amenorrhea
or oligomenorrhea have been recorded before and after drug administration. This study
was conducted from 15 November 2008 to 30 July 2009 in the Azadi General Hospital in
Kirkuk city. Data obtained from the study revealed a significant drop of serum prolactin
concentration after lisuride therapy. Normoprolactinemia has been achieved in 98% of
women treated with lisuride and 46% of them become pregnant, while galactorrhea
disappeared in 93.71% and restoration of normal menstrual cycle was noted in 81.81%.
No significant changes in kidney function parameters were noted. No correlation
between serum prolactin concentration and LH, FSH, TSH have been reported before
and after drug therapy, but a significant inverse correlation was noted between serum
prolactin concentration and serum progesterone concentration.
The study concludes that lisuride significantly reduces prolactin levels to normal
values and improves fertility and ameliorates symptoms of hyperp rolactinemia and
significantly increases serum progesterone level but within normal value s. In addition it
had no undesirable effects on kidney function parameter
KEY WORDS: Lisuride , Hyperprolactinemia, Infertile Women.
Correspondence
Dr. Kawa Dizaye.
Assist. Prof. of Pharmacology.
Head of department of Pharmacology
College of Medicine- Hawler Medical University- Erbil- Iraq.
dr_kawadizaye@yahoo.com (009647504452392).
1
INTRODUCTION:
Hyperprolactinemia is the most common endocrine disorder of the hypothalamicpituitary axis. It occurs more frequently in women than in men. Clinical symptoms are
amenorrhea, infertility, and galactorhea in women and decreased libido and impotence in men
(1,2) and in some cases, gynecomastia (3) Often but not invariably it is associated with
microadenoma (4) of the anterior pituitary gland. Hyperprolactinemia is the commonest
pituitary cause of amenorrhea.
There are many other causes of a mildly elevated serum prolactin (PRL) concentration such
as stress and physical and breast examination. Hyperprolactinemia may result from a PRL
secreting adenoma (5, 6) or from a non-functioning disconnection, tumour in the region of the
hypothalamus or pituitary, which disrupts inhibitor influence of dopamine on PRL secretion.
Hyperprolactinemia could also be because of hypothyroidism, polycystic ovarian syndrome
and several drugs, i.e. the dopaminergic antagonists like phenothiazines, domperidone and
metoclopramide.
The management of hyperprolactinemia centers on the use of dopamine agonists (7, 8).
Most patients show a fall in PRL levels within a few days to a few weeks of commencing the
therapy (9, 10). Bromocriptine is considered the gold standard for dopamine agonist therapy;
however it is associated with a range of side effects, leaving some patients intolerant to
treatment (11). Furthermore, its half-life is short so that it must be given two or 3 times daily
(12). Bromocriptine administrated via the vaginal route may reduce incidence of side effects
and offer an alternative to the oral form (13).
Lisuride in contrast to all other marketed ergot-derived drugs, is an 8-αergoline (iso-ergoline), which is a structure, not found in natural ergot. It is a very
potent peripheral serotonin (5-HT) antagonist used for migraine prophylaxis. Lisuride
was also discovered to be a potent dopamine agonist for the treatment of
hyperprolactinemia and pituitary tumours and Parkinson’s disease (14).
Data concerning comparison before and after Lisuride therapy on serum PRL level and
symptoms due to hyperprolactinemia and other related hormones and data concerning the
effects of Lisuride on kidney function are scanty.
The aim of the present study was designed to compare the effects before and after Lisuride
therapy on serum PRL level and other related hormones, symptoms of hyperprolactinemia
and kidney function parameters in infertile patients.
MATERIALS AND METHODS
This study was conducted from 15 November 2008 to 30 July 2009 to compare the
effects of 4 months treatment with Lisuride (Dopergin ®, 0.2 mg tablets, manufactured by
Schering AG, Germany) before and after, on serum prolactin level and other related
hormones, symptoms of hyperprolactinemia and kidney function parameters in infertile
patients. The patients were recruited from Azadi General Hospital Department of Obstetrics
and Gynecology in Kirkuk city.
Patients
The study involved 50 patients, with ages ranging between 19 and 40 years (mean=
28.76). All were infertile with or without amenorrhea, oligomenorrhoea and galactorrhea.
Their serum prolactin concentration was over the normal range which was considered 5-35
ng/ml by minividus.
2
Exclusion criteria
Patients with presence of pituitary macroadenoma, disorders that could prevent normal
menstruation, hyperprolactinemia related to polycystic ovary disease, thyroid or adrenal
disorder, renal or hepatic disease, history of allergy to ergot derivatives, women using drugs
that affect secretion of prolactin from the pituitary such as neuroleptics and any other
diseases, were excluded from the study.
Controls
Thirty healthy volunteer women were also included in the study as a control group.
Their age ranged between 21-35 years with mean=28.26.
Doses of Lisuride
Patients received 0.1 mg of Lisuride on the first day at night and 0.1mg in the
morning and evening on the second day and 0.1 mg three times daily from day three and
onwards.
Sampling
Five ml of blood was taken from each patient and control every visit, using
disposable syringes. The blood was allowed to clot in a plain tube at room temperature and
then serum was separated by centrifugation at 3000 rpm for three minutes. The serum was
then used for estimating renal function tests (blood urea and serum creatinine by ELIZA),
serum prolactin and TSH at any time of menstrual cycle and serum LH and FSH on the
second or third day of the menstrual cycle and serum progesterone levels at day 21 of the
menstrual cycle by minividus (ELFA).
Statistical analysis
All data are expressed as means± standard error means (M±SEM) and statistical
analysis was carried out using statistically available software (SPSS Version 11.5). Statistical
analyses were carried out using one-way analysis of variable (ANOVA) and Chi-square test.
The comparison between groups was done using Duncan test.
RESULTS
Effect of Lisuride on serum prolactin level in hyperprolactinemic infertile patients
Serum prolactin level was reduced from 52.42 2.56 to 17.05 1.79 after 2 weeks of
Lisuride administration which is statistically significant and to 8.931.12 after 4 months
which is also significant as shown in Table 1.
Table 1: Serum prolactin level in healthy subjects (n=30) and in patients before and
after treatment with Lisuride (n= 50 patients).
Parameters
Healthy
N=30
Prolactin
(ng/ml)
9.391.23 a
Mean SE
Before Lisuride
After 2 weeks
N=50
of Lisuride
52.42 2.56 c
17.05 1.79 b
after 4 months
of Lisuride
N=50
8.931.12 a
The different letters indicate there is significant difference at P < 0.05
Effect of Lisuride on serum LH, FSH and TSH levels
Lisuride had no significant effects on serum LH, FSH and TSH level but there was a
significant difference between serum FSH level of healthy subjects and patient before
Lisuride as shown in Table 2.
3
Table 2: Serum LH, FSH and TSH of the healthy subjects (n=30) and patients before
and after treatment with Lisuride (n=50).
Parameters
Healthy
Mean SE
Before Lisuride
after 4 months of Lisuride
LH (µIu/ml)
5.080.34 a
4.500.27 a
4.650.27 a
FSH (µIu/ml)
5.480.36 a
4.550.24 b
4.930.27 ab
TSH (µIu/ml)
2.100.20 a
1.670.11 a
1.960.13 a
The different letters mean there is significant difference at P < 0.05
Effect of Lisuride on serum progesterone in hyperprolactinemic women
Lisuride was increasing serum progesterone level from 3.480.64 ng/ml to
10.981.03 ng/ml after four months of therapy which is statistically significant as shown in
Table 3.
Table 3: Serum progesterone concentration in healthy subjects (n=30) and patients
before and after treatment with Lisuride (n=50).
Parameters
progesterone
Mean SE
Healthy
Before Lisuride
7.860.76
after 4 months of Lisuride
3.480.64
p-value
<0.05
10.981.03
Effect of Lisuride on fertility
Lisuride significantly improves fertility in hyperprolactinemic infertile womeO Table
4 shows that 44% of the patients become pregnant after four months of Lisuride
administration which is statistically significant.
Table 4: outcome of Lisuride on hyperprolactinemic infertile women (n=50)
Before Lisuride
After 4 months of Lisuride
Improved
p-value
Pregnancy
No.
%
No.
%
%
0
0%
23
46%
46%
<0.001
Effects of Lisuride on female menstrual cycle and hyperprolactinemia-galactorrhea
syndrome
Lisuride returned menstrual cycle to a normal state as shown in Table 5. It
significantly eliminated galactorrhea in hyperprolactinemic patients.
4
Table 5: Effect of Lisuride on syndromes of hyperprolactinemia (n=50)
Syndromes
Amenorrhea
Before
No.
Oligomenorrhoea
Galactorrhea
After
%
No.
Improved
p-value
%
%
3
6%
1
2%
66.66%
NS
8
16%
1
2%
87.5%
<0.05
16
32%
1
2%
93.75%
<0.001
NS= Not Significant
Side effects of Lisuride on the patients
Lisuride has side effects; nausea and dizziness were the most prominent side effects
in this study as shown in Table 6.
Table 6: Adverse effects of Lisuride, (noted in 15 women) during the period of study
(n=50).
Adverse Effects
Lisuride (n=50)
No.
%
Nausea
13
26%
0.001
Vomiting
2
4%
NS
Headache
8
16%
<0.01
Dizziness
13
26%
<0.001
p-value
Effects of Lisuride on kidney functions parameters
Lisuride had no significant effect on kidney function parameters after four months of
administration in hyperprolactinemic infertile patients as shown in Table 7.
Table 7: Kidney function parameters in healthy subjects (n=30), cases before and after
four months treatment with Lisuride (n=50).
Urea (mmol/L)
3.380.20
Mean SD
Before
Lisuride
4.190.11
Creatinine (µmol/L)
73.60.24
70.551.82
70.661.78
NS
CCl (ml/min)
96.810.95
112.522.94
112.202.92
NS
Parameters
Healthy subject
after 4 months of
Lisuride
4.230.12
p-value
NS
The relationship between serum prolactin and serum progesterone
There is an inverse relationship between serum prolactin and progesterone level in
hyperprolactinemic infertile patients Figure 1 shows that the serum progesterone level
5
significantly increased and serum prolactin level significantly decreased after four months of
Lisuride therapy.
Figure 1: Relationship between serum prolactin and progesterone concentration
DISCUSSION
Prolactin (PRL) is under dual regulation by hypothalamic hormones delivered
through the hypothalamic-pituitary portal circulation. Under most conditions the
predominant signal is inhibitory, preventing PRL release, and is mediated by the
neurotransmitter dopamine. The stimulatory signal is mediated by the hypothalamic
hormone thyrotropin-releasing hormone. The balance between the 2 signals determines
the amount of PRL released from the anterior pituitary gland (6). Dopamine agonist is a
compound that activates dopamine receptors, mimicking the effect of the
neurotransmitter dopamine able to lower PRL levels, and restore ovarian function (15).
Dopamine agonists have become the treatment of choice for the majority of patients with
hyperprolactinemic disorders. Lisuride is an ergot derivative with high dopamine agonist
potency. On the basis of pharmacological tests it was suggested that the unchanged drug
and not a metabolite was responsible for this activity. Low doses of Lisuride were shown
to stimulate dopaminergic receptors. One of the most important effects of Lisuride in
humans appears to be to lower the endogenous PRL level in plasma, which is presumably
mediated by its dopaminergic activity in the central nervous system (16).
This study showed that Lisuride significantly reduced serum PRL level to normal
value after two weeks and four months of administration as shown in Tables 1-3. This
agrees with other studies that showed similar effects in hyperprolactinemic patients (17,
18).
Hyperprolactinemia and anovulation may be associated with primary
hypothyroidism. Enlargement of the pituitary gland is frequently seen in long-standing
primary hypothyroidism. A number of mechanisms may be involved. Firstly, the
clearance of PRL tends to be decreased in hypothyroidism. Secondly, patients with
severe hypothyroidism may have elevated total and free estradiol levels, giving rise to
increased PRL production stimulated by excess free estrogen. Thirdly, and possibly most
significantly, the mechanism involves the inhibitory effects of T3 on TRH production
and on thyroid releasing hormone (TRH) receptor expression. A decrease in T3 feedback
in hypothyroidism may induce an increase in hypothalamic TRH production and in the
number of TRH receptors in the lactotroph. Increased TRH action on the lactotroph, in
turn, may stimulate PRL secretion (19).
6
On the contrary Lisuride had no significant effects on serum LH, FSH and TSH
before and after four months of its administration in hyperprolactinemic infertile patients
as shown in Table 2-3 which agrees with a study carried by Koizumi (20) who showed
that there were no significant changes on the secretion of anterior pituitary hormones
(LH, FSH and TSH) after administration of Lisuride.
Dopamine agonist treatment has been reported to correct luteal phase defect
associated with hyperprolactinemia (21). If galactorrhea is present, even if the PRL is
normal, ovulatory dysfunction responds well to dopamine agonist therapy. In the absence
of galactorrhea, a PRL elevation may be subtle (such as an increase in nocturnal peaks),
and this could explain occasional good responses to dopamine agonist treatment (22).
This study again demonstrated that Lisuride significantly increased luteal
progesterone secretion and decreased serum PRL level in hyperprolactinemic patients
after four months of treatment as shown in Tables 3 and this result agrees with other
studies (23,24) that showed that Lisuride significantly increased luteal progesterone
secretion and decreased serum PRL level after four months of treatment. Figure 1
showed a significant inverse correlation between serum PRL and serum progesterone
level. At the same time, no significant correlations where found between serum PRL and
serum LH, FSH and TSH.
Hyperprolactinemia is usually associated with anovulation, as exemplified by
postpartum lactational amenorrhea and the galactorrhea-amenorrhea syndrome. Increased
levels of PRL inhibit the hypothalamic-pituitary-ovarian axis. Both opioid peptides and
hypothalamic dopamine regulate the pulsatile secretion of luteinizing hormone releasing
hormone (LHRH). Hyperprolactinemia inhibits LHRH activity by interacting with the
hypothalamic dopaminergic and opioidergic systems through a short-loop feedback
mechanism or by a direct effect on LHRH neurons, in which PRL receptors are
expressed. Both possibilities are consistent with the observation that suppression of PRL
by the dopamine receptor agonist restores ovulatory function (25).
This study showed that Lisuride improved fertility in most infertile women due
to hyperprolactinemia via restoring ovarian function. Table 4 indicated that 46% of the
cases became pregnant after four months of Lisuride treatment which agrees with other
studies which showed that more than one third of hyperprolactinemic infertile patients
became pregnant after 4 months of using Lisuride (26).
Amenorrhea is sometimes associated with elevated PRL levels and this is due to
PRL inhibition of the pulsatile secretion of gonadotropine releasing hormone (GnRH).
The pituitary glands in these patients respond normally to GnRH (27). Nevertheless,
treatment that lowers the circulating levels of PRL restores ovarian responsiveness and
menstrual function. This is true whether the treatment consists of removal of a prolactinsecreting tumor or suppression of PRL secretion. Interestingly, postmenopausal women
with elevated levels of PRL do not experience vasomotor symptoms (hot flushes) until
PRL levels are restored to normal (28).
Moreover this study showed that Lisuride effectively restored normal menstrual
cycle in 66.66% of amenorrhic patients and 87.5% of oligominorrhic patients due to
hyperprolactinemia as shown in Table 5. This agreed with the results of other researches
which showed restoration of menstrual cycle in more than 80% after three months of
Lisuride therapy (29, 24, and 26).
The most common cause of galactorrhea is hyperprolactinemia (30). It is likely
that most patients with so-called idiopathic galactorrhea with amenorrhea harbor
microprolactinomas. Fifty-percent of patients with acromegaly also have
hyperprolactinemia. Even in the absence of hyperprolactinemia, human GH is a potent
lactogen and can cause galactorrhea when elevated (31). Treating the underlying cause of
7
galactorrhea is usually effective. Treating prolactinomas with dopamine agonists reduces
tumor size and PRL, and alleviates galactorrhea. If a pituitary tumor is not PRLsecreting, high PRL levels are normalized and galactorrhea is reduced by dopamine
agonists but the underlying disorder is not addressed. For medication-induced
galactorrhea, an alternative medication might be tried. Galactorrhea related to
hypothyroidism should be treated with thyroid hormone replacement. If the galactorrhea
is entirely due to inadequate thyroid hormone, thyroxin (T4) therapy should normalize
both TSH and PRL secretion and suppress nonpuerperal galactorrhea (32).
Furthermore Lisuride effectively and significantly improved patients who
presented with galactorrhea. In this study 32% of the cases presented with
hyperprolactinaemia - galactorrhea syndrome and more than 93% of these cases
improved as shown in Table 5. This result is similar to other studies which revealed that
Lisuride effectively treated galactorrhea in most patients (33, 26, 17, and 34).
Side effects of dopamine agonists are common. The most serious side effect,
postural hypotension, which can cause loss of consciousness, occurs infrequently and can
often be avoided by careful dosing (35). Dopamine agonists may cause nausea, headache,
lightheadedness, orthostatic hypotension, and fatigue. Psychiatric manifestations
occasionally occur even at lower doses and may take months to resolve. Erythromelalgia
occurs rarely. High dosages of ergot-derived preparations may cause cold induced
peripheral digital vasospasm. Pulmonary infiltrates may occur with chronic high-dosage
therapy. Dopamine agonist therapy during the early weeks of pregnancy has not been
associated with an increased risk of spontaneous abortion or congenital malformations
(10).
Patients using Lisuride in this study developed side effects such as nausea and
dizziness in 26 % of the cases due to stimulation of dopamine receptors which is shown
in Table 6. These side effects were mild and disappeared after a few days. Such findings
are in accord with the findings of other studies that shows that Lisuride has few, and mild
side effects and is more tolerable than bromocriptine (18, 23, 27).
Toxic effects on the kidneys related to medications are both common and
expected. Any drugs have nephrotoxic potential and some of them can cause more than
one pattern of injury (36). Glomerular, tubular and renal interstitial cells frequently
encounter concentrations of medications and their metabolites, which can induce changes
in kidney function and structure. Renal toxicity can be a result of hemodynamic changes,
direct injury to cells and tissue, inflammatory tissue injury, and/or obstruction of renal
excretion. Detection is often delayed until an overt change in renal functional capacity is
measured as an increase in serum blood urea, nitrogen or creatinine (37).
Lisuride had no significant effects on kidney function parameters (blood urea,
serum creatinine, creatinine clearance) as shown in Table 7 because only 0.05% of the
dose excreted unchanged in urine in 24 hours (38). Review of the literature showed no
study to agree or disagree with this finding.
CONCLUSIONS
1. Hyperprolactinemia is one of the important causes of female infertility.
2. Lisuride is one of the dopamine agonists that significantly decrease serum prolactin
level to normal value.
3. Lisuride restores ovarian function and induces ovulation so that improves infertility
due to hyperprolactinemia.
4. Lisuride regulates menstrual cycle abnormalities due to hyperprolactinemia.
5. Lisuride has no significant effect on serum LH, FSH and TSH levels.
8
6. Lisuride significantly increases luteal progesterone secretion especially in women
with corpus luteum insufficiency.
7. Lisuride has no undesirable effects on kidneys, so it can be used safely.
8. Lisuride has mild and tolerable side effects.
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