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 8.931.12 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) 9.391.23 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 8.931.12 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) 5.080.34 a 4.500.27 a 4.650.27 a FSH (µIu/ml) 5.480.36 a 4.550.24 b 4.930.27 ab TSH (µIu/ml) 2.100.20 a 1.670.11 a 1.960.13 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 3.480.64 ng/ml to 10.981.03 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 7.860.76 after 4 months of Lisuride 3.480.64 p-value <0.05 10.981.03 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) 3.380.20 Mean  SD Before Lisuride 4.190.11 Creatinine (µmol/L) 73.60.24 70.551.82 70.661.78 NS CCl (ml/min) 96.810.95 112.522.94 112.202.92 NS Parameters Healthy subject after 4 months of Lisuride 4.230.12 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. 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