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Upol.czEuropean Journal of Neurology 2004, 11: 483–488 Pergolide mesylate can improve sexual dysfunction in patientswith Parkinson’s disease: the results of an open,prospective, 6-month follow-up M. Pohankaa, P. Kanˇovsky´b, M. Baresˇb, J. Pulkra´bekb and I. RektorbaDepartment of Sexology, Teaching Hospital, Brno Bohunice; and bFirst Department of Neurology, Masaryk University, St Anne Hospital, One of the most disabling problems in males suﬀering from advanced Parkinson’s disease (PD) is complex sexual dysfunction. The eﬀect of dopamine replacement or dopaminergic stimulation on sexual dysfunction has been recently examined anddescribed in patients treated by L-DOPA or apomorphine. Pergolide mesylate is another dopamine agonist with a known high aﬃnity to hD(2S) subtype and a lower aﬃnity to hD(2L) subtype of D2 dopaminergic receptors. It has been repeatedlyshown to be a highly eﬀective treatment of the complicated and advanced stages ofPD. The current study has been designed to assess its eﬃcacy in the treatment ofsexual dysfunction, which frequently accompanies the complicated stage of PD inmales. Fourteen male patients suﬀering from PD, each of whom had been treated withL-DOPA, and in whom additional treatment with peroral dopaminergic agonist (DA)was needed, were followed for a 6-month period. Pergolide mesylate (Permax) wasgiven to each patient, and titrated to a total daily dose of 3 mg. All of the patients weretaking L-DOPA. The assessments performed before the start of pergolide treatmentconsisted of a neurological examination, including Uniﬁed Parkinson’s Disease RatingScale (UPDRS) III and IV subscales scoring, Mini Mental State Examination(MMSE) scoring, the neuropsychological examination including Zung scale scoring toexclude depression, biochemical and haematological examinations including theexamination of prolactine serum levels; and a sexological examination during whichthe patients ﬁlled-in the International Index of Erectile Function (IIEF) questionnaire.
These examinations were repeated during the control assessments at months 1, 3 and6. To compare the examination results, ANOVA, Friedmann’s ANOVA (non-parametric)and Tukey post hoc tests were used. There were statistically signiﬁcant diﬀerencesbetween the values of UPDRS III motor subscale, UPDRS IV (complications oftherapy) subscale and all subscales of IIEF when months 0 and 1 were compared withthe results obtained at months 3 and 6. The diﬀerences between months 0 and 1 andmonths 3 and 6 (in these items) were virtually insigniﬁcant. In conclusion, pergolidesubstantially improved sexual function in the younger male patients who were stillinterested in sexual activities. In such cases, the introduction of pergolide might be abetter choice than treatment with sildenaﬁle, which usually meets several contraindi-cations in common PD male population.
2002). It has been repeatedly shown to be a highly eﬀective and relatively safe treatment of the complica- Pergolide mesylate is an ergolinic dopamine agonist ted and advanced stages of Parkinson’s disease (PD) with a known high aﬃnity (100% when compared with (Olanow and Alberts, 1987). Recently, its eﬃcacy and natural dopamine) to hD(2S) subtype, and a lower tolerability have also been proven when it is used as a aﬃnity (80%) to hD(2L) subtype of D2 dopaminergic monotherapy in the early stage of the disease (Hunde- receptors (Millan et al., 2002; Newman-Tancredi et al., mer et al., 2000; Nausieda et al., 2002). Its pharmaco-logical proﬁle, more than 8-hour duration of action ondopamine receptors, and general tolerability createpergolide’s most important advantages (Baresˇ et al., Correspondence: Doc. MU Dr Petr Kanˇovsky´ CSc, First Department of Neurology, Masaryk University, St Anne Hospital, Pekarˇska´ 53, One of the most disabling problems in males suﬀering 656 91 Brno, Czech Republic (tel/fax: +420 5 4318 2624;e-mail: email@example.com, firstname.lastname@example.org).
from advanced PD is complex sexual dysfunction (Melis and Argiolas, 1995). The eﬀect of dopamine ishment following dopaminergic treatment in seven of replacement or dopaminergic stimulation on sexual 32 patients treated with dopaminergic agonist pergolide dysfunction has been examined and described in (Kanˇovsky´ et al., 2002). This observation kindled a patients treated by L-DOPA (Uitti et al., 1989; Cum- greater interest in this phenomenon, and we prepared mings, 1991; Rosen and Ashton, 1993; Weinman and an open, prospective study. To assess male sexual Ruskin, 1995; Jimenez-Jimenez and Tallon-Barranco, functions, we decided to use the validated questionnaire 1999) and apomorphine (O’Sullivan and Hughes, 1998).
ÔInternational Index of Erectile FunctionÕ (IIEF), which Sildenaﬁle, phospohodiesterase (PDE-5) – ﬁve selective is also available in national language, and which is, in inhibitor, probably the most commonly used drug for our opinion, better and less biased than the QoSL-Q the treatment of erectile dysfunction, can meet several (Rosen et al., 1997, 1999, 2002; Lukacs, 2001).
contraindications in common PD population, i.e. thehypertension or coronary heart disease with angina In the 1990s, a study was published that focused on All of the patients were well acquainted with the study, the sexual functions (or rather dysfunctions) of young and they all gave their informed consent. The study patients suﬀering from PD, both male and female protocol was approved by the institute’s ethical (Wermuth and Stenager, 1995). The method (already validated) of a structured interview and structured Fourteen male patients participated in the study. All questionnaire was used. There were 15 males and 10 of the patients suﬀered from PD, and were diagnosed females examined, all over 36-years old. The most on the basis of the UK–Parkinson’s Disease Brain Bank important ﬁnding was that the females were signiﬁ- criteria (Hughes et al., 1992); another inclusion criteria cantly more aﬀected: a decrease of libidinous functions were the normal cognition, assessed by neuropsycho- was reported by 40% of male patients, but, interest- logical examination, existing sexual relationship, cur- ingly, by 70% of female patients. Similarly, a signiﬁcant reduction of common daily sexual activities was Arzneimittel, Hamburg, Germany; NalcohÒ, CEK reported by 30% of male patients, but these activities Pharma, Ljubljana, Slovenia), and the intent to treat were reported to be signiﬁcantly reduced by more than the patients with dopaminergic agonist.
The mean age of patients was 58.2 (SD ¼ 9.9) years; Another important study also reviewed sexual dys- the mean age at the disease onset was 50.8 years function in PD, although the role of dopaminergic (SD ¼ 10.1); the mean duration of disease was medication was only brieﬂy mentioned (Lambert and 7.3 years (SD ¼ 3.6). All of the patients were treated Waters, 1998). Several years later, a psychosocial study with L-DOPA; the mean duration of L-DOPA treat- was published that dealt with the impact of PD on all ment was 5.9 years (SD ¼ 2.7), and the mean daily aspects of the daily activities (including sexual activity) dose of L-DOPA was 783.6 mg (SD ¼ 412.7).
of young women aﬀected by the disease (Posen et al., All of the patients were in the advanced, ﬂuctuating 2000). Probably the deepest insight into sexual dys- stage of disease, and all of them experienced frequent function in PD patients was brought by a study pub- daily Ôon-oﬀÕ ﬂuctuations with dyskinesias or Ôwearing- lished last year, in which sexual life quality was assessed oﬀÕ of the L-DOPA dose. The mean duration of this in more than 90 patients (Moore et al., 2002). For the advanced, complicated stage of disease (measured evaluation of sexual functions, the structured Quality of from the ﬁrst occurrence of the mentioned symptoms) Sexual Life Questionnaire (QoSL-Q) was used. The was 2.9 years (SD ¼ 1.7). This situation led to the quality of life was assessed using the Parkinson’s Dis- introduction of pergolide mesylate to the treatment.
ease Quality of Life (PDQ-39) questionnaire. The Prior to the start of pergolide treatment (month 0), quality of the sexual life, as assessed by the QoSL-Q, the following examinations were performed: clinical was signiﬁcantly decreased in all patients. It signiﬁ- neurological examination, magnetic resonance imaging cantly worsened with the disease progression and with (MRI) examination of the brain, biochemical and aging. However, no correlation between the results haematological examinations, plasma prolactine level, revealed using the PDQ-39 and those revealed by neuropsychological examination and Zung scale scor- QoSL-Q has been found. The authors recommended ing (to exclude dementia, depression, or signiﬁcant implementing the QoSL-Q into the common QOL test cognitive decline), Mini Mental State Examination battery, because PDQ-39 does not suﬃciently address (MMSE), Uniﬁed Parkinson’s Disease Rating Scale (UPDRS) III and UPDRS IV scoring, and all subscales When these ﬁndings were published, we had observed of the International Index of Erectile Function ques- the phenomenon of sexual dysfunction and its dimin- tionnaire (IIEF). The IIEF subscales and their point Ó 2004 EFNS European Journal of Neurology 11, 483–488 Improvement of sexual dysfunction in patients with Parkinson’s disease ranges are presented in Appendix. The side eﬀects of treatment were also recorded using a checklist.
Pergolide mesylate (PermaxÒ, Eli Lilly, Basingstoke, UK) was added to the stable L-DOPA dose and was titrated in all patients to a total daily dose of 3 mg. The titration lasted (according to the classical schema)28 days. The control visits were carried out at month 1 (at the end of titration period), at month 3 (titrationperiod + 2 months) and at month 6 (titration per- iod + 5 months). The examinations performed atmonth 0 were repeated at each control visit, except the brain MR. The examination of the prolactine plasmalevels were done only at months 3 and 6. Treatment continued after the month 6 visit. The study protocol decreed that in case of side-eﬀects, the withdrawal of pergolide was possible at any moment during the fol-low-up.
Figure 1 The ﬁgure illustrating the changes in the mean value The mean values of the items being tracked were of IIEF subscale Ôerectile functionÕ. SE, standard estimation; SD,standard deviation; M, months.
calculated at each follow-up visit. ANOVA, non-para-metric Friedmann’s ANOVA, and post hoc Tukey testswere used for the statistical analysis of the results.
The results are presented in Table 1 and Figs 1–5.
There were no biochemical or haematological value abnormalities present in any patient during the study.
The prolactine plasma level varied in all patients Table 1 The mean values of UPDRS III and IV, L-DOPA daily dose,MMSE, Zung scale, prolactine level, and IIEF subscores at months 0,1, 3, and 6 Figure 2 The ﬁgure illustrating the changes in the mean value of IIEF subscale Ôorgasmic functionÕ. SE, standard estimation; between 0.9 and 7.1 ng/ml (mean 3.9, SD ¼ 3.3) prior to pergolide treatment. There was a decrease of mean prolactine levels when the values between months 0, 3 and 6 were compared. There was no possibility ofestablishing statistical signiﬁcance, because the prolac- *The values, which are signiﬁcantly different at the level P < 0.00000, tine levels at months 3 and 6 reached <0.5 ng/l (under which the laboratory methods are not able to diﬀer- UPDRS III, Uniﬁed Parkinson’s Disease Rating Scale – Motor entiate); thus, the plasma level of prolactine was Subscore (III); UPDRS IV, Uniﬁed Parkinson’s Disease RatingScale – Complications Subscore (IV); L-DOPA Dose, daily dose of L-DOPA preparation (SinemetÒ, MadoparÒ, IsicomÒ, or NakomÒ) The UPDRS III score (measured when the patients expressed in milligrams of L-DOPA only (without dopa-decarboxylase were ÔONÕ) at month 0 was 35.7 points, and there was a inhibitor); MMSE, Mini Mental State Examination (according to statistically signiﬁcant (P < 0.001) diﬀerence when it Folstein et al.); Zung, Zung depression scale; Prolactine, prolactine was compared with the value at month 1. Nevertheless, levels in ng/ml in the blood plasma; IIEF, International Index ofErectile Function.
the level of statistical signiﬁcance was P < 0.00000 Ó 2004 EFNS European Journal of Neurology 11, 483–488 Figure 5 The ﬁgure illustrating the changes in the mean value Figure 3 The ﬁgure illustrating the changes in the mean value of IIEF subscale Ôoverall satisfaction with sex lifeÕ. SE, standard of IIEF subscale Ôsexual appetenceÕ. SE, standard estimation; estimation; SD, standard deviation; M, months.
There were statistically signiﬁcant changes in the mean values of all subscales of International Index ofErectile Function (the subscales and their point ranges are listed in the Appendix). The diﬀerences between thevalues at month 0 and month 1, and also between the values at month 3 and month 6 were minimal, without statistical signiﬁcance. In contrast, there were diﬀer-ences at statistical level P < 0.00000 in the mean values of all subscales when comparing month 0 and month 3, The diﬀerences between mean IIEF values (and their Practically no adverse or side-eﬀects were reported that might have led to the withdrawal of pergolide. Two patients reported increased daily sleepiness (withoutsleep attacks) during the ﬁrst month of the pergolide Figure 4 The ﬁgure illustrating the changes in the mean value of treatment, which disappeared within following 3 weeks.
IIEF subscale Ôsatisfaction with sexual intercourseÕ. SE, standardestimation; SD, standard deviation; M, months.
when the values at month 3 and 6 were compared with The results of our prospective (albeit open) study con- the value at month 0 (measured also when the patients ﬁrmed our initial observation, that pergolide can were ÔONÕ). The UPDRS IV subscore, measuring impressively improve disturbed sexual functions in men mainly the presence and duration of dyskinesias and suﬀering from PD (Kanˇovsky´ et al., 2002). From our ÔOFFÕ periods was improved at months 3 and 6; the clinical experience, it seems that action of pergolide in diﬀerence was statistically signiﬁcant only when the this ﬁeld is the best of the commonly used peroral mean value at month 0 was compared with values at dopamine agonists (however, such evidence still cannot months 3 and 6. There was a slight tendency to decrease be found in any medical database). Why pergolide the daily L-DOPA intake in all patients; however, the produces such results is not completely clear. It is diﬀerences of mean L-DOPA daily doses were not probably not due to pergolide-induced suppression of signiﬁcant when the values at months 0, 1, 3, and 6 were prolactine secretion, because in all of our patients the compared. The mean value of the MMSE score plasma levels of prolactine prior to pergolide treatment remained stable. The mean values of the Zung score were below the usual mean levels, and at the lower end remained practically identical as before treatment, of the normal laboratory range (2.8–19.2 ng/ml). It is showing no tendency to increase or decrease.
not clear whether this was caused by the disease itself, Ó 2004 EFNS European Journal of Neurology 11, 483–488 Improvement of sexual dysfunction in patients with Parkinson’s disease or by the previous L-DOPA treatment. Such eﬀect of L-DOPA has been repeatedly described, but its clinical Allard J, Giuliano F (2001). Central nervous system agents in relevance is (at least) doubtful (Franchimont et al., the treatment of erectile dysfunction: how do they work? 1976). Nevertheless, the behaviour and the role of prolactine and its plasma levels in males under stressful Baresˇ M, Rektor I, Kanˇovsky´ P et al. (2001). Pergolide conditions (which chronic disease undoubtedly is) has mesylate (PermaxÒ) in the add-on treatment of Parkinson’sdisease: six months, open, prospective follow-up (Czech).
only rarely been studied (Sivik et al., 1997), and Cˇes Slov Neurol Neurochir 64:231–236.
deserves deeper physiological research in the future.
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speciﬁc subtypes of dopaminergic receptors. It has been Folstein MF, Folstein SE, McHugh PR (1975). ‘‘Mini-mental already speculated by other authors that dopamine state’’. A practical method for grading the cognitive state of agonists act in male sexual dysfunction by the direct patients for the clinician. J Psychiatr Res 12:189–198.
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1999). Being aware of the speciﬁc action of pergolide on Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992). Accuracy the subtypes of dopaminergic receptors mentioned in of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Tancredi et al., 2002), it should be possible that a spe- ciﬁc subtype of D-2 dopamine receptor exists also in the Hundemer HP, Lledo A, van Laar T et al. (2000). The safety of pergolide monotherapy in early stage Parkinson’s human paraventricular nucleus. In such a case, pergo- disease. One-year interim analysis of a 3-year double-blind, lide may have a speciﬁc aﬃnity for this receptor, and randomized study of pergolide versus levodopa. Mov Disord can thus improve sexual dysfunction in this way better than other peroral and parenteral dopamine agonists.
Jimenez-Jimenez FJ, Tallon-Barranco A (1999). Fluctuating However, to support this hypothesis, we would need, penile erections related with levodopa therapy. Neurology52:210–212.
together with animal studies, clinical evidence from a Kanˇovsky´ P, Baresˇ M, Pohanka M, Rektor I (2002). Penile large number of male patients, studied in a double-blind erections and hypersexuality induced by pergolide treat- ment in advanced, ﬂuctuating Parkinson’s disease. J Neurol What remains as a proven clinical observation generated by our study is the fact that pergolide Lambert D, Waters CH (1998). Sexual dysfunction in Parkinson’s disease. Clin Neurosci 5:73–77.
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This study was supported by Research Project MSMTCR No. 112801.
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Sivik T, Delimar D, Korenjak P, Delimar N (1997). The role of blood pressure, cortisol, and prolactine among soldiers IIEF V: overall satisfaction with sex life (range 0–10) Ó 2004 EFNS European Journal of Neurology 11, 483–488
General Certificate of EducationJune 2003Advanced Level Examination CHEMISTRY Unit 6a Synoptic Assessment In addition to this paper you will require: Instructions • Use a black ball-point pen. Do not use pencil. • Fill in the boxes at the top of this page. • Answer all 40 questions. • For each item there are four responses. When you have selected the response which you thin