Abstract
Objective: To examine the effect of 17β-estradiol on the severity of the cardinal signs of PD in postmenopausal women.
Background: Although the impact of estrogens on the manifestations of PD has not been subjected to rigorous study, their use is generally thought to be associated with a detrimental antidopaminergic effect.
Methods: A double-blind, placebo-controlled, two-arm crossover study of high-dose transdermal 17β-estradiol was conducted in eight postmenopausal women with mild to moderate PD, all but one of whom exhibited levodopa-induced dyskinesias. Patients were randomized initially to either hormonal treatment or placebo for 2 weeks, followed by a 2-week washout period, and then another 2-week crossover treatment period. Active treatment employed four skin patches each releasing 0.1 mg of estradiol daily, replaced every 2 to 3 days.
Results: After 10 days of treatment a significant reduction was observed in the antiparkinsonian threshold dose of IV levodopa. Mean duration and magnitude of the antiparkinsonian response to threshold or high doses of levodopa were unchanged, and dyskinesia scores were unaltered during 17β-estradiol treatment compared with placebo. No worsening in “on” time or motor ratings with estrogen treatment was documented.
Conclusions: 17β-estradiol appears to display a slight prodopaminergic (or antiparkinsonian) effect without consistently altering dyskinesias. Standard postmenopausal replacement therapy with transdermal 17β-estradiol is likely to be well tolerated by many female parkinsonian patients.
In addition to its acute effects on symptoms associated with menopause, postmenopausal hormone replacement therapy may reduce the risk of cardiovascular mortality,1 osteoporosis, and perhaps AD.2,3 Given the possible increase in longevity and decrease in neural degeneration associated with estrogen use, estrogen supplementation might benefit parkinsonian patients. However, what little is known about the effects of estrogens on motor function suggests that they have an antidopaminergic effect associated with worsening of parkinsonism.4-6 These observations are difficult to reconcile with the experience of other women who report worsening of parkinsonism and of “off” period dyskinesias following withdrawal or reduction of oral conjugated estrogens,7 and those with cyclic exacerbations of PD symptoms during late luteal and menstrual phases when endogenous estradiol levels are dropping.8-10
Clarifying the effects of estrogens is of clinical interest. Moreover, estrogen effects on parkinsonian symptoms could confound the interpretation of neuroprotective trial results. We conducted a controlled study of estrogen replacement therapy to determine the short-term effects on motor function in parkinsonian women.
Methods.
Study subjects.
Ten women with PD were enrolled under an approved protocol that met the requirements of the National Institute of Neurological Disorders and Stroke institutional review board. Two women, after receiving instructions on the application of the patches, withdrew from the study for administrative reasons. Thus, data from eight patients were analyzed. Patients were otherwise healthy and postmenopausal, and diagnosed clinically with mild to moderate PD (Hoehn & Yahr stages, II to III) without evidence of dementia. Patients already taking hormonal therapy had to be willing to stop therapy for at least 1 month before the start of the study. Patients had to be willing to stop levodopa therapy for at least 12 hours before each inpatient treatment day and to stop dopamine agonist therapy for at least 2 weeks before the start of the study. Patients were excluded if they had a personal history of thrombophlebitis or if there was any personal or family history (first-degree relatives) of breast or gynecologic neoplasm. Patients were also excluded if there was evidence of active cardiovascular disease by history or EKG. All gave informed consent to participate in the study after full disclosure of its potential risks and benefits. Dopamine agonists were withdrawn for at least 2 weeks, and selegiline or preexisting hormonal therapy was withdrawn for at least 2 months before the study. One patient who was unable to stop selegiline was kept on a stable dose throughout the study.
Study design.
The effects of transdermal 17β-estradiol were evaluated in a double-blind, crossover, two-arm study design separated by a 2-week washout period (figure 1).
Figure 1. Participation of patients in the study.
Estradiol administration.
Patients were instructed initially on patch application to ensure compliance. Skin patches of 17β-estradiol (and matching placebo) were obtained from Ciba Pharmaceuticals (Summit, NJ) and dispensed in “blinded” coded wrappings by the NIH Pharmaceutical Development Section. All patients applied four 0.1-mg patches, each of which contained 8 mg of 17β-estradiol designed to deliver 0.1 mg daily through a surface area of 20 cm2. Skin patches were replaced every 3 days (first two patients) or on alternate days (last six patients) to avoid fluctuations in serum estradiol levels. Sites were rotated to avoid local skin irritation. Patients completed diaries every 30 minutes during waking hours twice toward the end of the first week of treatment in each arm of the study. Hormonal status was determined by plasma levels obtained during 17β-estradiol and placebo treatment.
Levodopa challenge.
Starting on the 10th day of the transdermal treatment, each patient was admitted briefly to the NIH Clinical Center to receive various doses of IV levodopa, all preceded by an oral dose of 100 mg carbidopa. Levodopa and placebo boluses were infused over 10 minutes twice daily with a 5-hour interval between doses. Patients were allowed a low-protein (<5 g each) breakfast and lunch before the morning and afternoon doses. The first dose was administered after overnight withdrawal of all antiparkinsonian medications. All patients were rated by the same experienced neurologist (J.F.) in a blinded fashion. Motor responses were assessed frequently using an abbreviated rating scale for parkinsonism (maximal score, 64 points), including subscores for tremor, rigidity, bradykinesia, and gait, and a modified Abnormal Involuntary Movement Scale for dyskinesias (maximal score, 20 points).11 The duration of the clinical response was defined as the time when disability scores were improved by at least 30% over baseline, and response was taken as the mean percentage of improvement during the 30 minutes after the onset of levodopa action. The threshold dose was defined as the lowest dose of levodopa that produced at least a 30% improvement in disability scores, and the high dose was defined as the dose above which no further improvement in disability score was observed. Dyskinesia severity represents the sum of all scores obtained after each infusion until the patient turned “off.”
Biochemical studies.
A lumbar puncture was performed at the end of each treatment phase in four patients at 8:00 AM after overnight bed rest and 12-hour withdrawal of levodopa. A total of 23 mL of CSF was collected in six different tubes, spun at 3,600 g for 10 minutes, and distributed in 4-mL aliquots in plastic vials kept at −80 °C. The same aliquot for each patient (20 to 23 mL) was assayed for 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), 5-hydroxyindoleacetic acid, 3-O-methyl-dopa, and tetrahydrobiopterin (THB). MHPG was measured by high-pressure liquid chromatography with an ESA Coularray electrochemical detection system (ESA, Chelmsford, MA).12,13 THB determinations were obtained with a similar system.14 Plasma estradiol levels were determined by radioimmunoassay through Mayo labs using a kit from Pandex (Santa Monica, CA).
Behavioral and biochemical data collected in each arm of the study are expressed in means ± SEM values and compared using paired t-tests.
Power analysis.
Primary outcome measures were threshold levodopa dose for antiparkinsonian efficacy and threshold levodopa dose for induction of dyskinesias on active treatment versus placebo. An initial sample size of 10 was calculated based on assuming 80% power, with a significance level of 5% for a 25% change in threshold levodopa dose (e.g., 24 mg to 30 mg). Secondary outcome measures included the other clinical measures and the biochemical data (tables 1 and 2⇓). Although the study allowed replacement of patients who withdrew, it was terminated after eight completed patients due to lower than expected patient availability. The actual power was therefore somewhat lower.
Impact of high-dose transdermal 17β-estradiol versus placebo on the response to IV levodopa in 8 patients
CSF monoamine metabolites and pterins levels in 4 parkinsonian women on transdermal 17β-estradiol versus placebo
Results.
Mean (± SEM) age of the subjects was 59 ± 4 years (range, 46 to 76 years); mean age at menopause, 48 ± 1 years (range, 44 to 52 years); mean PD symptom duration, 10 ± 1 years (range, 6 to 16 years); mean levodopa treatment duration, 7 ± 1 years (range, 2 to 13 years); and mean daily levodopa intake before study entry, 631 ± 73 mg (range, 400 to 1,050 mg). All showed mild to moderate parkinsonism (Hoehn & Yahr stage, 2.7 ± 0.2), and all but one patient exhibited levodopa-induced dyskinesias.
The threshold dose of levodopa necessary to provide definite antiparkinsonian efficacy was reduced significantly by 17β-estradiol from 29 ± 4 mg to 21 ± 4 mg (see table 1). On the other hand, the duration and magnitude of the motor response to the threshold dose and to a high dose of levodopa compared with placebo treatment were not changed significantly during 17β-estradiol treatment (see table 1). Moreover, mean baseline disability scores obtained before each levodopa infusion did not worsen during 17β-estradiol compared with placebo. In dyskinetic patients (n = 7), mean levodopa threshold dose necessary to induce dyskinesias appeared somewhat lower (23 ± 5 mg on 17β-estradiol versus 29 ± 5 mg on placebo) during 17β-estradiol treatment compared with placebo, but the difference was not statistically significant. Dyskinesia scores to threshold and high levodopa doses were variable between the two arms of the study, although mean scores were not changed appreciably with 17β-estradiol.
Analysis of self-kept diaries in seven patients maintained on the same oral levodopa dose throughout the study yielded similar mean “on” time on placebo (57 ± 2% of waking hours) compared with 17β-estradiol (61 ± 4% of waking hours). In the eighth patient, a reduction in oral levodopa dosage between the two arms of the study obscured the impact of 17β-estradiol on the resulting “on” time.
Transient adverse effects were reported during transdermal estradiol treatment, particularly breast/nipple tenderness (n = 7). Some patients reported more than one adverse event (table 3). Three patients noticed worsening of dyskinesias. One patient with severe diphasic dyskinesias reported more prolonged dyskinetic episodes starting the day estradiol treatment was initiated. A second patient became more aware of her dyskinesias toward the end of her levodopa response. A third patient experienced disabling continuous dyskinesias (“the worst ever”) starting on the fourth day of estradiol patch application, responding to a reduction in levodopa dosage.
Adverse events
None of the four patients consenting to CSF collection during both arms of the study showed any significant change in CSF monoamines, metabolites, and THB values during 17β-estradiol compared with placebo treatment (see table 2). Postmenopausal status and effective delivery of estradiol were confirmed in all patients, with serum estradiol levels rising from 14 ± 1 pg/mL (range, 9 to 17 pg/mL) at baseline to 325 ± 46 pg/mL (range, 117 to 477 pg/mL) during transdermal estradiol treatment.
Discussion.
This study documents for the first time the clinical effects of transdermal 17β-estradiol in postmenopausal parkinsonian patients. The high estrogen dose administered was intended to maximize central effects over a short period of time. The use of four patches, or four times the usual postmenopausal replacement dose, was selected to match mid-luteal phase 17β-estradiol levels. Based on previous reports of parkinsonian patients treated with oral conjugated equine estrogens, we might have anticipated a rapid deterioration in motor status.4-6 However, despite mean serum estradiol levels reaching as high as 24 times baseline, no change in mean parkinsonian “off” scores, duration and magnitude of response to IV levodopa, or mean “on” time from diaries occurred during transdermal 17β-estradiol treatment. These observations suggest the absence of any apparent short-term antidopaminergic effect of estradiol. It is unlikely that the duration of estradiol treatment was inadequate to document a potentially negative impact on motor function because such an effect was reported within 1 week of oral therapy with conjugated equine estrogens.5
The discrepancy between the lack of any apparent antidopaminergic effect in this study and other clinical reports may stem from the potency of transdermal 17β-estradiol compared with commonly used conjugated equine estrogens.4,5 The latter estrogens contain 45% estrone sulfate, and oral estrogens result in a higher serum estrone-to-estradiol ratio compared with transdermal treatment.15 Certain estrogens exert antidopaminergic effects at the striatal level,16 perhaps explaining the adverse clinical effects reported following therapy with oral conjugated equine estrogens. The contribution of increased dopamine release cannot be ruled out, although there was no significant change in CSF HVA levels during transdermal 17β-estradiol (see table 2). Variability in the density of dopamine transporters related to severity of the disease or to 17β-estradiol17 might also affect dopamine turnover18 unpredictably. It is unlikely that the IV administration of levodopa had any significant effect, given the congruent data from patient diaries collected during oral levodopa treatment.
The small number of patients in this study could lead to sampling error when attempting to extrapolate whether parkinsonian women in the general population will also experience a lowered levodopa threshold dose. The small number of patients used in the final analysis similarly makes calculation of actual power to detect significant changes in dyskinesia threshold difficult.
As with all crossover studies, the possibility of carryover effects from the first arm of the study into the second arm cannot be excluded entirely. However, all symptomatic adverse events resolved in less than 2 weeks, suggesting that the 2-week washout period was of appropriate duration.
Experimental data suggest complex actions of estrogens in the basal ganglia with enhancement or suppression of striatal dopamine functions in vivo.19,20 In contrast, 17β-estradiol has been shown to display many positive effects on the central dopaminergic system (figure 2), 21-28 suggesting a beneficial antiparkinsonian effect, consistent with the lowering of levodopa threshold dose observed in the current study. However, a purely dopaminergic effect for 17β-estradiol is unlikely given data from ovariectomized, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–lesioned female monkeys with levodopa-induced dyskinesias, indicating that 17β-estradiol administration had antidyskinetic properties without affecting the antiparkinsonian response to oral levodopa.29 Modulation of opioid,30 glutamatergic,31,32 or γ-aminobutyric acid26,33 systems could explain this improvement in dyskinesias. Our one patient with severe diphasic dyskinesias showed the greatest decline in threshold dose for dyskinesia production under 17β-estradiol (from 30 to 10 mg of levodopa), and developed more severe dyskinesias with a higher levodopa dose. Whether female parkinsonian patients with diphasic dyskinesias as a subgroup will consistently respond adversely to 17β-estradiol remains to be determined. Future neuroprotective trials of 17β-estradiol for PD will need to address the possible lower levodopa dose requirement.
Figure 2. Effects of 17β-estradiol on the central dopaminergic system. DA = dopamine; COMT = catechol-o-methyl transferase.
Acknowledgments
Supported in part by a fellowship grant from The Parkinson Foundation of Canada (P.J.B.).
Acknowledgment
The authors express their gratitude to the nursing staff of the NIH Clinical Center involved in the care of the patients, and to the Pharmaceutical Development Section for drug preparation. They also thank Thérèse Di Paolo, PhD, School of Pharmacy and Department of Molecular Endocrinology, Laval University Medical Center, Quebec City, Canada, for critical review of the manuscript. Ciba-Geigy generously provided the hormonal patches and matching placebo.
- Received September 4, 1998.
- Accepted February 13, 1999.
References
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