Doi:10.1016/j.maturitas.2007.08.009

Available online at www.sciencedirect.com Estrogen therapy reduces nocturnal periodic limb movements Helena Hachul , Edmund Chada Baracat , Jos´e Maria Soares Jr. , Mauro Abi Haidar , Marco T´ulio de Mello , S´ergio Tufik , Lia Rita Azeredo Bittencourt a Department of Medicine and Sleep Biology, Unifesp - Universidade Federal de S˜ao Paulo, SP, Brazil b Department of Gynecology, Unifesp - Universidade Federal de S˜ao Paulo, SP, Brazil Received 2 January 2007; received in revised form 27 July 2007; accepted 16 August 2007 Abstract
It is believed that periodic limb movement (PLM) and more specifically, restless leg syndrome (RLS), are a common cause of insomnia. And one study in the literature examined PLM when associated to the use of estrogens. Polo-Kantola et al. [Polo-KantolaP, Rauhala E, Erkkola R, Irjala K, Polo O. Estrogen replacement therapy and nocturnal periodic limb movements: a randomizedcontrolled trial. Obstet Gynecol 2001;97(4):548–54] observed that estrogen therapy improved subjective sleep quality regardlessof periodic limb movements or related arousals. Herein is a case of a symptomatic postmenopausal patient with high PLM indexwho complained of insomnia and leg pain. Given that the patient had hot flashes and a high Kupperman Menopausal Index (whichevaluates climacteric symptoms), we decided to administer transdermal ESTRADOT 25 ␮g (Novartis, Brazil) twice-a-week.
Our patient experienced a significant decrease in PLM as well as a great increase in REM and a slight increase in slow wavesleep (stages 3 and 4), as shown in the polysomnography. The patient reported an overall improvement in her condition.
2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: Periodic leg movements; Menopause; Estrogen therapy; Sleep; Sleep disturbances 1. Introduction
suffer from insomnia Periodic limb movement(PLM) and restless leg syndrome (RLS) feature as Sleep complaints increase with age and are more common in women than in men. It has been found that Although one study has addressed the effects of the incidence of sleep disturbance is higher in post- menopause on PLM and concluded that estrogen did menopause and over 60% of postmenopausal women not alter incidence or intensity of PLM stud-ies have demonstrated possible interactions between ∗ Corresponding author at: Rua Thirso Martins 264 apto 41, Vila Mariana CEP 04120 050, Brazil. Tel.: +55 11 55729539; The effect of estrogen therapy on periodic limb movements is not fully comprehended. Estrogen increases the number of dopamine receptors 0378-5122/$ – see front matter 2007 Elsevier Ireland Ltd. All rights reserved.
H. Hachul et al. / Maturitas 58 (2007) 319–322 increases dopamine intake in specific brain areas gen on the incidence and intensity of periodic limb and decreases dopamine catabolism Estrogen also movements with a randomized, placebo-controlled, reduces dopamine concentration and dopamine double-masked, cross-over study design. They con- receptor overactivity Decrease in PLM could then cluded that estrogen therapy in doses used to control be explained following administration of estrogen.
climateric symptoms does not alter the incidence or There is evidence that estrogen can prevent neu- intensity of nocturnal periodic limb movements ronal atrophy as well as improve tissue vascularization The aim of this report was to describe the case of a thereby leading to higher tissue concentration of oxy- postmenopausal woman who complained of insomnia gen. This could be yet another explanation for the and PLMD before and after hormone therapy.
decrease of PLM through the use of estrogen.
Restless Leg Syndrome (RLS) is a clinical mani- festation of a desire to move the lower limbs and is 2. Case report
usually associated with paresthesias, dysesthesias andmotor restlessness. Different motor strategies are used The research project received prior approval by the to relieve its discomfort. Symptoms of RLS become local Ethics Committee and informed, written consent worse at rest with at least partial and temporary relief was obtained after full explanation of the procedure through activity. Symptoms are worse however in the evening or at night and the prevalence of RLS is higher A patient, 62 years old, consulted her physician among the elderly. Epidemiological studies reveal a complaining of insomnia and excess nocturnal peri- 9–20% prevalence of RLS in this age group. Recent odic leg movements. She stated that she felt leg pain studies indicate that RLS is twice as prevalent in which became worse without movement but lessened older women as in older men and 5–10% of after movement. She said she had had these prob- adults in Northern European population-based studies lems for about 15 years and that they got worse report RLS symptoms. Additionally, 26% of women after menopause. She had been amenorrheic for 20 years following a hysterectomy. She did not report any Periodic limb movement disorder (PLMD) is char- other clinical problems except for arterial hyperten- acterized by periodic episodes of repetitive, highly sion which was controlled with the use of medications: stereotyped limb movement that occurs during sleep 50 mg/day atenol and captopril. She had a Kupper- (PLMS) and that, as a clinical sleep disturbance, cannot be accounted for by any other primary sleep disorder.
Epworth Sleepiness Scale as 0. Although she A difficulty to fall asleep or maintain sleep or both is had already undergone hormone replacement ther- consistently reported in association with PLMD apy, she was not under that therapy at the moment and epidemiological studies estimate the prevalence of of the project. When under hormone treatment, she would take equine conjugated estrogen 0.625 mg/day Previous reports have suggested a high prevalence of via oral for about 8 months, and then stopped periodic limb movements of up to 34% individ- treatment on her own. Normal rates were noted in uals 65 years of age and older. An elevated periodic leg exams: hemoglobin = 14.4 g/dL; glucose = 95 mg/dL, movement index (registered in the polysomnography) FSH = 67 mUI/mL and estradiol = 7 pg/mL. Clinical was found to correlate with severity or worsening of a and laboratory checks informed us that there was no disorder in certain groups such as in patients with essen- reason why she should not undertake hormonal therapy.
tial hypertension, end-stage renal disease and alcohol She took her first polysomnography (PSG) record- dependency. Early observational studies described an ing, after which she began using transdermal increase of PLM in depressed patients treated with psy- ESTRADOT 25 ␮g (Novartis, Brazil) twice-a-week for choactive substances such as clomipramine, lithium, 2 months. During the study, the patient wore each patch for 3.5 days (84 h) on the abdomen, below the waistline.
There is only one study which addressed the The patches were applied on a clean, dry, non-oily and effects of menopause on periodic limb movements non-irritated skin and the initial application was on the Polo-Kantola et al. evaluated the effect of estro- right side of the lower abdomen with subsequent appli- H. Hachul et al. / Maturitas 58 (2007) 319–322 cation alternated to the opposite side. Subsequently a changes in sleep efficiency, PLM reduced significantly, second PSG recording was made. An all-night PSG and the patient reported leg pain had disappeared.
recording was performed consisting of a computerizedSleep Analyzer Computer (SAC version 9.3, OxfordInstruments Inc.). Surface electrodes were used to 3. Discussion
record electroencephalogram (EEG), electromyogram(EMG), electrooculogram (EOG), electrocardiogram (ECG), pneumographic impedance for recording of of PLM in postmenopausal women with 48% being thoracic-abdominal movements, thermal sensors for administered placebo and 44% on estrogen. They con- recording nasal and oral airflow, body position sensors cluded that short-term ET did not alter the incidence or and infra-red sensor for pulse oxymeter, which was intensity of periodic limb movements or frequencies of connected to the distal phalanx for recording oxyhe- periodic limb movement arousal indices.
moglobin saturation. A snoring sensor was also used.
Estrogen has been linked to movement disorders A footnote is that the patient has elected to maintain associated with excessive dopamine activity especially the use of estrogen ever since the PSG recording.
during pregnancy and while using contraceptives. The Upon completion of the exam, a trained sleep physi- hormonal condition associated with pregnancy consists cian analyzed and staged the recordings according to of a high serum estrogen concentration accompanied by the criteria established by Rechschaffen and Kales high levels of serum progestin. The higher frequency of The necessary alterations for respiratory events were movement disorders during those states might depend incorporated according to the criteria established by more on progestin than on estrogen concentration. The the American Academy of Sleep Medicine Committee estrogen effect might also depend on simultaneous pro- Practice parameters for the treatment of Rest- gestin availability. Although unopposed estrogen was less Legs Syndrome and Periodic Limb Movement found to increase the number of progesterone recep- Disorders followed the guidelines established by the tors the absence of progestin in HT might play American Sleep Disorders Association Periodic a key role in any movement effect. The inconsistent limb movements were scored only if movements were effect of estrogen on the extrahypothalamic dopamine part of a series of four or more consecutive ones with system might depend on the dose, duration and tim- duration of 0.5–5 s and an interval of 5–90 s ing of HT. We examined studies showing that exercise the treatment the patient reported an improvement in can decrease periodic leg movement in individuals with sleep quality and fewer leg movements at night. PSG paraplegia possible explanation for this is results are shown in Although there were no the fact that exercise can lead to higher tissue concen-tration of oxygen. It is also possible that once estrogenimproves vascularization additional supply of oxygen might lead to a decrease in periodic leg move- Polysomnography results before and after ET ments. In fact, estrogen may increase NO production that results in vasodilation of the vascular bed, most likely increasing the arterial flow to the tissue estrogen has antiinflamatory action upon the brain Moreover, there is a circadian variability in PLM fre- quency, which by itself could explain the decrease of PLM rather than as a result of estrogen.
Polo-Kantola et al. that the average con- centrations of estrogen in their study might have been too low to affect the incidence or intensity of periodic limb movements. Patients had periodic limb move- ments without subjective symptoms at the beginning of AHI: Apnea Hypopnea Index; PLM: periodic leg movement; REM: their study. They posit that more studies on women with symptomatic periodic limb movements are warranted.
H. Hachul et al. / Maturitas 58 (2007) 319–322 Some investigators believe that periodic limb move- [10] Hornyak M, Trenkwalder C. Restless legs syndrome and peri- ment is a common cause of insomnia. Polo-Kantola odic limb movement disorder in the elderly. J Psychosom Res et al. ed that ET improved subjective sleep [11] Manconi M, Govoni V, De Vito A, et al. Restless legs syndrome quality independently of periodic limb movements or and pregnancy. Neurology 2004;28(63(6)):1065–9.
[12] American Academy of Sleep Medicine. International classi- In our study, the patient was symptomatic, mean- fication of sleep disorders. In: Diagnostic and coding manual.
ing she displayed symptoms of PLM despite the fact 2nd ed. Werchester, IL: American Academy of Sleep Medicine; these were significantly decreased. Although sleep effi- [13] Ancoli-Israel S, Kripke DF, Mason W, Kaplan OJ. Sleep ciency did not alter, we observed an expressive increase apnea and periodic movements in an aging sample. J Gerontol in REM and a slight increase in stages 3 and 4 (deep sleep). She did, however, report an overall improve- [14] Hornyak M, Feige B, Reirmann D, Voderholzer U. Periodic leg movements in sleep and periodic limb movement disorder; We believe that future studies in individuals dis- prevalence, clinical significance and treatment. Sleep Med Rev2006;10:169–77.
playing symptoms of PLM and under hormone therapy [15] Kupperman HS, Wetchler BB, Blatt MHG. Contemporary are needed to evaluate whether estrogen and/or proges- therapy of the menopausal syndrome. J Am Med Assoc terone alter the incidence of restless legs syndrome.
[16] Johns MW. A new method of measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991;14:540–5.
[17] Rechschaffen A, Kales A. A manual of standardized terminol- References
ogy, techniques and scoring system for sleep stages of humansubjects. Los Angeles: UCLA Brain Information Service/Brain [1] Von Muhlen DG, Kritz-Silverstein D, Barrett-Connor E. A community-based study of menopause symptoms and estrogen [18] American Academy of Sleep. Sleep-related breathing disor- replacement in older women. Maturitas 1995;22:71–8.
ders in adults: recommendations for syndrome definitions and [2] Kuh DL, Wadworth M, Hardy R. Women’s health in midlife: the measurements techniques in clinical research. The report of influence of the menopause social factors and health in earlier an American Academy of Sleep Medicine Task Force. Sleep life. Br J Obstet Gynaecol 1997:923–33.
[3] Guilleminault C, Raynal D, Weitzman ED, Dement WC.
[19] American Sleep Disorders Association. Practice Parameters for Sleep-related periodic myoclonus in patients complaining of the treatment of restless legs Syndrome and Periodic Limb insomnia. Trans Am Neurol Assoc 1975;100:19–21.
Movement Disorders. Sleep 1999;22:968.
[4] Polo-Kantola P, Rauhala E, Erkkola R, Irjala K, Polo O.
[20] Brodeur P, Mockus M, McCullough R, Moore LG. Proges- Estrogen replacement therapy and nocturnal periodic limb terone receptors and ventilatory stimulation by progestin. J Appl movements: a randomized controlled trial. Obstet Gynecol [21] Mello MT, Esteves AM, Tufik S. Comparison between [5] Hruska RE, Silbergeld EK. Increased dopamine receptor sen- dopaminergic agents and physical exercise as treatment for limb sitivity after estrogen treatment using the rat rotation model.
movements in patients with spinal cord injury. Spinal Cord, [6] Morissette M, Di Paolo T. Effect of chronic estradiol and pro- [22] Mello MT, Esteves AM, Silva AC, Tufik S. Reduction gesterone treatments of ovariectomized rats on brain dopamine of periodic leg movement in individuals with paraple- uptake sites. J Neurochem 1993;60:1876–83.
gia following physical exercise. Spinal Cord, Reino Unido [7] Ball P, Knuppen R, Haupt M, Breuer H. Interactions between estrogens and catechol aminesInteractions between estrogens [23] Weston GC, Haviv I, Rogers PA. Microarray analysis of VEGF- and catechol amines. 3. Studies on the methylation of catechol responsive genes in myometrial endothelial cells. Mol Hum estrogens, catechol amines and other catechols by the ctechol- O-methyltransferases of human liver. J Clin Endocrinol Metab [24] Kim JK, Levin ER. Estrogen signaling in the cardiovascular system. Nucl Recept signal 2006 [4 e013 Epub2006 July 7].
[8] Foreman MM, Porter JC. Effects of catchol estrogens and [25] Suzuki S, Brown CM, Dela Cruz CD, Yang E, Bridwell DA, catecholamines on hypothalamic and corpus striatal tyrosine Wise PM. Estrogen signaling in the cardiovascular system. Tim- hydroxylase activity. J Neurochem 1980;34:1175–8.
ing of estrogen therapy after ovariectomy dictates the efficacy [9] Koller WC, Weiner WJ, Klawans HJ, Nausieda PA. Influence of of its neuroprotective and antiinflammatory actions. Proc Natl female sex hormones on neuroleptic-induced behavioral super- Acad Sci U S A 2007;3(104(14)):6013–8 [Epub 2007 March sensitivity. Neuropharmacology 1980;19:387–91.

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