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Carpal tunnel syndrome in postmenopausal women
Journal of the Neurological Sciences 270 (2008) 77 – 81 www.elsevier.com/locate/jns
Carpal tunnel syndrome in postmenopausal women Yuksel Kaplan ⁎, Semiha G. Kurt, Hatice Karaer Gaziosmanpasa University Faculty of Medicine, Department of Neurology, Tokat, Turkey Received 16 September 2007; received in revised form 1 February 2008; accepted 7 February 2008 Available online 6 March 2008
Abstract Objective: Hormonal changes that accompany menopause have a significant impact on the nervous and other physiological systems. Our objective was to evaluate the relationship between carpal tunnel syndrome (CTS) and the clinical features of menopause in postmenopausal women, in comparison to age-matched healthy controls. Methods: Overall, 6230 women were seen during the study period. Of these, 5587 were not eligible because they were premenopausal or perimenopausal. 537 women did not meet the criteria used in the study for a diagnosis of idiopathic CTS and were excluded. Finally, one hundred and six patients with CTS and 115 controls were examined. The presence of CTS was confirmed both clinically and electrophysiologically. Socio-demographic variables and reproductive histories were evaluated via a structured interview. Results: In comparison to healthy controls, patients with CTS showed a significantly greater number of pregnancies and an earlier age at menopause. Regarding the type of menopause, patients and controls showed similar frequencies for natural versus surgical menopause. The frequency of natural menopause was significantly higher than that of surgical menopause in both groups. Conclusion: Our results suggest that age at menopause may be a significant factor in the development of CTS. Pregnancy-related hormonal changes may have long-term effects that increase the incidence of CTS in postmenopausal women. © 2008 Elsevier B.V. All rights reserved. Keywords: Carpal Tunnel Syndrome (CTS); Hypoestrogenemia; Menopause; Pregnancy; Age
1. Introduction The World Health Organization defines menopause as the permanent cessation of menses as a result of the loss of ovarian follicular function or the surgical removal of ovaries. The mean age of natural menopause is approximately 50 years [1]. Carpal tunnel syndrome (CTS) is by far the most common entrapment neuropathy. Although many factors may increase pressure on the median nerve as it passes through the carpal tunnel, idiopathic CTS far outnumbers all other types [2]. Idiopathic CTS often occurs in middle-aged women without other known pathologies. Because CTS occurs more fre-
quently in women, particularly around menopause, it is suspected that sex-specific risk factors influence the incidence of CTS [3]. Furthermore, the use of combined oral contraceptives, bilateral oophorectomy, and pregnancy appear to be associated with CTS [3]. It has been suggested that naturally occurring hormonal changes related to menopause may predispose individuals to CTS. Our objective was to evaluate the relationship between CTS and the clinical features of menopause in postmenopausal women. 2. Materials and methods 2.1. Subjects and evaluation
⁎ Corresponding author. Inonu University, Turgut Ozal Tip merkezi, Noroloji ABD, Malatya, Turkey. Tel.: +90 532 468 71 69; fax: +90 356 212 94 17. E-mail address: [email protected] (Y. Kaplan). 0022-510X/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2008.02.003
This case-control study was conducted between January 2005 and January 2007. All women were consecutively admitted to the Department of Neurology at faculty of medicine
78
Y. Kaplan et al. / Journal of the Neurological Sciences 270 (2008) 77–81
of our university. This study was performed in accordance with the Declaration of Helsinki. After a detailed explanation of the study, all subjects provided written informed consent. Both hands were examined in each patient, and the presence of CTS was confirmed both clinically and electrophysiologically. All clinical evaluations were performed by the same neurologist (Y.K.) and the electrophysiological evaluations were conducted independently by the Department of Neurophysiology. The clinical diagnosis of CTS was based on typical clinical symptoms (nocturnal pain, paresthesia or numbness in the hand, symptoms provoked by sleep, and activity-related pain and paresthesia) and the presence of neurological deficits. All patients underwent a neurologic examination. Both hands were examined for motor deficits and thenar atrophies. Sensory deficits were examined using static two-point discrimination and the Semmes−Weinstein monofilament threshold test. Special care was taken to check for sensory involvement in the area innervated by the median nerve. Tinnel's and Phalen's provocation tests were also performed. CTS was diagnosed when individuals exhibited typical clinical symptoms and responded to non-surgical treatment without other evident neurological deficits. We did not rely solely on Tinnel's sign or Phalen's test to detect CTS. Standard nerve conduction studies (NCS) were performed with a Medelec-Oxford Synergy EMG machine, using a filter setting of 0.020−10 kHz and an analysis time of 50 ms. Impulses were recorded using surface electrodes. Conduction studies were performed in a warm room, such that the skin temperature of the extremities registered at 32 °C or above. Skin temperature was measured at the site where nerve conduction velocity measurements (NCV) were taken. Median motor and sensory (finger-wrist, wrist-elbow) nerve conduction velocities were measured in the bilateral upper extremities using the method described by Oh [4]. We also performed both motor and sensory conduction studies of the ulnar nerve. Patients with abnormalities in ulnar motor or sensory conduction were not included in the study. The electrophysiological criteria for the diagnosis of CTS are based on the parameters for electrodiagnostic studies established by the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation [5]. As described by Padua et al. [6], we classified the severity of CTS into four grades: mild, moderate, extreme, and severe. 2.2. Control group The control group was selected from among the healthy people. If a suitable control was unavailable for a case then an extra control was identified from the next available case seen. These control subjects were matched to the patients based on age (± 2 years). It was not deemed ethically justi-
fiable to perform nerve conduction testing on asymptomatic subjects; thus, healthy female subjects were selected based on the absence of clinical manifestations and neurological deficits suggestive of CTS. The same evaluations and examinations applied to each patient were also applied to each control subject. The same investigator (H.K.), who was unaware of the subject's clinical assessment at the time of the interview, conducted the interviews for both groups. Socio-demographic characteristics, body mass index (BMI), and detailed reproductive history were evaluated using a structured interview. Socio-demographic characteristics included age, marital status, occupation, level of education, and the number of pregnancies. BMI was calculated as bodyweight divided by the square of height (kg/m2). Reproductive history included age at menarche, age at menopause, type of menopause (natural or surgical), duration of menopause, and the use of postmenopausal hormone replacement therapy. Menopause was defined as the cessation of menses for 12 or more continuous months, as ascertained via self-reporting at the interview. Age at menopause was determined based on the date at which the subject stopped having regular periods. Menopause was classified as natural in the absence of surgical procedures that cause the cessation of menses. The duration of menopause was calculated for each woman by subtracting the age at menarche from the age at menopause. To limit our patients to those with purely idiopathic CTS, blood and urine analysis and wrist imaging were performed to detect diseases that might predispose an individual to CTS. We excluded all patients with diabetes mellitus, rheumatoid arthritis, chronic renal failure, gout, thyroid diseases, hyperlipidemia, wrist fractures, space-occupying lesions, gynecologic and non-gynecologic malignancies, and patients undergoing chemotherapy and/or radiotherapy. We also excluded patients and healthy subjects who were taking or had taken hormone replacement therapy. At the end of this process, cases comprised postmenopausal women with CTS and the control comprised agematched postmenopausal women without CTS. These groups were compared in terms of socio-demographic characteristics, BMI, and reproductive characteristics. 2.3. Statistical analysis Data are presented as the mean ± standard deviation (SD). We used Student's t-test to compare age, BMI, number of pregnancies, and age at menarche between groups. The Mann−Whitney U test was used to compare the age at menopause between groups. The Fisher exact chi-square test was used to compare categorical variables like marital status, occupation, level of education, and type of menopause. The Pearson correlation test was used to analyze the correlation between the duration of menopause and CTS. The Statistical Package for the Social Sciences (SPSS, version 12; SPSS
Y. Kaplan et al. / Journal of the Neurological Sciences 270 (2008) 77–81
79
Inc., Chicago, IL) was used for all statistical analyses. The level of statistical significance was set at p b 0.05.
Table 2 Comparison of reproductive characteristics between postmenopausal women with CTS and age-matched controls
3. Results
Parameter
Cases (n = 106)
Control group (n = 115)
p value
Overall, 6230 women were seen in our Neurology Department during the study period. Of these, 5587 were not eligible because they were premenopausal or perimenopausal. We saw 643 women who were both postmenopausal and had CTS. Of these, 537 women did not meet the criteria used in the study for a diagnosis of idiopathic CTS and were excluded. Finally, the cases and the control group contained 106 and 115 postmenopausal women, respectively. In the cases, the mean duration of CTS symptoms was 5.51 ± 4.46 years (range, 1−30). In these patients, CTS was classified as mild in 34 patients, moderate in 47 patients, severe in 16 patients, and extreme in 9 patients. Sixty-three (59.4%) patients exhibited bilateral CTS. These data indicate that most patients had mild or moderate, and bilateral CTS.
Age at menarche (years) a Age at menopause (years) a
12.75 ± 1.76 47.59 ± 5.18
12.60 ± 1.74 49.89 ± 3.09
NS 0.001
Type of menopause b Natural Surgical
76 (71.7) 30 (28.3)
91 (79.1) 24 (20.9)
NS
3.1. Socio-demographic data The subjects ranged in age from 37 to 69 years in the cases and from 39 to 67 years in the control. No significant difference in age, marital status, education, occupation, or BMI was observed between groups. However, the mean number of pregnancies was significantly higher in the cases (2.84 ± 1.61) compared to the control (1.77 ± 1.37; t, 5.30; p, 0.0001). The socio-demographic characteristics of both groups are presented in Table 1. Table 1 Comparison of sociodemographic characteristics between postmenopausal women with CTS and age-matched controls Features
Cases (n = 106)
Control group (n = 115)
p value
Age (years) a
55.49 ± 6.19
56.34 ± 5.76
NS
Marital status Married Other
90 (84.9) 16 (15.1)
94 (81.7) 21 (18.3)
NS
Education b Little education Primary Secondary High school University
14 (13.2) 36 (34) 42 (39.6) 6 (5.7) 8 (7.5)
12 (10.4) 35 (30.4) 48 (41.7) 7 (6.1) 13 (11.3)
NS
Occupation b Employed outside Home Home maker BMI (kg/m2) a Number of pregnancies a
44 (41.5) 62 (58.5) 30.58 ± 5.58 2.84 ± 1.61
45 (39.1) 70 (60.9) 29.72 ± 5.85 1.77 ± 1.37
NS
NS. non significant a Values represent the mean ± SD. b Values represent number (%).
NS 0.0001
NS. non significant. a Values represent the mean ± SD. b Values represent number (%).
3.2. Comparison of reproductive characteristics between groups No significant difference was observed in the age at menarche between groups. In addition, both groups showed similar frequencies regarding the type of menopause (natural versus surgical: 71.7/28.3 in the cases, 79.1/20.9 in the control). The frequency of natural menopause was significantly higher in both groups (p b 0.05). Furthermore, age at menopause was significantly lower in the cases (47.59 ± 5.18 years) compared to the control (49.89 ± 3.09 years; z, 4.221; p, 0.001) (Table 2). The mean duration of menopause was 7.91 ± 5.55 and the mean duration of CTS was 5.51 ± 4.46 years. The Pearson correlation analysis revealed a strong, significant correlation between these variables (r, 0.824; p, 0.0001). 4. Discussion We investigated the clinical features of menopause in postmenopausal women diagnosed with CTS. Although there are numerous studies regarding CTS and its associated conditions, very few studies have assessed the relationship between menopause and CTS. A number of investigators have reported that pregnancy is associated with an increased incidence of CTS [3,7–10]. The association between parity and CTS may be the result of the long-term hormonal effects of pregnancy or mechanisms associated with child rearing [3]. Ferry et al. found a weak but statistically significant link between parity and CTS [3]. However, Dieck et al. found that the number of pregnancies was not associated with a change in the frequency of CTS [11]. We found that the mean number of pregnancies is higher in postmenopausal women with CTS. Although CTS normally resolves toward the end of pregnancy or the postpartum period [10,11], these results suggest that hormonal changes related to pregnancy have long-term effects on the development of CTS in postmenopausal women. Finally, our results show that women with CTS underwent menopause at a younger age than women without, and there is a strong and significant positive correlation between the duration of CTS and menopause.
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Estrogen receptors are found throughout the central and peripheral nervous systems. In the peripheral nervous system, estrogen receptors are found in the spinal cord [12– 15], dorsal root ganglia [16–19], autonomic pelvic ganglia [14,15], sympathetic ganglia [20,21], and Schwann cells [22]. Numerous studies have shown that estrogens affect the nervous system via both genomic and non-genomic mechanisms, including the development, proliferation, and regeneration of neuronal cells, gene expression, energy metabolism, hormone sensitivity, and the biosynthesis of structural proteins and enzymes [12,15,17,19,23]. The hormonal changes that accompany menopause (i.e., decreased estrogen levels) have a significant impact on the nervous system and other physiological systems. Estrogen deficiency has long-term cumulative effects on many tissues. Previous studies showed a significant association between lesser age at menopause and a higher risk of cardiovascular disease, urogenital atrophy, cognitive impairment, epilepsy, and chronic degenerative diseases such as osteoporosis, Parkinson's disease, and Alzheimer's disease [24–26]. We could not find any published study which has evaluated the age at menopause of women with CTS except one study. A study by de Krom et al. examined the relationship between age at menopause and CTS in women, but was unable to demonstrate a clear relationship between these variables [27]. Although previous studies have demonstrated that surgical menopause may be a precipitating factor for CTS [7,28], we found that both groups experienced similar frequencies of natural versus surgical menopause. The frequency of natural menopause was significantly higher than surgical menopause in both groups. These findings suggest that age at menopause may be more significant than menopause type in the development of CTS. Based on this information, we hypothesize that hypoestrogenemia, which is characterized by a decreased ovarian follicular response to gonadotropins and estrogen secretion, may influence the median nerve and/or other components of the carpal tunnel. This study has several limitations. First, we did not establish a causal mechanism between hypoestrogenemia and CTS. Second, the accuracy of self-reported menopausal status and age at menopause may be potential concern. To further strengthen our data set, we excluded women who were using or had used postmenopausal hormone replacement therapy. Hormone replacement during the perimenopausal period may artificially prolong cyclic menstrual bleeding [29]. In addition, previous studies have shown that estrogen has therapeutic value in CTS patients [7,30]. Despite these limitations, our results suggest that number of pregnancies and age at menopause may be precipitating factors for CTS in postmenopausal women. Further controlled clinical studies are required to determine the longterm effects of hypoestrogenemia on the median nerve and other components of the carpal tunnel, and to determine the possible therapeutic effects of hormone replacement therapy in postmenopausal women with CTS.
References [1] WHO Scientific Group on Research on the Menopause in the 1990s. WHO technical report series. Geneva; 1996. p. 1–1007. [2] Sud V, Freeland AE. Biochemistry of carpal tunnel syndrome. Microsurgery 2005;25:44–6. [3] Ferry S, Hannaford P, Warskyj M, Lewis M, Croft P. Carpal tunnel syndrome: a nested case-control study of risk factors in women. Am J Epidemiol 2000;151:566–74. [4] Oh SJ. Clinical electromyography. Part 1: Anatomical guide for common nerve conduction studies. Second ed. Baltimore: Williams Wilkins Book Company; 1993. p. 57–1001. [5] American Academy of Neurology. American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Practice parameter for electrodiagnostic studies in carpal tunnel syndrome (summary statement). Neurology 1993;43: 2404–5. [6] Padua L, LoMonaco M, Gregori B, Valente EM, Padua R, Tonali P. Neurophysiological classification and sensitivity in 500 carpal tunnel syndrome hands. Acta Neurol Scand 1997;96:211–7. [7] Bjorkqvist SE, Lang AH, Punnonen R, Rauramo L. Carpal tunnel syndrome in ovariectomized women. Acta Obstet Gynecol Scand 1977;56:127–30. [8] Stevens JC, Beard CM, O'Fallon WM, Kurland LT. Conditions associated with carpal tunnel syndrome. Mayo Clin Proc 1992;67: 541–8. [9] Wand JS. Carpal tunnel syndrome in pregnancy and lactation. J Hand Surg 1990;15B:93–5. [10] Gould JS, Wissinger HA. Carpal tunnel syndrome in pregnancy. South Med J 1978;71:144–145, 154. [11] Dieck GS, Kelsey JL. An epidemiologic study of the carpal tunnel syndrome in an adult female population. Prev Med 1985;14:63–9. [12] Islamov RR, Hendricks WA, Katwa LC, McMurray RJ, Pak ES, Spanier NS, et al. Effect of 17 beta-estradiol on gene expression in lumbar spinal cord following sciatic nerve crush injury in ovariectomized mice. Brain Res 2003;966:65–75. [13] Papka RE, Hafemeister J, Puder BA, Usip S, Storey-Workley M. Estrogen receptor-alpha and neural circuits to the spinal cord during pregnancy. J Neurosci Res 2002;70:808–16. [14] Papka RE, Mowa CN. Estrogen receptors in the spinal cord, sensory ganglia, and pelvic autonomic ganglia. Int Rev Cytol 2003;231: 91–127. [15] Papka RE, Storey-Workley M, Shughrue PJ, Merchenthaler I, Collins JJ, Usip S, et al. Estrogen receptor-alpha and beta-immunoreactivity and mRNA in neurons of sensory and autonomic ganglia and spinal cord. Cell Tissue Res 2001;304:193–214. [16] Cui S, Goldstein RS. Expression of estrogen receptors in the dorsal root ganglia of the chick embryo. Brain Res 2000;882:236–40. [17] Liu J, Chen D, Goldstein RS, Cui S. Effect of male and female sex steroids on the development of normal and the transient Froriep's dorsal root ganglia of the chick embryo. Brain Res Dev 2005;155: 14–25. [18] Luizzi FJ, Scoville SA, Bufton SM. Effect of short-term estrogen replacement on trk mRNA levels in axotomized dorsal root ganglion neurons. Exp Neurol 1999;159:433–40. [19] Sohrabji F, Miranda RC, Toran-Allerand CD. Estrogen differentially regulates estrogen and nerve growth factor receptor mRNAs in adult sensory neurons. JNeurosci 1994;14:459–71. [20] Zoubina EV, Smith PG. Expression of estrogen receptors alpha and beta by sympathetic ganglion neurons projecting to the proximal urethra of female rats. J Urol 2003;169:382–5. [21] Zoubina EV, Smith PG. Distributions of estrogen receptors alpha and beta in sympathetic neurons of female rats: enriched expression by uterine innervation. J Neurobiol 2002;52:14–23. [22] Jung-Testas I, Schumacher M, Robel P, Baulieu EE. Actions of steroid hormones-and growth factors on glial cells of the central and peripheral nervous system. J Steroid Biochem Mol Biol 1994;48:145–54.
Y. Kaplan et al. / Journal of the Neurological Sciences 270 (2008) 77–81 [23] Purves-Tyson TD, Keast JR. Rapid actions of estradiol on cyclic AMP response element binding protein phosphorylation in dorsal root ganglion neurons. Neuroscience 2004;129:629–37. [24] Henderson VW. The neurology of menopause. Neurologist 2006;12: 149–59. [25] Maturana MA, Irigoyen MC, Spritzer PM. Menopause, estrogens, and endothelial dysfunction: current concepts. Clinics 2007;62:77–86. [26] Hu FB, Grodstein F, Hennekens CH, Colditz GA, Johnson M, Manson JE, et al. Age at natural menopause and risk of cardiovascular disease. Arch Intern Med 1999;159:1061–6. [27] de Krom MC, Kester AD, Knipschild PG, Spaans F. Risk factors for carpal tunnel syndrome. Am J Epidemiol 1990;132:1102–10.
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[28] Pascual E, Giner V, Arostegui A, Conill J, Ruiz MT, Pico A. Higher incidence of carpal tunnel syndrome in oophorectomized women. Br J Rheumatol 1991;30:60–2. [29] Whelan EA, Sandler DP, McConnaughey DR, Weinberg CR. Menstrual and reproductive characteristics and age at natural menopause. Am J Epidemiol 1990;131:625–32. [30] Confino-Cohen R, Lishner M, Savin H, Lang R, Ravid M. Response of carpal tunnel syndrome to hormone replacement therapy. BMJ 1991;303(6816):1514–9.
Carpal tunnel syndrome in postmenopausal women Yuksel Kaplan ⁎, Semiha G. Kurt, Hatice Karaer Gaziosmanpasa University Faculty of Medicine, Department of Neurology, Tokat, Turkey Received 16 September 2007; received in revised form 1 February 2008; accepted 7 February 2008 Available online 6 March 2008
Abstract Objective: Hormonal changes that accompany menopause have a significant impact on the nervous and other physiological systems. Our objective was to evaluate the relationship between carpal tunnel syndrome (CTS) and the clinical features of menopause in postmenopausal women, in comparison to age-matched healthy controls. Methods: Overall, 6230 women were seen during the study period. Of these, 5587 were not eligible because they were premenopausal or perimenopausal. 537 women did not meet the criteria used in the study for a diagnosis of idiopathic CTS and were excluded. Finally, one hundred and six patients with CTS and 115 controls were examined. The presence of CTS was confirmed both clinically and electrophysiologically. Socio-demographic variables and reproductive histories were evaluated via a structured interview. Results: In comparison to healthy controls, patients with CTS showed a significantly greater number of pregnancies and an earlier age at menopause. Regarding the type of menopause, patients and controls showed similar frequencies for natural versus surgical menopause. The frequency of natural menopause was significantly higher than that of surgical menopause in both groups. Conclusion: Our results suggest that age at menopause may be a significant factor in the development of CTS. Pregnancy-related hormonal changes may have long-term effects that increase the incidence of CTS in postmenopausal women. © 2008 Elsevier B.V. All rights reserved. Keywords: Carpal Tunnel Syndrome (CTS); Hypoestrogenemia; Menopause; Pregnancy; Age
1. Introduction The World Health Organization defines menopause as the permanent cessation of menses as a result of the loss of ovarian follicular function or the surgical removal of ovaries. The mean age of natural menopause is approximately 50 years [1]. Carpal tunnel syndrome (CTS) is by far the most common entrapment neuropathy. Although many factors may increase pressure on the median nerve as it passes through the carpal tunnel, idiopathic CTS far outnumbers all other types [2]. Idiopathic CTS often occurs in middle-aged women without other known pathologies. Because CTS occurs more fre-
quently in women, particularly around menopause, it is suspected that sex-specific risk factors influence the incidence of CTS [3]. Furthermore, the use of combined oral contraceptives, bilateral oophorectomy, and pregnancy appear to be associated with CTS [3]. It has been suggested that naturally occurring hormonal changes related to menopause may predispose individuals to CTS. Our objective was to evaluate the relationship between CTS and the clinical features of menopause in postmenopausal women. 2. Materials and methods 2.1. Subjects and evaluation
⁎ Corresponding author. Inonu University, Turgut Ozal Tip merkezi, Noroloji ABD, Malatya, Turkey. Tel.: +90 532 468 71 69; fax: +90 356 212 94 17. E-mail address: [email protected] (Y. Kaplan). 0022-510X/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2008.02.003
This case-control study was conducted between January 2005 and January 2007. All women were consecutively admitted to the Department of Neurology at faculty of medicine
78
Y. Kaplan et al. / Journal of the Neurological Sciences 270 (2008) 77–81
of our university. This study was performed in accordance with the Declaration of Helsinki. After a detailed explanation of the study, all subjects provided written informed consent. Both hands were examined in each patient, and the presence of CTS was confirmed both clinically and electrophysiologically. All clinical evaluations were performed by the same neurologist (Y.K.) and the electrophysiological evaluations were conducted independently by the Department of Neurophysiology. The clinical diagnosis of CTS was based on typical clinical symptoms (nocturnal pain, paresthesia or numbness in the hand, symptoms provoked by sleep, and activity-related pain and paresthesia) and the presence of neurological deficits. All patients underwent a neurologic examination. Both hands were examined for motor deficits and thenar atrophies. Sensory deficits were examined using static two-point discrimination and the Semmes−Weinstein monofilament threshold test. Special care was taken to check for sensory involvement in the area innervated by the median nerve. Tinnel's and Phalen's provocation tests were also performed. CTS was diagnosed when individuals exhibited typical clinical symptoms and responded to non-surgical treatment without other evident neurological deficits. We did not rely solely on Tinnel's sign or Phalen's test to detect CTS. Standard nerve conduction studies (NCS) were performed with a Medelec-Oxford Synergy EMG machine, using a filter setting of 0.020−10 kHz and an analysis time of 50 ms. Impulses were recorded using surface electrodes. Conduction studies were performed in a warm room, such that the skin temperature of the extremities registered at 32 °C or above. Skin temperature was measured at the site where nerve conduction velocity measurements (NCV) were taken. Median motor and sensory (finger-wrist, wrist-elbow) nerve conduction velocities were measured in the bilateral upper extremities using the method described by Oh [4]. We also performed both motor and sensory conduction studies of the ulnar nerve. Patients with abnormalities in ulnar motor or sensory conduction were not included in the study. The electrophysiological criteria for the diagnosis of CTS are based on the parameters for electrodiagnostic studies established by the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation [5]. As described by Padua et al. [6], we classified the severity of CTS into four grades: mild, moderate, extreme, and severe. 2.2. Control group The control group was selected from among the healthy people. If a suitable control was unavailable for a case then an extra control was identified from the next available case seen. These control subjects were matched to the patients based on age (± 2 years). It was not deemed ethically justi-
fiable to perform nerve conduction testing on asymptomatic subjects; thus, healthy female subjects were selected based on the absence of clinical manifestations and neurological deficits suggestive of CTS. The same evaluations and examinations applied to each patient were also applied to each control subject. The same investigator (H.K.), who was unaware of the subject's clinical assessment at the time of the interview, conducted the interviews for both groups. Socio-demographic characteristics, body mass index (BMI), and detailed reproductive history were evaluated using a structured interview. Socio-demographic characteristics included age, marital status, occupation, level of education, and the number of pregnancies. BMI was calculated as bodyweight divided by the square of height (kg/m2). Reproductive history included age at menarche, age at menopause, type of menopause (natural or surgical), duration of menopause, and the use of postmenopausal hormone replacement therapy. Menopause was defined as the cessation of menses for 12 or more continuous months, as ascertained via self-reporting at the interview. Age at menopause was determined based on the date at which the subject stopped having regular periods. Menopause was classified as natural in the absence of surgical procedures that cause the cessation of menses. The duration of menopause was calculated for each woman by subtracting the age at menarche from the age at menopause. To limit our patients to those with purely idiopathic CTS, blood and urine analysis and wrist imaging were performed to detect diseases that might predispose an individual to CTS. We excluded all patients with diabetes mellitus, rheumatoid arthritis, chronic renal failure, gout, thyroid diseases, hyperlipidemia, wrist fractures, space-occupying lesions, gynecologic and non-gynecologic malignancies, and patients undergoing chemotherapy and/or radiotherapy. We also excluded patients and healthy subjects who were taking or had taken hormone replacement therapy. At the end of this process, cases comprised postmenopausal women with CTS and the control comprised agematched postmenopausal women without CTS. These groups were compared in terms of socio-demographic characteristics, BMI, and reproductive characteristics. 2.3. Statistical analysis Data are presented as the mean ± standard deviation (SD). We used Student's t-test to compare age, BMI, number of pregnancies, and age at menarche between groups. The Mann−Whitney U test was used to compare the age at menopause between groups. The Fisher exact chi-square test was used to compare categorical variables like marital status, occupation, level of education, and type of menopause. The Pearson correlation test was used to analyze the correlation between the duration of menopause and CTS. The Statistical Package for the Social Sciences (SPSS, version 12; SPSS
Y. Kaplan et al. / Journal of the Neurological Sciences 270 (2008) 77–81
79
Inc., Chicago, IL) was used for all statistical analyses. The level of statistical significance was set at p b 0.05.
Table 2 Comparison of reproductive characteristics between postmenopausal women with CTS and age-matched controls
3. Results
Parameter
Cases (n = 106)
Control group (n = 115)
p value
Overall, 6230 women were seen in our Neurology Department during the study period. Of these, 5587 were not eligible because they were premenopausal or perimenopausal. We saw 643 women who were both postmenopausal and had CTS. Of these, 537 women did not meet the criteria used in the study for a diagnosis of idiopathic CTS and were excluded. Finally, the cases and the control group contained 106 and 115 postmenopausal women, respectively. In the cases, the mean duration of CTS symptoms was 5.51 ± 4.46 years (range, 1−30). In these patients, CTS was classified as mild in 34 patients, moderate in 47 patients, severe in 16 patients, and extreme in 9 patients. Sixty-three (59.4%) patients exhibited bilateral CTS. These data indicate that most patients had mild or moderate, and bilateral CTS.
Age at menarche (years) a Age at menopause (years) a
12.75 ± 1.76 47.59 ± 5.18
12.60 ± 1.74 49.89 ± 3.09
NS 0.001
Type of menopause b Natural Surgical
76 (71.7) 30 (28.3)
91 (79.1) 24 (20.9)
NS
3.1. Socio-demographic data The subjects ranged in age from 37 to 69 years in the cases and from 39 to 67 years in the control. No significant difference in age, marital status, education, occupation, or BMI was observed between groups. However, the mean number of pregnancies was significantly higher in the cases (2.84 ± 1.61) compared to the control (1.77 ± 1.37; t, 5.30; p, 0.0001). The socio-demographic characteristics of both groups are presented in Table 1. Table 1 Comparison of sociodemographic characteristics between postmenopausal women with CTS and age-matched controls Features
Cases (n = 106)
Control group (n = 115)
p value
Age (years) a
55.49 ± 6.19
56.34 ± 5.76
NS
Marital status Married Other
90 (84.9) 16 (15.1)
94 (81.7) 21 (18.3)
NS
Education b Little education Primary Secondary High school University
14 (13.2) 36 (34) 42 (39.6) 6 (5.7) 8 (7.5)
12 (10.4) 35 (30.4) 48 (41.7) 7 (6.1) 13 (11.3)
NS
Occupation b Employed outside Home Home maker BMI (kg/m2) a Number of pregnancies a
44 (41.5) 62 (58.5) 30.58 ± 5.58 2.84 ± 1.61
45 (39.1) 70 (60.9) 29.72 ± 5.85 1.77 ± 1.37
NS
NS. non significant a Values represent the mean ± SD. b Values represent number (%).
NS 0.0001
NS. non significant. a Values represent the mean ± SD. b Values represent number (%).
3.2. Comparison of reproductive characteristics between groups No significant difference was observed in the age at menarche between groups. In addition, both groups showed similar frequencies regarding the type of menopause (natural versus surgical: 71.7/28.3 in the cases, 79.1/20.9 in the control). The frequency of natural menopause was significantly higher in both groups (p b 0.05). Furthermore, age at menopause was significantly lower in the cases (47.59 ± 5.18 years) compared to the control (49.89 ± 3.09 years; z, 4.221; p, 0.001) (Table 2). The mean duration of menopause was 7.91 ± 5.55 and the mean duration of CTS was 5.51 ± 4.46 years. The Pearson correlation analysis revealed a strong, significant correlation between these variables (r, 0.824; p, 0.0001). 4. Discussion We investigated the clinical features of menopause in postmenopausal women diagnosed with CTS. Although there are numerous studies regarding CTS and its associated conditions, very few studies have assessed the relationship between menopause and CTS. A number of investigators have reported that pregnancy is associated with an increased incidence of CTS [3,7–10]. The association between parity and CTS may be the result of the long-term hormonal effects of pregnancy or mechanisms associated with child rearing [3]. Ferry et al. found a weak but statistically significant link between parity and CTS [3]. However, Dieck et al. found that the number of pregnancies was not associated with a change in the frequency of CTS [11]. We found that the mean number of pregnancies is higher in postmenopausal women with CTS. Although CTS normally resolves toward the end of pregnancy or the postpartum period [10,11], these results suggest that hormonal changes related to pregnancy have long-term effects on the development of CTS in postmenopausal women. Finally, our results show that women with CTS underwent menopause at a younger age than women without, and there is a strong and significant positive correlation between the duration of CTS and menopause.
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Estrogen receptors are found throughout the central and peripheral nervous systems. In the peripheral nervous system, estrogen receptors are found in the spinal cord [12– 15], dorsal root ganglia [16–19], autonomic pelvic ganglia [14,15], sympathetic ganglia [20,21], and Schwann cells [22]. Numerous studies have shown that estrogens affect the nervous system via both genomic and non-genomic mechanisms, including the development, proliferation, and regeneration of neuronal cells, gene expression, energy metabolism, hormone sensitivity, and the biosynthesis of structural proteins and enzymes [12,15,17,19,23]. The hormonal changes that accompany menopause (i.e., decreased estrogen levels) have a significant impact on the nervous system and other physiological systems. Estrogen deficiency has long-term cumulative effects on many tissues. Previous studies showed a significant association between lesser age at menopause and a higher risk of cardiovascular disease, urogenital atrophy, cognitive impairment, epilepsy, and chronic degenerative diseases such as osteoporosis, Parkinson's disease, and Alzheimer's disease [24–26]. We could not find any published study which has evaluated the age at menopause of women with CTS except one study. A study by de Krom et al. examined the relationship between age at menopause and CTS in women, but was unable to demonstrate a clear relationship between these variables [27]. Although previous studies have demonstrated that surgical menopause may be a precipitating factor for CTS [7,28], we found that both groups experienced similar frequencies of natural versus surgical menopause. The frequency of natural menopause was significantly higher than surgical menopause in both groups. These findings suggest that age at menopause may be more significant than menopause type in the development of CTS. Based on this information, we hypothesize that hypoestrogenemia, which is characterized by a decreased ovarian follicular response to gonadotropins and estrogen secretion, may influence the median nerve and/or other components of the carpal tunnel. This study has several limitations. First, we did not establish a causal mechanism between hypoestrogenemia and CTS. Second, the accuracy of self-reported menopausal status and age at menopause may be potential concern. To further strengthen our data set, we excluded women who were using or had used postmenopausal hormone replacement therapy. Hormone replacement during the perimenopausal period may artificially prolong cyclic menstrual bleeding [29]. In addition, previous studies have shown that estrogen has therapeutic value in CTS patients [7,30]. Despite these limitations, our results suggest that number of pregnancies and age at menopause may be precipitating factors for CTS in postmenopausal women. Further controlled clinical studies are required to determine the longterm effects of hypoestrogenemia on the median nerve and other components of the carpal tunnel, and to determine the possible therapeutic effects of hormone replacement therapy in postmenopausal women with CTS.
References [1] WHO Scientific Group on Research on the Menopause in the 1990s. WHO technical report series. Geneva; 1996. p. 1–1007. [2] Sud V, Freeland AE. Biochemistry of carpal tunnel syndrome. Microsurgery 2005;25:44–6. [3] Ferry S, Hannaford P, Warskyj M, Lewis M, Croft P. Carpal tunnel syndrome: a nested case-control study of risk factors in women. Am J Epidemiol 2000;151:566–74. [4] Oh SJ. Clinical electromyography. Part 1: Anatomical guide for common nerve conduction studies. Second ed. Baltimore: Williams Wilkins Book Company; 1993. p. 57–1001. [5] American Academy of Neurology. American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Practice parameter for electrodiagnostic studies in carpal tunnel syndrome (summary statement). Neurology 1993;43: 2404–5. [6] Padua L, LoMonaco M, Gregori B, Valente EM, Padua R, Tonali P. Neurophysiological classification and sensitivity in 500 carpal tunnel syndrome hands. Acta Neurol Scand 1997;96:211–7. [7] Bjorkqvist SE, Lang AH, Punnonen R, Rauramo L. Carpal tunnel syndrome in ovariectomized women. Acta Obstet Gynecol Scand 1977;56:127–30. [8] Stevens JC, Beard CM, O'Fallon WM, Kurland LT. Conditions associated with carpal tunnel syndrome. Mayo Clin Proc 1992;67: 541–8. [9] Wand JS. Carpal tunnel syndrome in pregnancy and lactation. J Hand Surg 1990;15B:93–5. [10] Gould JS, Wissinger HA. Carpal tunnel syndrome in pregnancy. South Med J 1978;71:144–145, 154. [11] Dieck GS, Kelsey JL. An epidemiologic study of the carpal tunnel syndrome in an adult female population. Prev Med 1985;14:63–9. [12] Islamov RR, Hendricks WA, Katwa LC, McMurray RJ, Pak ES, Spanier NS, et al. Effect of 17 beta-estradiol on gene expression in lumbar spinal cord following sciatic nerve crush injury in ovariectomized mice. Brain Res 2003;966:65–75. [13] Papka RE, Hafemeister J, Puder BA, Usip S, Storey-Workley M. Estrogen receptor-alpha and neural circuits to the spinal cord during pregnancy. J Neurosci Res 2002;70:808–16. [14] Papka RE, Mowa CN. Estrogen receptors in the spinal cord, sensory ganglia, and pelvic autonomic ganglia. Int Rev Cytol 2003;231: 91–127. [15] Papka RE, Storey-Workley M, Shughrue PJ, Merchenthaler I, Collins JJ, Usip S, et al. Estrogen receptor-alpha and beta-immunoreactivity and mRNA in neurons of sensory and autonomic ganglia and spinal cord. Cell Tissue Res 2001;304:193–214. [16] Cui S, Goldstein RS. Expression of estrogen receptors in the dorsal root ganglia of the chick embryo. Brain Res 2000;882:236–40. [17] Liu J, Chen D, Goldstein RS, Cui S. Effect of male and female sex steroids on the development of normal and the transient Froriep's dorsal root ganglia of the chick embryo. Brain Res Dev 2005;155: 14–25. [18] Luizzi FJ, Scoville SA, Bufton SM. Effect of short-term estrogen replacement on trk mRNA levels in axotomized dorsal root ganglion neurons. Exp Neurol 1999;159:433–40. [19] Sohrabji F, Miranda RC, Toran-Allerand CD. Estrogen differentially regulates estrogen and nerve growth factor receptor mRNAs in adult sensory neurons. JNeurosci 1994;14:459–71. [20] Zoubina EV, Smith PG. Expression of estrogen receptors alpha and beta by sympathetic ganglion neurons projecting to the proximal urethra of female rats. J Urol 2003;169:382–5. [21] Zoubina EV, Smith PG. Distributions of estrogen receptors alpha and beta in sympathetic neurons of female rats: enriched expression by uterine innervation. J Neurobiol 2002;52:14–23. [22] Jung-Testas I, Schumacher M, Robel P, Baulieu EE. Actions of steroid hormones-and growth factors on glial cells of the central and peripheral nervous system. J Steroid Biochem Mol Biol 1994;48:145–54.
Y. Kaplan et al. / Journal of the Neurological Sciences 270 (2008) 77–81 [23] Purves-Tyson TD, Keast JR. Rapid actions of estradiol on cyclic AMP response element binding protein phosphorylation in dorsal root ganglion neurons. Neuroscience 2004;129:629–37. [24] Henderson VW. The neurology of menopause. Neurologist 2006;12: 149–59. [25] Maturana MA, Irigoyen MC, Spritzer PM. Menopause, estrogens, and endothelial dysfunction: current concepts. Clinics 2007;62:77–86. [26] Hu FB, Grodstein F, Hennekens CH, Colditz GA, Johnson M, Manson JE, et al. Age at natural menopause and risk of cardiovascular disease. Arch Intern Med 1999;159:1061–6. [27] de Krom MC, Kester AD, Knipschild PG, Spaans F. Risk factors for carpal tunnel syndrome. Am J Epidemiol 1990;132:1102–10.
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[28] Pascual E, Giner V, Arostegui A, Conill J, Ruiz MT, Pico A. Higher incidence of carpal tunnel syndrome in oophorectomized women. Br J Rheumatol 1991;30:60–2. [29] Whelan EA, Sandler DP, McConnaughey DR, Weinberg CR. Menstrual and reproductive characteristics and age at natural menopause. Am J Epidemiol 1990;131:625–32. [30] Confino-Cohen R, Lishner M, Savin H, Lang R, Ravid M. Response of carpal tunnel syndrome to hormone replacement therapy. BMJ 1991;303(6816):1514–9.