Menopause: The Journal of The North American Menopause Society Vol. 20, No. 11, pp. 1200/1203 DOI: 10.1097/gme.0000000000000101 * 2013 by The North American Menopause Society
BRIEF REPORT Menopause after a history of intrahepatic cholestasis of pregnancy Kaisa Turunen, MD,1 Kristiina Helander, MA,1 Kari J. Mattila, MD, PhD,1,2 and Markku Sumanen, MD, PhD1 Abstract Objective: Intrahepatic cholestasis of pregnancy is a hormone-provoked disorder that fades quickly after parturition. The aim of this study was to establish whether a history of intrahepatic cholestasis of pregnancy reduces the use of hormone therapy for menopausal symptoms and, irrespective of hormone therapy, whether intrahepatic cholestasis is associated with other health aspects after menopause. Methods: In 2010, questionnaires were sent to a cohort of women who delivered in Tampere University Hospital, Finland, from 1969 to 1988. The study population comprised postmenopausal women with a history of intrahepatic cholestasis of pregnancy (n = 189) and their controls (n = 416). The main outcome measures were the use of hormone therapy and other means of alleviating menopausal symptoms, and the diseases the women reported. Results: There were no differences in the use of hormone therapy between the two groups. Of the diseases reported, breast cancer, hepatobiliary diseases, and hypothyroidism were more frequent among women with a history of intrahepatic cholestasis of pregnancy, whereas cardiac arrhythmia was less frequent. With respect to other diseases, there were no differences. Conclusions: A history of intrahepatic cholestasis of pregnancy does not reduce the use of hormone therapy. However, when physicians prescribe hormone therapy for these women, a history of intrahepatic cholestasis of pregnancy calls for attention in view of its association with gallstones. Key Words: Intrahepatic cholestasis of pregnancy Y Hormone therapy Y Menopause Y Breast cancer Y Gallstones Y Hypothyroidism.
W
hen a pregnant woman in her third trimester complains of itching on otherwise healthy skin, laboratory tests to detect intrahepatic cholestasis of pregnancy (ICP) are indicated. The incidence of ICP is 1% of pregnancies.1 ICP is a minor complaint among mothers that abates quickly after parturition but calls for alterations in obstetric management because of fetal risks,2,3 which result in increased induction of labor and cesarean section in these women.4,5 With respect to the subsequent health of women with a history of ICP, our recent study showed higher frequencies of reported breast cancer, hypothyroidism, and hepatobiliary diseases, and lower frequencies of hypertension, elevated cholesterol level, and cardiac arrhythmia.6 ICP is familial in 16% of cases,7 and pedigree structures show dominant inheritance. Different gene expression profiles
Received June 3, 2013; revised and accepted August 22, 2013. From the 1Department of General Practice, School of Medicine, University of Tampere, Finland; and 2Center for General Practice, Pirkanmaa Hospital District, Tampere, Finland. Funding/support: The Center for General Practice at the Tampere University Hospital District funded the postal survey. Financial disclosure/conflicts of interest: None reported. Address correspondence to: Kaisa Turunen, MD, Department of General Practice, School of Medicine, FI-33014 University of Tampere, Finland. E-mail: [email protected]
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may contribute to the complex pathogenesis of ICP.8 It is possible that this condition, coinciding with the intense hormonal activity of pregnancy, might predispose women to changes in liver metabolism and to variations in hormonal changes, hormone-linked symptoms and diseases, or hormonal interventions. Research has been performed to assess the risk-to-benefit ratio of hormone therapy (HT) in alleviating menopausal symptoms and in preventing or postponing certain diseases. Women with a history of ICP have previously been advised not to use hormonal medications. However, oral or transdermal HT does not affect the levels of hyaluronic acid and other liver markers in women with a history of ICP.9 After menopause, the risks for osteoporosis and osteoporotic fractures increase; it has been estimated that up to half of women develop a bone fracture during their postmenopausal life.10 Estrogen increases bone mineral density, especially in older women, even at very low doses.11 The Women’s Health Initiative reported a decreased risk of bone fractures with estrogen or estrogen-progestin treatment.12 Among postmenopausal women, small elevations in C-reactive proteinVwithin the range not indicative of infectionVpredict cardiovascular risk.13 Oral or transdermal HT does not affect C-reactive protein levels either in the presence or in the absence of ICP.14 Some early evidence indicated that HT reduces the risk of
Menopause, Vol. 20, No. 11, 2013
Copyright © 2013 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
ICP AND MENOPAUSE
coronary heart disease events when started on healthy women within a few years of menopause,15 but new research on these women is warranted. Estrogen use for less than 5 years is associated with a reduced risk of breast cancer, whereas estrogen use for 5 years or more leads to four to six extra breast cancers for every 10,000 woman-years.16 Estrogen combined with progestin increases the risk of breast cancer even when used for less than 5 years.17 An episode of intrahepatic cholestasis in 1969-1988 reduced women’s later use of hormonal contraception.18 Our aim here was to test the hypothesis that a history of ICP reduces the use of HT for menopausal symptoms andV irrespective of HTVinfluences other health aspects after menopause. METHODS The basic study population comprised 575 women with ICP and 1,374 controls who all delivered in Tampere University Hospital, Finland, between 1969 and 1988.6 The women with a diagnosis of ICP were selected from the hospital discharge register. The diagnosis was verified from patient recordsVwith the main symptom being itchingVtogether with at least one elevated liver test value. The parturient previous to and the parturient following each index woman in the delivery ward diary were chosen as controls. A postal survey was conducted in 2010. Questionnaires were sent to 544 women with ICP and 1,235 controls. Research approval was obtained from the Ethics Committee of the Pirkanmaa Hospital District (R02149). Women in the ICP and control groups received similar questionnaires. They were asked for their age at menarche and their last period indicating menopause. The questions BHave you ever had any disease or symptom during pregnancy that has prevented you from using hormones (such as oral contraceptive pills, other hormonal medication, menopausal hormone therapy)?[ and BHave you ever been told that because of a liver problem you cannot use oral contraceptive pills or be treated with hormonal medication?[ were conceived to explore any problems regarding the use of contraception and HT. A panel of 24 common symptoms and complaints was presented, and the question read as follows: BIn the past 12 months, have you been bothered by any of the following symptoms or complaints?[ Here, only those which might have been relevant to menopause or postmenopause are discussed. Furthermore, questions regarding HT read: BHave you ever used hormone therapy?[ and BDo you currently use hormone therapy?[ Tibolone use was later queried using a separate question. Respondents were also asked to indicate any alternative nonhormone medications or other methods they had used in managing menopausal symptoms. The question concerning diseases was BHas a doctor ever told you that you have or have had any of the following diseases or conditions?[ Respondents were asked to tick boxes on a panel of 45 diseases and conditions, and to report any wrist, hip, and vertebral column fractures they had experienced. Of these conditions, breast cancer, cardiovascular diseases, osteoporosis,
and hepatobiliary diseases were most relevant to menopause and a history of ICP. Statistical analyses were performed using the SPSS System for Windows, release 20.0. Results are presented as frequencies, percentages, means, and medians. Statistical significance was tested with W2 test. RESULTS Acceptable responses to the questionnaire survey (with one reminder) were received from a total of 1,178 women, with the response rate being 66.2% (68.2% among women with ICP and 65.3% among control women). The two groups did not differ statistically significantly in age, education, or present body mass index. The study population, in keeping with the whole Finnish population in 1969-1988, was extremely homogeneous in ethnicity. The postmenopausal study population comprised 189 women with a history of ICP and 416 control women who had all reported that their menstruation had ceased naturally because of menopause. Age at menarche and age at menopause did not separate the ICP and control groups. The mean and median ages at menarche were 13 years in both groups. When menstruation ceased, the mean ages were 51.4 versus 51.5 years, and the median age was 52 years in both groups. More women with a history of ICP than women without a history of ICP reported obstacles or prohibitions with respect to hormone use. Of the total respondents, 23.2% of the ICP group and 1.9% of the control group reported having had a disease or symptom during pregnancy that prevented them from using hormones, with the difference being statistically significant (P G 0.001). In the ICP group, 31% of those women who had been told not to use hormones had used HT, whereas 51% of those who did not report a denial of hormones had used HT. The difference was statistically significant (P = 0.021). Altogether, 37.8% of the ICP group and 2.7% of the control group reported having been told not to use oral contraceptive pills or not to be treated with HT because of a liver problem (P G 0.001). Despite preconditions, however, there were no statistically significant differences in HT use between the groups. Among women with ICP and controls, 46.6% and 43.3% (P = 0.450), respectively, reported having used HT at some time (Table 1), whereas current use of HT was reported by 30.7% versus 34.4% (P = 0.540). All those who reported having used tibolone also reported having used HT, and tibolone use did not differ between the groups. HT was the most common means for alleviating menopausal symptoms. One of seven respondents had used health food store or similar products, but none of the nonhormonal methods brought out differences between the groups (Table 1). The prevalences of common symptoms and complaints during the past 12 months, as well as diseases or conditions confirmed by a doctor as reported by the respondents, are presented in Table 2. There were no statistically significant between-group differences in the frequencies of recently experienced symptoms and complaints. Menopause, Vol. 20, No. 11, 2013
Copyright © 2013 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
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TURUNEN ET AL TABLE 1. Use of hormone therapy, other medications, or treatments to alleviate menopausal symptoms in the ICP (n = 189) and control (n = 416) groups Difference ICP group (%)
Control group (%)
% Units
P
46.6 6.9 8.5 1.1 6.9 15.3 1.1 1.6
43.3 5.3 7.7 0.7 7.0 15.6 3.4 4.1
3.3 1.6 0.8 0.4 j0.1 j0.3 j2.3 j2.5
0.450 0.438 0.744 0.671 0.967 0.930 0.101 0.111
Hormone therapy Sleeping pills Other medications and/or methods Sedatives Vitamins Health food store or similar products Medicine for heart arrhythmia and palpitations Antidepressants ICP, intrahepatic cholestasis of pregnancy.
Breast cancer was reported by 14 women (7.4%) in the ICP group and 8 women (1.9%) in the control group, with the difference being statistically significant (P = 0.001; Table 2). Among breast cancer patients, 7 of 14 in the ICP group and 3 of 8 in the control group had at some time used HT. Acute myocardial infarction was reported by no one in the ICP group and by eight women (2.0%) in the control group, with the difference, however, being not statistically significant (P = 0.054). Cardiac arrhythmia diagnosed by a doctor was less common in the ICP group than in the control group, but high cholesterol or blood pressure medication prescribed by a doctor showed no marked differences between the groups. Hepatobiliary and thyroid gland diseases showed increased frequencies among women with ICP. There were no differences in the occurrences of asthma, diabetes, gastrointestinal diseases, or rheumatoid arthritis. Likewise, the frequencies of osteoporosis or bone fractures (wrist, hip, or vertebral column) showed no statistically significant differences between the
groups. Moreover, no woman reported having had a fracture of the vertebral column.
DISCUSSION Our hypothesis that a history of ICP reduced women’s use of HT was not confirmed. On the other hand, ICP was reflected in women’s postmenopausal life, with a higher occurrence of breast cancer. Cardiac arrhythmia was more common in the control group than in the ICP group; however, with respect to other diseases or conditions and recent symptoms or complaints, there were no differences between the groups. The original study population was comprehensive, including all verified ICP cases in Tampere University Hospital from 1969 to 1988, and the ICP and control groups did not differ significantly with respect to age, body mass index, or educational level. For a postal survey, the 66% response rate
TABLE 2. Symptoms, complaints, and diseases of postmenopausal respondents in the ICP (n = 189) and control (n = 416) groups Difference
Symptoms and complaints in the past 12 mo Vaginal and vulvar dryness Chest pain Blushing Headache Insomnia Heart palpitations Nervousness Sweating Urinary problems Depression Current or past diseases of respondents (according to the doctor) Gallstones Rise in liver function test (except during pregnancy) Hypothyroidism Goiter Breast cancer Chronic choledochitis Bone fractures Angina pectoris Osteoporosis Myocardial infarction Cardiac arrhythmia ICP, intrahepatic cholestasis of pregnancy.
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Menopause, Vol. 20, No. 11, 2013
ICP group (%)
Control group (%)
% Units
P
40.2 13.2 21.2 33.9 38.6 27.5 18.5 45.0 14.3 13.2
33.2 9.1 19.7 32.7 37.5 27.9 19.7 46.2 16.3 16.1
7.0 4.1 1.5 1.2 1.1 j0.4 j1.2 j1.2 j2.0 j2.9
0.093 0.127 0.680 0.777 0.792 0.925 0.731 0.787 0.519 0.361
39.2 14.8 15.9 9.5 7.4 6.3 11.1 4.2 4.8 0.0 14.3
12.0 7.9 9.9 3.8 1.9 1.2 9.1 3.4 6.5 1.9 21.2
27.2 6.9 6.0 5.7 5.5 5.1 2.0 0.8 j1.7 j1.9 j6.9
G0.001 0.009 0.033 0.005 0.001 G0.001 0.448 0.597 0.405 0.055 0.046
* 2013 The North American Menopause Society
Copyright © 2013 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
ICP AND MENOPAUSE
can be considered high. Thus, the data can be regarded as reliable, and the results can be considered generalizable. Our questionnaire survey produced information with a focus on the respondents’ own experience. It is conceivable that some of the answers may be objectively wrong, as they may have been derived from misremembered details, misunderstandings, or wrong interpretations, but this pertains to both the ICP group and the control group. A higher occurrence of breast cancer among women with ICP in our study is a new finding. The association between ICP, HT, and breast cancer cannot be established based solely on our data because of the small number of breast cancer patients who used HT. A conspicuous weakness in our study was that we could not present the length of use of estrogen, progesterone, and/or tibolone. Future research will establish whether a history of ICP should be considered a contraindication for HT use in view of an increased risk of breast cancer. One explanation for the higher breast cancer occurrence among women with ICP might be that, compared with controls, they have fewer children,18 which is a known risk factor for breast cancer.19 In the short run, gene research of ICP may explain the genetics behind the pathophysiology of ICP and breast cancer. According to previous research, hypothyroidism is associated with gallstones.20 ICP is associated with a higher occurrence of hypothyroidism and hepatobiliary diseases such as gallstones.6 Our study confirms prior findings. Caution is thus warranted in prescribing estrogen therapy for women with a history of ICP because estrogen is causally associated with gallbladder disease, and women with asymptomatic gallstones should not receive estrogens in view of the risk of cholecystitis.21,22 In this cohort, a history of ICP did not reduce the use of HT, which has probably been important for the quality of life of these women. The number of women who reported having been advised against the use of contraceptive hormones or HT because of a liver problem was higher than the number of women who reported having been told not to use hormones because of a liver problem during pregnancy. One explanation for this might lie in testing: Up to the 1990s, a few months after the introduction of oral contraceptive use, aminotransferases were commonly tested in Finnish health center family planning offices. We suggest that slight rises in aminotransferase values may have prevented hormone use unnecessarily. We cannot tell whether gallstones were diagnosed before or during HT. It is thus possible that, in some cases, HT has turned asymptomatic gallstones into symptomatic ones and even complicated them. CONCLUSIONS A history of ICP does not reduce the use of HT. However, a history of ICP calls for attention when physicians prescribe HT because ICP is associated with a higher occurrence of gallstones. Further research is needed before any conclusions can
be drawn regarding associations between HT and an elevated breast cancer risk among women with a history of ICP. REFERENCES 1. Lammert F, Marschall HU, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol 2000;33:1012-1021. 2. Laatikainen T, Tulenheimo A. Maternal serum bile acid levels and fetal distress in cholestasis of pregnancy. Int J Gynaecol Obstet 1984; 22:91-94. 3. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology 2004;40:467-474. 4. Heinonen S, Kirkinen P. Pregnancy outcome with intrahepatic cholestasis. Obstet Gynecol 1999;94:189-193. 5. Turunen K, Sumanen M, Haukilahti RL, Kirkinen P, Mattila K. Good pregnancy outcome despite intrahepatic cholestasis. Scand J Prim Health Care 2010;28:102-107. 6. Turunen K, Mo¨lsa¨ A, Helander K, Sumanen M, Mattila KJ. Health history after intrahepatic cholestasis of pregnancy. Acta Obstet Gynecol Scand 2012;9:679-685. 7. Savander M, Ropponen A, Avela K, et al. Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy. Gut 2003;52:1025-1029. 8. Floreani A, Caroli D, Lazzari R, et al. Intrahepatic cholestasis of pregnancy: new insights into its pathogenesis. J Matern Fetal Neonatal Med 2013;26:1410-1415. 9. Tuomikoski P, Aittoma¨ki K, Mikkola TS, et al. Effect of oral and transdermal hormone therapy on hyaluronic acid in women with and without a history of intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol 2008;198:375.e1-375.e5. 10. Gallagher JC, Levine JP. Preventing osteoporosis in symptomatic postmenopausal women. Menopause 2011;18:109-118. 11. Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M. Ultra low-dose micronized 17A-estradiol and bone density in older women: a randomized controlled trial. JAMA 2003;290:1042-1048. 12. Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA 2003;290:1729-1738. 13. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836-843. 14. Ropponen A, Aittoma¨ki K, Tikkanen MJ, Ylikorkala O. Levels of serum C-reactive protein during oral and transdermal estradiol in postmenopausal women with and without a history of intrahepatic cholestasis of pregnancy. J Clin Endocrinol Metab 2005;90:142-146. 15. Harman SM, Vittinghoff E, Brinton EA, et al. Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. Am J Med 2011;124:199-205. 16. Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmenopausal women using estrogen-only therapy. Obstet Gynecol 2006;108: 1354-1360. 17. Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmenopausal women using estradiol-progestogen therapy. Obstet Gynecol 2009;113:65-73. 18. Mo¨lsa¨ A, Turunen K, Mattila KJ, Sumanen M. Unnecessary confusion about family planning after intrahepatic cholestasis of pregnancy. Contraception 2012:86;639-644. 19. DiSaia PJ, Creasman WT. Breast diseases. In: DiSaia PJ, Creasman WT, eds. Clinical Gynecologic Oncology, 6th ed. St Louis, MO: Mosby, 2002: 399-402. 20. Laukkarinen J, Kiudelis G, Lempinen M, et al. Increased prevalence of subclinical hypothyroidism in common bile duct stone patients. J Clin Endocrinol Metab 2007;92:4260-4264. 21. Hart AR, Luben R, Welch A, Bingham S, Khaw KT. Hormone replacement therapy and symptomatic gallstonesVa prospective population study in the EPIC-Norfolk cohort. Digestion 2008;77:4-9. 22. Dhiman RK, Chawla YK. Is there a link between oestrogen therapy and gallbladder disease? Expert Opin Drug Saf 2006;5:117-129.
Menopause, Vol. 20, No. 11, 2013
Copyright © 2013 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
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BRIEF REPORT Menopause after a history of intrahepatic cholestasis of pregnancy Kaisa Turunen, MD,1 Kristiina Helander, MA,1 Kari J. Mattila, MD, PhD,1,2 and Markku Sumanen, MD, PhD1 Abstract Objective: Intrahepatic cholestasis of pregnancy is a hormone-provoked disorder that fades quickly after parturition. The aim of this study was to establish whether a history of intrahepatic cholestasis of pregnancy reduces the use of hormone therapy for menopausal symptoms and, irrespective of hormone therapy, whether intrahepatic cholestasis is associated with other health aspects after menopause. Methods: In 2010, questionnaires were sent to a cohort of women who delivered in Tampere University Hospital, Finland, from 1969 to 1988. The study population comprised postmenopausal women with a history of intrahepatic cholestasis of pregnancy (n = 189) and their controls (n = 416). The main outcome measures were the use of hormone therapy and other means of alleviating menopausal symptoms, and the diseases the women reported. Results: There were no differences in the use of hormone therapy between the two groups. Of the diseases reported, breast cancer, hepatobiliary diseases, and hypothyroidism were more frequent among women with a history of intrahepatic cholestasis of pregnancy, whereas cardiac arrhythmia was less frequent. With respect to other diseases, there were no differences. Conclusions: A history of intrahepatic cholestasis of pregnancy does not reduce the use of hormone therapy. However, when physicians prescribe hormone therapy for these women, a history of intrahepatic cholestasis of pregnancy calls for attention in view of its association with gallstones. Key Words: Intrahepatic cholestasis of pregnancy Y Hormone therapy Y Menopause Y Breast cancer Y Gallstones Y Hypothyroidism.
W
hen a pregnant woman in her third trimester complains of itching on otherwise healthy skin, laboratory tests to detect intrahepatic cholestasis of pregnancy (ICP) are indicated. The incidence of ICP is 1% of pregnancies.1 ICP is a minor complaint among mothers that abates quickly after parturition but calls for alterations in obstetric management because of fetal risks,2,3 which result in increased induction of labor and cesarean section in these women.4,5 With respect to the subsequent health of women with a history of ICP, our recent study showed higher frequencies of reported breast cancer, hypothyroidism, and hepatobiliary diseases, and lower frequencies of hypertension, elevated cholesterol level, and cardiac arrhythmia.6 ICP is familial in 16% of cases,7 and pedigree structures show dominant inheritance. Different gene expression profiles
Received June 3, 2013; revised and accepted August 22, 2013. From the 1Department of General Practice, School of Medicine, University of Tampere, Finland; and 2Center for General Practice, Pirkanmaa Hospital District, Tampere, Finland. Funding/support: The Center for General Practice at the Tampere University Hospital District funded the postal survey. Financial disclosure/conflicts of interest: None reported. Address correspondence to: Kaisa Turunen, MD, Department of General Practice, School of Medicine, FI-33014 University of Tampere, Finland. E-mail: [email protected]
1200
may contribute to the complex pathogenesis of ICP.8 It is possible that this condition, coinciding with the intense hormonal activity of pregnancy, might predispose women to changes in liver metabolism and to variations in hormonal changes, hormone-linked symptoms and diseases, or hormonal interventions. Research has been performed to assess the risk-to-benefit ratio of hormone therapy (HT) in alleviating menopausal symptoms and in preventing or postponing certain diseases. Women with a history of ICP have previously been advised not to use hormonal medications. However, oral or transdermal HT does not affect the levels of hyaluronic acid and other liver markers in women with a history of ICP.9 After menopause, the risks for osteoporosis and osteoporotic fractures increase; it has been estimated that up to half of women develop a bone fracture during their postmenopausal life.10 Estrogen increases bone mineral density, especially in older women, even at very low doses.11 The Women’s Health Initiative reported a decreased risk of bone fractures with estrogen or estrogen-progestin treatment.12 Among postmenopausal women, small elevations in C-reactive proteinVwithin the range not indicative of infectionVpredict cardiovascular risk.13 Oral or transdermal HT does not affect C-reactive protein levels either in the presence or in the absence of ICP.14 Some early evidence indicated that HT reduces the risk of
Menopause, Vol. 20, No. 11, 2013
Copyright © 2013 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
ICP AND MENOPAUSE
coronary heart disease events when started on healthy women within a few years of menopause,15 but new research on these women is warranted. Estrogen use for less than 5 years is associated with a reduced risk of breast cancer, whereas estrogen use for 5 years or more leads to four to six extra breast cancers for every 10,000 woman-years.16 Estrogen combined with progestin increases the risk of breast cancer even when used for less than 5 years.17 An episode of intrahepatic cholestasis in 1969-1988 reduced women’s later use of hormonal contraception.18 Our aim here was to test the hypothesis that a history of ICP reduces the use of HT for menopausal symptoms andV irrespective of HTVinfluences other health aspects after menopause. METHODS The basic study population comprised 575 women with ICP and 1,374 controls who all delivered in Tampere University Hospital, Finland, between 1969 and 1988.6 The women with a diagnosis of ICP were selected from the hospital discharge register. The diagnosis was verified from patient recordsVwith the main symptom being itchingVtogether with at least one elevated liver test value. The parturient previous to and the parturient following each index woman in the delivery ward diary were chosen as controls. A postal survey was conducted in 2010. Questionnaires were sent to 544 women with ICP and 1,235 controls. Research approval was obtained from the Ethics Committee of the Pirkanmaa Hospital District (R02149). Women in the ICP and control groups received similar questionnaires. They were asked for their age at menarche and their last period indicating menopause. The questions BHave you ever had any disease or symptom during pregnancy that has prevented you from using hormones (such as oral contraceptive pills, other hormonal medication, menopausal hormone therapy)?[ and BHave you ever been told that because of a liver problem you cannot use oral contraceptive pills or be treated with hormonal medication?[ were conceived to explore any problems regarding the use of contraception and HT. A panel of 24 common symptoms and complaints was presented, and the question read as follows: BIn the past 12 months, have you been bothered by any of the following symptoms or complaints?[ Here, only those which might have been relevant to menopause or postmenopause are discussed. Furthermore, questions regarding HT read: BHave you ever used hormone therapy?[ and BDo you currently use hormone therapy?[ Tibolone use was later queried using a separate question. Respondents were also asked to indicate any alternative nonhormone medications or other methods they had used in managing menopausal symptoms. The question concerning diseases was BHas a doctor ever told you that you have or have had any of the following diseases or conditions?[ Respondents were asked to tick boxes on a panel of 45 diseases and conditions, and to report any wrist, hip, and vertebral column fractures they had experienced. Of these conditions, breast cancer, cardiovascular diseases, osteoporosis,
and hepatobiliary diseases were most relevant to menopause and a history of ICP. Statistical analyses were performed using the SPSS System for Windows, release 20.0. Results are presented as frequencies, percentages, means, and medians. Statistical significance was tested with W2 test. RESULTS Acceptable responses to the questionnaire survey (with one reminder) were received from a total of 1,178 women, with the response rate being 66.2% (68.2% among women with ICP and 65.3% among control women). The two groups did not differ statistically significantly in age, education, or present body mass index. The study population, in keeping with the whole Finnish population in 1969-1988, was extremely homogeneous in ethnicity. The postmenopausal study population comprised 189 women with a history of ICP and 416 control women who had all reported that their menstruation had ceased naturally because of menopause. Age at menarche and age at menopause did not separate the ICP and control groups. The mean and median ages at menarche were 13 years in both groups. When menstruation ceased, the mean ages were 51.4 versus 51.5 years, and the median age was 52 years in both groups. More women with a history of ICP than women without a history of ICP reported obstacles or prohibitions with respect to hormone use. Of the total respondents, 23.2% of the ICP group and 1.9% of the control group reported having had a disease or symptom during pregnancy that prevented them from using hormones, with the difference being statistically significant (P G 0.001). In the ICP group, 31% of those women who had been told not to use hormones had used HT, whereas 51% of those who did not report a denial of hormones had used HT. The difference was statistically significant (P = 0.021). Altogether, 37.8% of the ICP group and 2.7% of the control group reported having been told not to use oral contraceptive pills or not to be treated with HT because of a liver problem (P G 0.001). Despite preconditions, however, there were no statistically significant differences in HT use between the groups. Among women with ICP and controls, 46.6% and 43.3% (P = 0.450), respectively, reported having used HT at some time (Table 1), whereas current use of HT was reported by 30.7% versus 34.4% (P = 0.540). All those who reported having used tibolone also reported having used HT, and tibolone use did not differ between the groups. HT was the most common means for alleviating menopausal symptoms. One of seven respondents had used health food store or similar products, but none of the nonhormonal methods brought out differences between the groups (Table 1). The prevalences of common symptoms and complaints during the past 12 months, as well as diseases or conditions confirmed by a doctor as reported by the respondents, are presented in Table 2. There were no statistically significant between-group differences in the frequencies of recently experienced symptoms and complaints. Menopause, Vol. 20, No. 11, 2013
Copyright © 2013 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
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TURUNEN ET AL TABLE 1. Use of hormone therapy, other medications, or treatments to alleviate menopausal symptoms in the ICP (n = 189) and control (n = 416) groups Difference ICP group (%)
Control group (%)
% Units
P
46.6 6.9 8.5 1.1 6.9 15.3 1.1 1.6
43.3 5.3 7.7 0.7 7.0 15.6 3.4 4.1
3.3 1.6 0.8 0.4 j0.1 j0.3 j2.3 j2.5
0.450 0.438 0.744 0.671 0.967 0.930 0.101 0.111
Hormone therapy Sleeping pills Other medications and/or methods Sedatives Vitamins Health food store or similar products Medicine for heart arrhythmia and palpitations Antidepressants ICP, intrahepatic cholestasis of pregnancy.
Breast cancer was reported by 14 women (7.4%) in the ICP group and 8 women (1.9%) in the control group, with the difference being statistically significant (P = 0.001; Table 2). Among breast cancer patients, 7 of 14 in the ICP group and 3 of 8 in the control group had at some time used HT. Acute myocardial infarction was reported by no one in the ICP group and by eight women (2.0%) in the control group, with the difference, however, being not statistically significant (P = 0.054). Cardiac arrhythmia diagnosed by a doctor was less common in the ICP group than in the control group, but high cholesterol or blood pressure medication prescribed by a doctor showed no marked differences between the groups. Hepatobiliary and thyroid gland diseases showed increased frequencies among women with ICP. There were no differences in the occurrences of asthma, diabetes, gastrointestinal diseases, or rheumatoid arthritis. Likewise, the frequencies of osteoporosis or bone fractures (wrist, hip, or vertebral column) showed no statistically significant differences between the
groups. Moreover, no woman reported having had a fracture of the vertebral column.
DISCUSSION Our hypothesis that a history of ICP reduced women’s use of HT was not confirmed. On the other hand, ICP was reflected in women’s postmenopausal life, with a higher occurrence of breast cancer. Cardiac arrhythmia was more common in the control group than in the ICP group; however, with respect to other diseases or conditions and recent symptoms or complaints, there were no differences between the groups. The original study population was comprehensive, including all verified ICP cases in Tampere University Hospital from 1969 to 1988, and the ICP and control groups did not differ significantly with respect to age, body mass index, or educational level. For a postal survey, the 66% response rate
TABLE 2. Symptoms, complaints, and diseases of postmenopausal respondents in the ICP (n = 189) and control (n = 416) groups Difference
Symptoms and complaints in the past 12 mo Vaginal and vulvar dryness Chest pain Blushing Headache Insomnia Heart palpitations Nervousness Sweating Urinary problems Depression Current or past diseases of respondents (according to the doctor) Gallstones Rise in liver function test (except during pregnancy) Hypothyroidism Goiter Breast cancer Chronic choledochitis Bone fractures Angina pectoris Osteoporosis Myocardial infarction Cardiac arrhythmia ICP, intrahepatic cholestasis of pregnancy.
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ICP group (%)
Control group (%)
% Units
P
40.2 13.2 21.2 33.9 38.6 27.5 18.5 45.0 14.3 13.2
33.2 9.1 19.7 32.7 37.5 27.9 19.7 46.2 16.3 16.1
7.0 4.1 1.5 1.2 1.1 j0.4 j1.2 j1.2 j2.0 j2.9
0.093 0.127 0.680 0.777 0.792 0.925 0.731 0.787 0.519 0.361
39.2 14.8 15.9 9.5 7.4 6.3 11.1 4.2 4.8 0.0 14.3
12.0 7.9 9.9 3.8 1.9 1.2 9.1 3.4 6.5 1.9 21.2
27.2 6.9 6.0 5.7 5.5 5.1 2.0 0.8 j1.7 j1.9 j6.9
G0.001 0.009 0.033 0.005 0.001 G0.001 0.448 0.597 0.405 0.055 0.046
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ICP AND MENOPAUSE
can be considered high. Thus, the data can be regarded as reliable, and the results can be considered generalizable. Our questionnaire survey produced information with a focus on the respondents’ own experience. It is conceivable that some of the answers may be objectively wrong, as they may have been derived from misremembered details, misunderstandings, or wrong interpretations, but this pertains to both the ICP group and the control group. A higher occurrence of breast cancer among women with ICP in our study is a new finding. The association between ICP, HT, and breast cancer cannot be established based solely on our data because of the small number of breast cancer patients who used HT. A conspicuous weakness in our study was that we could not present the length of use of estrogen, progesterone, and/or tibolone. Future research will establish whether a history of ICP should be considered a contraindication for HT use in view of an increased risk of breast cancer. One explanation for the higher breast cancer occurrence among women with ICP might be that, compared with controls, they have fewer children,18 which is a known risk factor for breast cancer.19 In the short run, gene research of ICP may explain the genetics behind the pathophysiology of ICP and breast cancer. According to previous research, hypothyroidism is associated with gallstones.20 ICP is associated with a higher occurrence of hypothyroidism and hepatobiliary diseases such as gallstones.6 Our study confirms prior findings. Caution is thus warranted in prescribing estrogen therapy for women with a history of ICP because estrogen is causally associated with gallbladder disease, and women with asymptomatic gallstones should not receive estrogens in view of the risk of cholecystitis.21,22 In this cohort, a history of ICP did not reduce the use of HT, which has probably been important for the quality of life of these women. The number of women who reported having been advised against the use of contraceptive hormones or HT because of a liver problem was higher than the number of women who reported having been told not to use hormones because of a liver problem during pregnancy. One explanation for this might lie in testing: Up to the 1990s, a few months after the introduction of oral contraceptive use, aminotransferases were commonly tested in Finnish health center family planning offices. We suggest that slight rises in aminotransferase values may have prevented hormone use unnecessarily. We cannot tell whether gallstones were diagnosed before or during HT. It is thus possible that, in some cases, HT has turned asymptomatic gallstones into symptomatic ones and even complicated them. CONCLUSIONS A history of ICP does not reduce the use of HT. However, a history of ICP calls for attention when physicians prescribe HT because ICP is associated with a higher occurrence of gallstones. Further research is needed before any conclusions can
be drawn regarding associations between HT and an elevated breast cancer risk among women with a history of ICP. REFERENCES 1. Lammert F, Marschall HU, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol 2000;33:1012-1021. 2. Laatikainen T, Tulenheimo A. Maternal serum bile acid levels and fetal distress in cholestasis of pregnancy. Int J Gynaecol Obstet 1984; 22:91-94. 3. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology 2004;40:467-474. 4. Heinonen S, Kirkinen P. Pregnancy outcome with intrahepatic cholestasis. Obstet Gynecol 1999;94:189-193. 5. Turunen K, Sumanen M, Haukilahti RL, Kirkinen P, Mattila K. Good pregnancy outcome despite intrahepatic cholestasis. Scand J Prim Health Care 2010;28:102-107. 6. Turunen K, Mo¨lsa¨ A, Helander K, Sumanen M, Mattila KJ. Health history after intrahepatic cholestasis of pregnancy. Acta Obstet Gynecol Scand 2012;9:679-685. 7. Savander M, Ropponen A, Avela K, et al. Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy. Gut 2003;52:1025-1029. 8. Floreani A, Caroli D, Lazzari R, et al. Intrahepatic cholestasis of pregnancy: new insights into its pathogenesis. J Matern Fetal Neonatal Med 2013;26:1410-1415. 9. Tuomikoski P, Aittoma¨ki K, Mikkola TS, et al. Effect of oral and transdermal hormone therapy on hyaluronic acid in women with and without a history of intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol 2008;198:375.e1-375.e5. 10. Gallagher JC, Levine JP. Preventing osteoporosis in symptomatic postmenopausal women. Menopause 2011;18:109-118. 11. Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M. Ultra low-dose micronized 17A-estradiol and bone density in older women: a randomized controlled trial. JAMA 2003;290:1042-1048. 12. Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women’s Health Initiative randomized trial. JAMA 2003;290:1729-1738. 13. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836-843. 14. Ropponen A, Aittoma¨ki K, Tikkanen MJ, Ylikorkala O. Levels of serum C-reactive protein during oral and transdermal estradiol in postmenopausal women with and without a history of intrahepatic cholestasis of pregnancy. J Clin Endocrinol Metab 2005;90:142-146. 15. Harman SM, Vittinghoff E, Brinton EA, et al. Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. Am J Med 2011;124:199-205. 16. Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmenopausal women using estrogen-only therapy. Obstet Gynecol 2006;108: 1354-1360. 17. Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmenopausal women using estradiol-progestogen therapy. Obstet Gynecol 2009;113:65-73. 18. Mo¨lsa¨ A, Turunen K, Mattila KJ, Sumanen M. Unnecessary confusion about family planning after intrahepatic cholestasis of pregnancy. Contraception 2012:86;639-644. 19. DiSaia PJ, Creasman WT. Breast diseases. In: DiSaia PJ, Creasman WT, eds. Clinical Gynecologic Oncology, 6th ed. St Louis, MO: Mosby, 2002: 399-402. 20. Laukkarinen J, Kiudelis G, Lempinen M, et al. Increased prevalence of subclinical hypothyroidism in common bile duct stone patients. J Clin Endocrinol Metab 2007;92:4260-4264. 21. Hart AR, Luben R, Welch A, Bingham S, Khaw KT. Hormone replacement therapy and symptomatic gallstonesVa prospective population study in the EPIC-Norfolk cohort. Digestion 2008;77:4-9. 22. Dhiman RK, Chawla YK. Is there a link between oestrogen therapy and gallbladder disease? Expert Opin Drug Saf 2006;5:117-129.
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