The European Journal of Contraception and Reproductive Health Care, 2014; 19: 39–44
Association of oestrogen-containing contraceptives with pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex – Findings from a survey Matthias Sauter∗,†, Jannina Sigl∗, Klaus-Jürgen Schotten‡, Margit Günthner-Biller †,§ , Julia Knabl§ and Michael Fischereder∗,† ∗Medizinische Klinik und Poliklinik IV, Nephrologisches Zentrum, Klinikum der Universität München, †Interdisziplinäres Tuberöse Sklerose Zentrum des Klinikums der Universität München, ‡Institut für medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians Universität München, and §Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe – Innenstadt, Klinikum der Universität München, Munich, Germany
ABSTRACT
Objectives About 30–40% of women with tuberous sclerosis complex (TSC) develop pulmonary lymphangioleiomyomatosis (LAM). Oestrogen seems to be involved in LAM pathogenesis and oestrogen-containing contraception should be avoided in women with known LAM. However, there is very little data on the use of contraceptives in TSC patients. Methods We conducted a survey on the use of contraception and disease characteristics. The questionnaire was forwarded to all adult female TSC patients listed in the database of a German patient organisation. Results Data from 39 such patients could be analysed. Of these, 15 were diagnosed with LAM. Twenty-five patients (65%) confirmed current or past use of oestrogencontaining contraceptives. We found a suggestive correlation between the history of oestrogen-containing contraception, and LAM (Odds ratio: 6.500; 95% confidence interval: 1.199–35.230). However, oestrogen use was not associated with LAM complications. Conclusions Based on our findings, oestrogen-containing contraceptives should be resorted to by these patients only with great caution, and avoided whenever possible.
K E Y WO R D S
Tuberous sclerosis; Lymphangioleiomyomatosis; Oestrogen; Contraception; Combined hormonal contraceptives
Correspondence: Matthias Sauter, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Nephrologisches Zentrum, Ziemssenstr. 1, 80336 München, Germany. Tel: ⫹ 49 89 5160 3325. Fax: ⫹ 49 89 5610 4485. E-mail: [email protected]
© 2014 The European Society of Contraception and Reproductive Health DOI: 10.3109/13625187.2013.859667
Oestrogen and lymphangioleiomyomatosis
Sauter et al.
I N T RO D U C T I O N
Lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC) are two rare systemic disorders with common molecular anomalies. In TSC, which is an autosomal-dominant inherited disease, mutations in one of two tumour suppressor genes (TSC1 and TSC2) lead to the development of hamartomas in various organ systems. Clinical manifestations, among others, comprise epilepsy, mental retardation, renal angiomyolipoma and skin tumours1. LAM can occur either as a manifestation of TSC or as a sporadic variant that has been attributed to mutations of mainly the TSC2 gene2. This disorder primarily affects the lung and results in a cystic destruction of the lung parenchyma. Patients concerned are at an increased risk of developing recurrent pneumothorax, chylous pleural effusions, and progressive respiratory failure2. The sporadic variant of LAM (sLAM) is very rare: it affects approximately one in 400,000 adult women, whereas the estimated prevalence of TSC is 1:10,0003 and an associated LAM can be found in 30–40% of female TSC patients4. Although TSC-associated LAM is five to ten times more frequent than sLAM, most registries or interventional studies included mainly sLAM patients5–8. It has been suggested that the co-morbidities of TSC might prevent pulmonary problems from becoming health priorities, or that TSC-associated LAM might be a milder disease than sLAM2. Nevertheless, LAM accounted for 10% of TSC-related deaths in a historic cohort9. LAM, which nearly exclusively affects women, is thought to be accelerated by oestrogen4. Immunohistochemistry has shown that oestrogen receptors are present on LAM cells10, and endogenous or exogenous oestrogen excess has been associated with the onset or exacerbation of the disease11,12. Symptoms of LAM have been reported to express themselves earlier among women taking oral contraceptives (OCs). However, no distinction between oestrogencontaining combined oral contraceptives (COCs) and progestin-only pills (POPs) was made in the study concerned13. There are numerous case reports on record dealing with therapeutic attempts at hormonal manipulation with a view to diminishing or suppressing the suspected noxious influence of oestrogen. These strategies included oophorectomy and the use of tamoxifen14. However, the outcome
40
of these measures has varied14 and the European Respiratory Society LAM guidelines recommend the avoidance of such interventions because of the weakness of data and the associated side effects4. Intramuscular progesterone might be tried in patients with a rapid decline in lung function, although the data in support of this therapy are weak and conflicting4. Given the suspected role of oestrogen in the pathogenesis of the disorder, it has been recommended to avoid COCs in patients with diagnosed LAM4. However, there is no recommendation to date concerning the use of COCs in TSC-affected women (who are at high risk of developing LAM). Contraception in se is a challenge in these patients: especially in cases of an associated mental retardation or the concomitant use of an enzyme-inducing anti-epileptic drug15. The methods used need to be safe, easily applicable, and reliable. In view of all that is mentioned above, we wished to investigate the current practice of contraception in women affected by TSC, and to examine the correlation of LAM with exogenous oestrogen use in these subjects.
METHODS
The German Tuberous Sclerosis patient organisation (Tuberöse Sklerose Deutschland e.V.) database lists 163 women with definite TSC who were 18 years or older in 2010. All of them received a detailed questionnaire in November 2010 that would gather demographic data as well as information concerning TSC manifestations, pregnancies, current practice of contraception (if applicable), use of oral contraceptives or other hormone therapies in the past, and clinical manifestations of LAM. Participants or (in case of mental retardation) their legal representatives gave written consent for enrolment in the study. Whenever possible, relevant additional information was sought or the available information amended based on forwarded medical reports or interviews over the telephone with the attending physicians. After setting up an electronic database with all relevant information, the records were anonymised for data protection. All documents from which information was gathered, the questionnaire and the performance of the study were in accordance with the local ethics board’s instructions.
The European Journal of Contraception and Reproductive Health Care
Oestrogen and lymphangioleiomyomatosis
Sauter et al.
Statistical analysis of the database data Statistical analysis was performed using IBM SPSS Statistics 20. Calculations included cross tabs, Chisquared test, Fisher’s exact test, Wilcoxon-MannWhitney-test or Kruskal-Wallis analysis, if applicable. A p-value ⬍ 0.05 was considered statistically significant indicating a probability of less than 5% of wrongly rejecting the null hypothesis (no difference between the examined groups). When calculating odds ratios a confidence interval (CI) of 95% was used to assess statistical significance.
R E S U LT S
Table 2 Overview of currently used contraceptive methods in the examined cohort (N ⫽ 39). Use of contraceptives None Contraceptive use Female sterilisation Combined oral contraceptive Depot-progestin injection Progestin-only pill Intrauterine device LNG-IUS Barrier methods Vasectomy
Number of patients (%) 21 (54) 18 (46) 5 3 3 2 2 1 1 1
LNG-IUS, levonorgestrel releasing-intrauterine system.
Patient characteristics We received 39 completed questionnaires, corresponding with a return rate of 24%. The median age of the patients was 40 years (mean: 37.4 years), with a range of 19–59 years. Ten women were older than 45 years. The median age at the first diagnosis of TSC was nine years (mean 14.2 years). Organ involvement of skin, brain, kidney and lung was assessed in accordance with previous reports in the literature4,16–18 (Table 1). Fifteen participants (39%) reported at least one pregnancy. Current contraception and previous use of oestrogen-containing medication At the time of the survey, 21 (54%) of the evaluated women were not using any contraceptive method. Table 2 shows the distribution of contraceptive methods currently resorted to by the respondents; only three of them (8%) used a COC. However, 25 respondents (64%), including the three aforementioned,
Table 1 Distribution of tuberous sclerosis complex (TSC) organ manifestations in the examined cohort (N ⫽ 39). TSC manifestations
Number of patients (%)
Skin Brain Kidney Lung ( ⫽ LAM) Intellectual disability
39 (100) 38 (97) 35 (90) 15 (39) 13 (33)
LAM, pulmonary lymphangioleiomyomatosis.
reported having taken a COC at some time, whereas the 14 others (36%) had not. None of the women had ever resorted to oestrogen-containing products for reasons other than contraception. The median duration of oestrogen intake was five years (mean 7.94 years, range 0.04–31 years). Fourteen respondents (36%) knew about potential adverse effects of treatment with oestrogen on the course of their disease. Their major source of information in this regard had been the patients’ association (43%), followed by physicians with expertise in the domain of TSC treatment (29%), gynaecologists (7%), and the internet (7%). Use of oestrogen-containing medication is associated with LAM Thirteen of the 25 respondents who had taken a COC at some point stated they had been diagnosed with LAM, as compared to only two of the 14 who had never used oestrogen-containing medications (Odds ratio: 6.500; 95% CI: 1.199–35.230). There was no correlation between oestrogen intake duration and the existence of LAM; nor was oestrogen use statistically related to the occurrence of pneumothorax, the necessity of oxygen use, or the age at LAM diagnosis (ever use of COCs: median age 30 years; never use of COCs: median age 28 years). We found no link between the age at menarche and LAM. Pregnancy was not associated with a higher risk of pulmonary involvement; on the contrary, among subjects with a prior gravidity, the diagnosis of LAM was made significantly later than among those who never were pregnant (median age 38.0 vs. 26.5 years, p ⫽ 0.049). Table 3
The European Journal of Contraception and Reproductive Health Care
41
Oestrogen and lymphangioleiomyomatosis
Sauter et al.
Table 3 Correlation of oestrogen use at any time, pregnancy and age at menarche with the occurrence of pulmonary lymphangioleiomyomatosis (LAM).
Use of oestrogen-containing medication at any time Pregnancy Median age at menarche, years
LAM, n ⫽ 15 (39%)
No LAM, n ⫽ 24 (61%)
Yes n ⫽ 13 No n⫽2 Yes n ⫽ 7 No n⫽8 13 [range 11–14]
Yes n ⫽ 12 No n ⫽ 12 Yes n ⫽ 8 No n ⫽ 16 13 [range 11–16]
p-value (Fisher’s exact test) 0.038 n.s. n.s.
n.s., not significant; CI, confidence interval.
summarises the information on oestrogen intake, age at menarche and pregnancy in relation to LAM.
DISCUSSION
Findings and interpretation In this study, we examined the practice of contraception in a cohort of female, adult German TSC patients. It is difficult to interpret the overall small number of patients using contraception as ten of the women were older than 45 years and an even greater proportion of individuals possibly were not sexually active due to their underlying disease. Be that as it may, a low percentage of participants currently resorting to some contraception method used COCs (17% vs. 38% of the general female population of reproductive age residing in Germany)19. This may reflect the uncertainty and lack of knowledge about the practice of contraception among women with TSC. Although data on potential adverse effects of oestrogens on TSC manifestations are scarce, 36% of the participants in our survey were aware of this risk. The German patient organisation (and not their healthcare providers) was their major source of information in this respect. With regard to pulmonary manifestations of TSC, we found a suggestive correlation of LAM with intake of COCs by comparing with the Fisher’s exact test the groups with and without oestrogen use, and by calculating the odds ratio. It should be noted that the 95% confidence interval with regard to the relative risk minimally overlaps 1 (RR: 3.640, 95% CI: 0.956–13.863), thus indicating a lack of statistical significance. This might be due to the small number of participants. Furthermore, a prolonged oestrogen exposure, such as that associated 42
with an early menarche or with a long duration of COC intake, could not be identified as a potential risk factor for LAM. Systematic screening for LAM among female TSC patients once they have reached the age of 18 years may account for our finding that LAM was diagnosed significantly later in women who had been pregnant: systematic screening has only been performed for a few years. Older patients (who did not realise they had LAM for a length of time) may have been more likely to become pregnant than younger individuals (who submitted to systematic screening and were diagnosed with LAM at an earlier age) because LAM patients should be counselled that pregnancy may worsen their disease4. Limitations of the study Our study has several limitations, namely, the low response rate, the small number of participants, the retrospective data retrieval, and the self-reporting by patients. We also cannot exclude a selection bias as the patient organisation was used to forward the questionnaires and patients having developed LAM might more likely have participated. However, the pre-existing literature dealing with this topic is very limited, often focused on sLAM patients, and does not mention whether the OCs used contained an oestrogen. Our study was not affected by these weaknesses. Differences in results and conclusions in relation to other studies The early occurrence of LAM has been attributed to the use of oral contraceptives in a survey of 91 LAM patients13. However, the authors of that study did not discriminate between the use of COCs and POPs, nor
The European Journal of Contraception and Reproductive Health Care
Oestrogen and lymphangioleiomyomatosis
did they mention the proportion of TSC patients in the examined cohort. In another survey involving 23 women with LAM, the authors did not report a difference in the frequency of oral contraceptive usage compared to an age-matched control group20. But given the small number of patients, the very low incidence of LAM and the high prevalence of oral contraceptive use in the population, the comparison with an age-matched healthy control group might not be helpful to assess the influence the pill may have on LAM development. In addition, also that study did not discriminate between COCs and POPs, and did not differentiate between sLAM and TSCassociated LAM. Franz et al. examined 23 women with TSC but without symptoms of lung disease by means of computed tomography of the chest and found cystic changes consistent with LAM in nine of them. No difference with regard to oral contraception use was found between patients with- and those without LAM findings. Again, no distinction was made between COCs and POPs21. Unlike the authors of the aforementioned study (that is most comparable to our own investigation with regard to the patient cohort) we did find a suggestive correlation between the use of COCs and LAM in our cohort of TSC patients. In contrast to the findings reported by Oberstein et al.13 the age at LAM diagnosis was not related to the use of an oestrogen at some point. A possible explanation for this may be that TSC patients are routinely screened for LAM, even if they are asymptomatic4, whereas the diagnosis in sporadic LAM patients is usually made only once clinical symptoms have supervened.
Sauter et al.
disabilities. Enzyme-inducing anti-epileptic drugs are frequently used by TSC patients and they may considerably reduce the efficacy of certain contraceptives releasing synthetic sex steroids. Progestin-only pills (POPs) as well as COCs, when used in the usual dosage, are considered unsafe when taken in conjunction with an enzyme inducer. Some authors have suggested administering a COC with a high oestrogen content (50 μg ethinylestradiol) or even a higher dose15,22. In view of our findings and other potentially negative effects on TSC manifestations23,24 use of an alternative, preferably long-acting, method such as a copper intrauterine device or a levonorgestrel releasingintrauterine system should be recommended. Unanswered questions and future research Although the European Respiratory Society advises avoiding oestrogen-containing contraceptives in the presence of LAM4, little if any data are on record concerning the impact of combined hormonal contraceptives on TSC-associated LAM. Our findings add some hints to extend this recommendation to TSC patients at risk for LAM. However, a stronger base of evidence including reports of more cases is necessary.
CONCLUSION
Choosing a contraception method for a woman suffering from TSC is an arduous task and this is reflected in the uncertainty of patients and caregivers in this respect. Our data indicate a correlation between COC use and LAM in these patients. Oestrogens should be administered with great caution.
Relevance of the findings: implications for clinicians AC K N OW L E D G E M E N T S
Medical care for TSC-affected children is well established and mostly coordinated by paediatric neurologists. In contrast, transition to adult care is difficult and comprehensive care for adults often is not provided, even in specialised centres. Contraceptive counselling is frequently inappropriate. There is a strong desire for easily applicable, safe and reliable contraceptive methods in the context of an autosomal-dominant inherited disease like TSC. Sterilisation is often not requested now that there is a possibility of pre-implantation and prenatal genetic diagnosis, and it may raise ethical problems when one deals with patients with intellectual
This work was supported by Tuberöse Sklerose Deutschland e.V., which provided the database and forwarded the questionnaires. The authors are much indebted to Dr Klaus Schotten for verifing the statistical analysis of the data, and to Professor Dr Peter Nelson for undertaking a language edit of the manuscript. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper.
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Oestrogen and lymphangioleiomyomatosis
Sauter et al.
REFERENCES
1. Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008;372:657–68. 2. McCormack FX. Lymphangioleiomyomatosis: a clinical update. Chest 2008;133:507–16. 3. Krueger DA, Franz DN. Current management of tuberous sclerosis complex. Paediatr Drugs 2008;10: 299–313. 4. Johnson SR, Cordier JF, Lazor R, et al. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J 2010;35:14–26. 5. Ryu JH, Moss J, Beck GJ, et al. The NHLBI lymphangioleiomyomatosis registry: Characteristics of 230 patients at enrollment. Am J Resp Crit Care Med 2006;173:105–11. 6. McCormack FX, Inoue Y, Moss J, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011;364:1595–606. 7. Neurohr C, Hoffmann AL, Huppmann P, et al. Is sirolimus a therapeutic option for patients with progressive pulmonary lymphangioleiomyomatosis? Respir Res 2011;12:66. 8. Taveira-DaSilva AM, Hathaway O, Stylianou M, Moss J. Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus. Ann Int Med 2011;154:797–805. 9. Shepherd CW, Gomez MR, Lie JT, Crowson CS. Causes of death in patients with tuberous sclerosis. Mayo Clinic Proc 1991;66:792–6. 10. Matsui K, Takeda K, Yu ZX, et al. Downregulation of estrogen and progesterone receptors in the abnormal smooth muscle cells in pulmonary lymphangioleiomyomatosis following therapy. An immunohistochemical study. Am J Resp Crit Care Med 2000;161: 1002–9. 11. Wilson AM, Slack HL, Soosay SA, et al. Lymphangioleiomyomatosis. A series of three case reports illustrating the link with high oestrogen states. Scott Med J 2001;46:150–2. 12. Yano S. Exacerbation of pulmonary lymphangioleiomyomatosis by exogenous oestrogen used for infertility treatment. Thorax 2002;57:1085–6. 13. Oberstein EM, Fleming LE, Gomez-Marin O, Glassberg MK. Pulmonary lymphangioleiomyomatosis (LAM): Examining oral contraceptive pills and the onset of disease. J Womens Health 2003;12:81–5.
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14. Taylor JR, Ryu J, Colby TV, Raffin TA. Lymphangioleiomyomatosis. Clinical course in 32 patients. N Engl J Med 1990;323:1254–60. 15. Reddy DS. Clinical pharmacokinetic interactions between antiepileptic drugs and hormonal contraceptives. Expert Rev Clin Pharmacol 2010;3: 183–92. 16. Jozwiak S, Schwartz RA, Janniger CK, et al. Skin lesions in children with tuberous sclerosis complex: Their prevalence, natural course, and diagnostic significance. Int J Dermatol 1998;37:911–7. 17. Rakowski SK, Winterkorn EB, Paul E, et al. Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney Int 2006;70: 1777–82. 18. Joinson C, O’Callaghan FJ, Osborne JP, et al. Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychol Med 2003;33:335–44. 19. Gorenoi V, Schönermark MP, Hagen A. Nutzen und Risiken hormonaler Kontrazeptiva bei Frauen. Cologne: Deutsches Institut für Medizinische Dokumentation und Information (DIMDI) 2007. [In German] 20. Wahedna I, Cooper S, Williams J, et al. Relation of pulmonary lymphangio-leiomyomatosis to use of the oral contraceptive pill and fertility in the UK: A national case control study. Thorax 1994;49:910–4. 21. Franz DN, Brody A, Meyer C, et al. Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Resp Crit Care Med 2001;164:661–8. 22. French JA, Pedley TA. Clinical practice. Initial management of epilepsy. N Engl J Med 2008;359: 166–76. 23. El-Hashemite N, Walker V, Kwiatkowski DJ. Estrogen enhances whereas tamoxifen retards development of Tsc mouse liver hemangioma: A tumor related to renal angiomyolipoma and pulmonary lymphangioleiomyomatosis. Cancer Res 2005;65: 2474–81. 24. Gould Rothberg BE, Grooms MC, Dharnidharka VR. Rapid growth of a kidney angiomyolipoma after initiation of oral contraceptive therapy. Obstet Gynecol 2006;108:734–6.
The European Journal of Contraception and Reproductive Health Care
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Association of oestrogen-containing contraceptives with pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex – Findings from a survey Matthias Sauter∗,†, Jannina Sigl∗, Klaus-Jürgen Schotten‡, Margit Günthner-Biller †,§ , Julia Knabl§ and Michael Fischereder∗,† ∗Medizinische Klinik und Poliklinik IV, Nephrologisches Zentrum, Klinikum der Universität München, †Interdisziplinäres Tuberöse Sklerose Zentrum des Klinikums der Universität München, ‡Institut für medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians Universität München, and §Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe – Innenstadt, Klinikum der Universität München, Munich, Germany
ABSTRACT
Objectives About 30–40% of women with tuberous sclerosis complex (TSC) develop pulmonary lymphangioleiomyomatosis (LAM). Oestrogen seems to be involved in LAM pathogenesis and oestrogen-containing contraception should be avoided in women with known LAM. However, there is very little data on the use of contraceptives in TSC patients. Methods We conducted a survey on the use of contraception and disease characteristics. The questionnaire was forwarded to all adult female TSC patients listed in the database of a German patient organisation. Results Data from 39 such patients could be analysed. Of these, 15 were diagnosed with LAM. Twenty-five patients (65%) confirmed current or past use of oestrogencontaining contraceptives. We found a suggestive correlation between the history of oestrogen-containing contraception, and LAM (Odds ratio: 6.500; 95% confidence interval: 1.199–35.230). However, oestrogen use was not associated with LAM complications. Conclusions Based on our findings, oestrogen-containing contraceptives should be resorted to by these patients only with great caution, and avoided whenever possible.
K E Y WO R D S
Tuberous sclerosis; Lymphangioleiomyomatosis; Oestrogen; Contraception; Combined hormonal contraceptives
Correspondence: Matthias Sauter, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Nephrologisches Zentrum, Ziemssenstr. 1, 80336 München, Germany. Tel: ⫹ 49 89 5160 3325. Fax: ⫹ 49 89 5610 4485. E-mail: [email protected]
© 2014 The European Society of Contraception and Reproductive Health DOI: 10.3109/13625187.2013.859667
Oestrogen and lymphangioleiomyomatosis
Sauter et al.
I N T RO D U C T I O N
Lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC) are two rare systemic disorders with common molecular anomalies. In TSC, which is an autosomal-dominant inherited disease, mutations in one of two tumour suppressor genes (TSC1 and TSC2) lead to the development of hamartomas in various organ systems. Clinical manifestations, among others, comprise epilepsy, mental retardation, renal angiomyolipoma and skin tumours1. LAM can occur either as a manifestation of TSC or as a sporadic variant that has been attributed to mutations of mainly the TSC2 gene2. This disorder primarily affects the lung and results in a cystic destruction of the lung parenchyma. Patients concerned are at an increased risk of developing recurrent pneumothorax, chylous pleural effusions, and progressive respiratory failure2. The sporadic variant of LAM (sLAM) is very rare: it affects approximately one in 400,000 adult women, whereas the estimated prevalence of TSC is 1:10,0003 and an associated LAM can be found in 30–40% of female TSC patients4. Although TSC-associated LAM is five to ten times more frequent than sLAM, most registries or interventional studies included mainly sLAM patients5–8. It has been suggested that the co-morbidities of TSC might prevent pulmonary problems from becoming health priorities, or that TSC-associated LAM might be a milder disease than sLAM2. Nevertheless, LAM accounted for 10% of TSC-related deaths in a historic cohort9. LAM, which nearly exclusively affects women, is thought to be accelerated by oestrogen4. Immunohistochemistry has shown that oestrogen receptors are present on LAM cells10, and endogenous or exogenous oestrogen excess has been associated with the onset or exacerbation of the disease11,12. Symptoms of LAM have been reported to express themselves earlier among women taking oral contraceptives (OCs). However, no distinction between oestrogencontaining combined oral contraceptives (COCs) and progestin-only pills (POPs) was made in the study concerned13. There are numerous case reports on record dealing with therapeutic attempts at hormonal manipulation with a view to diminishing or suppressing the suspected noxious influence of oestrogen. These strategies included oophorectomy and the use of tamoxifen14. However, the outcome
40
of these measures has varied14 and the European Respiratory Society LAM guidelines recommend the avoidance of such interventions because of the weakness of data and the associated side effects4. Intramuscular progesterone might be tried in patients with a rapid decline in lung function, although the data in support of this therapy are weak and conflicting4. Given the suspected role of oestrogen in the pathogenesis of the disorder, it has been recommended to avoid COCs in patients with diagnosed LAM4. However, there is no recommendation to date concerning the use of COCs in TSC-affected women (who are at high risk of developing LAM). Contraception in se is a challenge in these patients: especially in cases of an associated mental retardation or the concomitant use of an enzyme-inducing anti-epileptic drug15. The methods used need to be safe, easily applicable, and reliable. In view of all that is mentioned above, we wished to investigate the current practice of contraception in women affected by TSC, and to examine the correlation of LAM with exogenous oestrogen use in these subjects.
METHODS
The German Tuberous Sclerosis patient organisation (Tuberöse Sklerose Deutschland e.V.) database lists 163 women with definite TSC who were 18 years or older in 2010. All of them received a detailed questionnaire in November 2010 that would gather demographic data as well as information concerning TSC manifestations, pregnancies, current practice of contraception (if applicable), use of oral contraceptives or other hormone therapies in the past, and clinical manifestations of LAM. Participants or (in case of mental retardation) their legal representatives gave written consent for enrolment in the study. Whenever possible, relevant additional information was sought or the available information amended based on forwarded medical reports or interviews over the telephone with the attending physicians. After setting up an electronic database with all relevant information, the records were anonymised for data protection. All documents from which information was gathered, the questionnaire and the performance of the study were in accordance with the local ethics board’s instructions.
The European Journal of Contraception and Reproductive Health Care
Oestrogen and lymphangioleiomyomatosis
Sauter et al.
Statistical analysis of the database data Statistical analysis was performed using IBM SPSS Statistics 20. Calculations included cross tabs, Chisquared test, Fisher’s exact test, Wilcoxon-MannWhitney-test or Kruskal-Wallis analysis, if applicable. A p-value ⬍ 0.05 was considered statistically significant indicating a probability of less than 5% of wrongly rejecting the null hypothesis (no difference between the examined groups). When calculating odds ratios a confidence interval (CI) of 95% was used to assess statistical significance.
R E S U LT S
Table 2 Overview of currently used contraceptive methods in the examined cohort (N ⫽ 39). Use of contraceptives None Contraceptive use Female sterilisation Combined oral contraceptive Depot-progestin injection Progestin-only pill Intrauterine device LNG-IUS Barrier methods Vasectomy
Number of patients (%) 21 (54) 18 (46) 5 3 3 2 2 1 1 1
LNG-IUS, levonorgestrel releasing-intrauterine system.
Patient characteristics We received 39 completed questionnaires, corresponding with a return rate of 24%. The median age of the patients was 40 years (mean: 37.4 years), with a range of 19–59 years. Ten women were older than 45 years. The median age at the first diagnosis of TSC was nine years (mean 14.2 years). Organ involvement of skin, brain, kidney and lung was assessed in accordance with previous reports in the literature4,16–18 (Table 1). Fifteen participants (39%) reported at least one pregnancy. Current contraception and previous use of oestrogen-containing medication At the time of the survey, 21 (54%) of the evaluated women were not using any contraceptive method. Table 2 shows the distribution of contraceptive methods currently resorted to by the respondents; only three of them (8%) used a COC. However, 25 respondents (64%), including the three aforementioned,
Table 1 Distribution of tuberous sclerosis complex (TSC) organ manifestations in the examined cohort (N ⫽ 39). TSC manifestations
Number of patients (%)
Skin Brain Kidney Lung ( ⫽ LAM) Intellectual disability
39 (100) 38 (97) 35 (90) 15 (39) 13 (33)
LAM, pulmonary lymphangioleiomyomatosis.
reported having taken a COC at some time, whereas the 14 others (36%) had not. None of the women had ever resorted to oestrogen-containing products for reasons other than contraception. The median duration of oestrogen intake was five years (mean 7.94 years, range 0.04–31 years). Fourteen respondents (36%) knew about potential adverse effects of treatment with oestrogen on the course of their disease. Their major source of information in this regard had been the patients’ association (43%), followed by physicians with expertise in the domain of TSC treatment (29%), gynaecologists (7%), and the internet (7%). Use of oestrogen-containing medication is associated with LAM Thirteen of the 25 respondents who had taken a COC at some point stated they had been diagnosed with LAM, as compared to only two of the 14 who had never used oestrogen-containing medications (Odds ratio: 6.500; 95% CI: 1.199–35.230). There was no correlation between oestrogen intake duration and the existence of LAM; nor was oestrogen use statistically related to the occurrence of pneumothorax, the necessity of oxygen use, or the age at LAM diagnosis (ever use of COCs: median age 30 years; never use of COCs: median age 28 years). We found no link between the age at menarche and LAM. Pregnancy was not associated with a higher risk of pulmonary involvement; on the contrary, among subjects with a prior gravidity, the diagnosis of LAM was made significantly later than among those who never were pregnant (median age 38.0 vs. 26.5 years, p ⫽ 0.049). Table 3
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Table 3 Correlation of oestrogen use at any time, pregnancy and age at menarche with the occurrence of pulmonary lymphangioleiomyomatosis (LAM).
Use of oestrogen-containing medication at any time Pregnancy Median age at menarche, years
LAM, n ⫽ 15 (39%)
No LAM, n ⫽ 24 (61%)
Yes n ⫽ 13 No n⫽2 Yes n ⫽ 7 No n⫽8 13 [range 11–14]
Yes n ⫽ 12 No n ⫽ 12 Yes n ⫽ 8 No n ⫽ 16 13 [range 11–16]
p-value (Fisher’s exact test) 0.038 n.s. n.s.
n.s., not significant; CI, confidence interval.
summarises the information on oestrogen intake, age at menarche and pregnancy in relation to LAM.
DISCUSSION
Findings and interpretation In this study, we examined the practice of contraception in a cohort of female, adult German TSC patients. It is difficult to interpret the overall small number of patients using contraception as ten of the women were older than 45 years and an even greater proportion of individuals possibly were not sexually active due to their underlying disease. Be that as it may, a low percentage of participants currently resorting to some contraception method used COCs (17% vs. 38% of the general female population of reproductive age residing in Germany)19. This may reflect the uncertainty and lack of knowledge about the practice of contraception among women with TSC. Although data on potential adverse effects of oestrogens on TSC manifestations are scarce, 36% of the participants in our survey were aware of this risk. The German patient organisation (and not their healthcare providers) was their major source of information in this respect. With regard to pulmonary manifestations of TSC, we found a suggestive correlation of LAM with intake of COCs by comparing with the Fisher’s exact test the groups with and without oestrogen use, and by calculating the odds ratio. It should be noted that the 95% confidence interval with regard to the relative risk minimally overlaps 1 (RR: 3.640, 95% CI: 0.956–13.863), thus indicating a lack of statistical significance. This might be due to the small number of participants. Furthermore, a prolonged oestrogen exposure, such as that associated 42
with an early menarche or with a long duration of COC intake, could not be identified as a potential risk factor for LAM. Systematic screening for LAM among female TSC patients once they have reached the age of 18 years may account for our finding that LAM was diagnosed significantly later in women who had been pregnant: systematic screening has only been performed for a few years. Older patients (who did not realise they had LAM for a length of time) may have been more likely to become pregnant than younger individuals (who submitted to systematic screening and were diagnosed with LAM at an earlier age) because LAM patients should be counselled that pregnancy may worsen their disease4. Limitations of the study Our study has several limitations, namely, the low response rate, the small number of participants, the retrospective data retrieval, and the self-reporting by patients. We also cannot exclude a selection bias as the patient organisation was used to forward the questionnaires and patients having developed LAM might more likely have participated. However, the pre-existing literature dealing with this topic is very limited, often focused on sLAM patients, and does not mention whether the OCs used contained an oestrogen. Our study was not affected by these weaknesses. Differences in results and conclusions in relation to other studies The early occurrence of LAM has been attributed to the use of oral contraceptives in a survey of 91 LAM patients13. However, the authors of that study did not discriminate between the use of COCs and POPs, nor
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did they mention the proportion of TSC patients in the examined cohort. In another survey involving 23 women with LAM, the authors did not report a difference in the frequency of oral contraceptive usage compared to an age-matched control group20. But given the small number of patients, the very low incidence of LAM and the high prevalence of oral contraceptive use in the population, the comparison with an age-matched healthy control group might not be helpful to assess the influence the pill may have on LAM development. In addition, also that study did not discriminate between COCs and POPs, and did not differentiate between sLAM and TSCassociated LAM. Franz et al. examined 23 women with TSC but without symptoms of lung disease by means of computed tomography of the chest and found cystic changes consistent with LAM in nine of them. No difference with regard to oral contraception use was found between patients with- and those without LAM findings. Again, no distinction was made between COCs and POPs21. Unlike the authors of the aforementioned study (that is most comparable to our own investigation with regard to the patient cohort) we did find a suggestive correlation between the use of COCs and LAM in our cohort of TSC patients. In contrast to the findings reported by Oberstein et al.13 the age at LAM diagnosis was not related to the use of an oestrogen at some point. A possible explanation for this may be that TSC patients are routinely screened for LAM, even if they are asymptomatic4, whereas the diagnosis in sporadic LAM patients is usually made only once clinical symptoms have supervened.
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disabilities. Enzyme-inducing anti-epileptic drugs are frequently used by TSC patients and they may considerably reduce the efficacy of certain contraceptives releasing synthetic sex steroids. Progestin-only pills (POPs) as well as COCs, when used in the usual dosage, are considered unsafe when taken in conjunction with an enzyme inducer. Some authors have suggested administering a COC with a high oestrogen content (50 μg ethinylestradiol) or even a higher dose15,22. In view of our findings and other potentially negative effects on TSC manifestations23,24 use of an alternative, preferably long-acting, method such as a copper intrauterine device or a levonorgestrel releasingintrauterine system should be recommended. Unanswered questions and future research Although the European Respiratory Society advises avoiding oestrogen-containing contraceptives in the presence of LAM4, little if any data are on record concerning the impact of combined hormonal contraceptives on TSC-associated LAM. Our findings add some hints to extend this recommendation to TSC patients at risk for LAM. However, a stronger base of evidence including reports of more cases is necessary.
CONCLUSION
Choosing a contraception method for a woman suffering from TSC is an arduous task and this is reflected in the uncertainty of patients and caregivers in this respect. Our data indicate a correlation between COC use and LAM in these patients. Oestrogens should be administered with great caution.
Relevance of the findings: implications for clinicians AC K N OW L E D G E M E N T S
Medical care for TSC-affected children is well established and mostly coordinated by paediatric neurologists. In contrast, transition to adult care is difficult and comprehensive care for adults often is not provided, even in specialised centres. Contraceptive counselling is frequently inappropriate. There is a strong desire for easily applicable, safe and reliable contraceptive methods in the context of an autosomal-dominant inherited disease like TSC. Sterilisation is often not requested now that there is a possibility of pre-implantation and prenatal genetic diagnosis, and it may raise ethical problems when one deals with patients with intellectual
This work was supported by Tuberöse Sklerose Deutschland e.V., which provided the database and forwarded the questionnaires. The authors are much indebted to Dr Klaus Schotten for verifing the statistical analysis of the data, and to Professor Dr Peter Nelson for undertaking a language edit of the manuscript. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper.
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