Chest ACCP Education Calendar
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (16)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Taveira-DaSilva, A. M.
Right arrow Articles by Moss, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Taveira-DaSilva, A. M.
Right arrow Articles by Moss, J.
(Chest. 2004;126:1867-1874.)
© 2004 American College of Chest Physicians

Decline in Lung Function in Patients With Lymphangioleiomyomatosis Treated With or Without Progesterone*

Angelo M. Taveira-DaSilva, MD, PhD; Mario P. Stylianou, PhD; Carolyn J. Hedin, CRNP; Olanda Hathaway, CRNP and Joel Moss, MD, PhD

* From the Pulmonary-Critical Care Medicine Branch (Dr. Taveira-DaSilva, Ms. Hedin, Ms. Hathaway, and Dr. Moss) and Office of Biostatistics Research (Dr. Stylianou), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.

Correspondence to: Joel Moss, MD, PhD, Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 6D-05, MSC 1590, Bethesda, MD 20892-1590; e-mail: mossj{at}nhlbi.nih.gov


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: Lymphangioleiomyomatosis (LAM), a disease affecting women and causing cystic lung lesions, and, in some instances, leading to respiratory failure and death, appears to be exacerbated by estrogens. Hence, hormonal therapy with progesterone is frequently employed; however, efficacy has not been demonstrated. Our aim was to determine whether progesterone administration slowed the decline in lung function in LAM.

Design: Retrospective study.

Setting: National Institutes of Health, Bethesda, MD.

Design and subjects: The study population comprised 348 patients with LAM participating in a longitudinal research protocol. Declines in diffusion capacity of the lung for carbon monoxide (DLCO) and FEV1 were measured in 275 patients observed for approximately 4 years. The declines in DLCO and FEV1 of patients treated with progesterone, po (n = 67) or IM (n = 72), were compared with those of untreated patients (n = 136).

Measurements and results: Overall yearly rates of decline in DLCO and FEV1 were 2.4 ± 0.4% predicted (0.69 ± 0.07 mL/min/mm Hg) and 1.7 ± 0.4% predicted (75 ± 9 mL), respectively (mean ± SEM). The most significant predictors of functional decline were initial lung function and age. After adjusting for initial FEV1, age, and duration of disease, patients treated with IM progesterone tended to have lower rates of decline in FEV1 than patients treated po (1.9 ± 0.6% predicted vs 3.2 ± 0.8% predicted, respectively; p = 0.081). However, there was no significant difference in rates of decline in FEV1 between patients treated with IM progesterone and untreated patients (1.9 ± 0.6% predicted vs 0.8 ± 0.5% predicted, respectively; p = 0.520), and patients treated with po progesterone and untreated patients (3.2 ± 0.8% predicted vs 0.8 ± 0.5% predicted, respectively; p = 0.064). After adjusting for initial DLCO, rates of decline in DLCO were significantly higher in patients treated with po progesterone (3.6 ± 0.7% predicted, p = 0.002) and IM progesterone (2.8 ± 0.5% predicted, p = 0.022) than in untreated patients (1.6 ± 0.6% predicted).

Conclusions: Within the limitations of a retrospective study, our data suggest that progesterone therapy does not slow the decline in lung function in LAM.

Key Words: interstitial lung diseases • progesterone • respiratory function


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Lymphangioleiomyomatosis (LAM), a multisystem disorder affecting primarily middle-aged women, is characterized by cystic lung disease, recurrent pneumothoraces, chylous effusions, lymphatic abnormalities, and angiomyolipomas.1234 The primary pathologic findings in LAM include the proliferation of abnormal immature-appearing smooth-muscle cells (LAM cells) in the lung and along axial lymphatics in the thorax and abdomen, leading to the formation of thin-walled cysts in the lungs and fluid-filled cystic structures in the axial lymphatics.1234 In the lungs, LAM cells reside in the interstitium and in nodules lining the air-filled cysts. Angiomyolipomas, which occur predominantly in the kidney,1234 are characterized by abnormal smooth-muscle cells, similar to those found in the lungs and axial lymphatics, and the presence of adipose tissue, intermixed with incompletely developed vascular structures.

LAM occurs sporadically in patients with no evidence of genetic disease and in approximately one third of women with tuberous sclerosis complex (TSC).5678 Based on the prevalence of TSC,9 it is estimated that there may be as many as 7,500 TSC patients with LAM in the United States.567 Sporadic LAM, however, which is not associated with a TSC phenotype, is a relatively uncommon disease with a clinical prevalence estimated at 2 to 6 per million women.1234

Pulmonary function abnormalities in LAM consist of gas exchange abnormalities, characterized by a decreased diffusion capacity of the lung for carbon monoxide (DLCO) and airflow obstruction.1011 In many patients, progressive lung damage occurs and functional impairment is severe, leading to incapacitation and complete disability, requiring long-term oxygen therapy and lung transplantation, or causing death. The rate of progression of disease, however, is variable, and some patients have a long-term course lasting > 20 years.1011

There is some evidence suggesting that LAM may be influenced by hormonal factors. Indeed, not only does LAM affect primarily women,1234 but the disease appears to progress during pregnancy,1213 or following the administration of estrogens.141516 In addition, there is evidence for the colocalization of estrogen and progesterone receptors in LAM cells.17181920 These findings have prompted the use of hormonal therapy, especially with progesterone, for the treatment of LAM. However, no studies have been undertaken in large populations of patients with LAM to evaluate the rate of decline of lung function in LAM and to determine whether this decline is affected by treatment with progesterone.

The aim of this study was to determine whether progesterone therapy slowed the decline in lung function in LAM. To this end, we evaluated our population of 348 patients with LAM for progesterone use. We were able to determine the rates of decline in lung function in 275 patients, and compared the rates of patients treated with progesterone with those of patients who did not receive progesterone.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
The study population consisted of 348 patients with LAM referred to the National Institutes of Health since 1996 for participation in a longitudinal study (National Heart, Lung, and Blood Institute [NHLBI] protocol 95-H-0186) approved by the NHLBI Institutional Review Board. In addition to self-referral or referral through individual physicians, subjects were informed of the study by the LAM Foundation and the Tuberous Sclerosis Alliance. All subjects gave informed consent before enrollment. Patients who had only one set of pulmonary function tests (n = 55), had undergone lung transplantation (n = 14), or had recent surgery (n = 4) were excluded. Complete data for analysis were available from 275 patients. The diagnosis of LAM was made using lung biopsy in 170 patients and using intra-abdominal tissue biopsy in 38 patients. In the remaining patients, clinical and radiographic diagnostic criteria1234 consisted of a history of recurrent pneumothoraces and/or chylothorax, chylous ascites, abdominal lymphangioleiomyomas and/or angiomyolipomas, and a CT scan of the thorax showing multiple thin-walled cysts throughout the lungs.

The decision to initiate progesterone therapy, and the choice of route of administration, was not part of the NHLBI protocol and was made, in the majority of the patients, independently, by the patients’ physicians. Patients were evaluated approximately every 6 months (range, 5 to 7 months). Compliance with progesterone therapy was monitored by interviewing the patient at the time of each visit. Patients were considered to have reached menopause when menopause occurred naturally (low estradiol levels and elevated follicle-stimulating hormone levels) or was surgically induced (bilateral oophorectomy, without hormonal replacement therapy).

Pulmonary Function Tests
Lung volumes, flow rates, and DLCO were measured using a computerized system (Collins Gold Standard Plus; Warren E. Collins; Braintree, MA; or Master Screen PFT, Erich Jaeger; Wuerzburg, Germany) according to American Thoracic Society standards.212223

Statistical Analysis
The available data set contained multiple pulmonary function measurements for each of the 275 patients. We summarized the information from each subject by using the estimated yearly rate of decline (slope), calculated from a linear regression using the percentage of predicted DLCO and FEV1 as the response variables and the time of each test as the independent variable, considering the first test as time zero. No covariate adjustment was used in deriving the rate of change in lung function, since the percentage of predicted lung function is already covariate adjusted. The effect of progesterone treatment on the yearly rate of lung function decline was tested using a two-sided t test. In addition, we ran univariate and multivariate regression analyses to identify factors related to the rate of decline in pulmonary function. Among the explanatory variables considered were age; duration of disease, measured as time since diagnosis and time since first LAM-related symptoms; menopausal state; treatment or no treatment with progesterone; route of administration of progesterone therapy; initial DLCO or FEV1; and time under observation.

The three groups of patients were as follows: patients with no progesterone administered, patients with progesterone administered po, and patients with progesterone administered IM. A one-way analysis of variance with a Fisher adjustment was employed to compare patient groups.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patient Characteristics
The mean age of the 275 patients at the time of the first test was 42.3 ± 0.6 years (range, 19 to 77 years). Sixteen patients were Asian, 9 patients were African American, 2 patients were African, and the rest (248) were white. Twelve patients were smokers (10 ± 5 pack-years), 25 patients were ex-smokers (20 ± 2 pack-years), and the rest were nonsmokers. Mean age at the time of diagnosis was 41.0 ± 0.6 years. However, based on the history of LAM-related symptoms (pneumothorax, chylous effusions, hemoptysis, breathlessness, or angiomyolipoma-related hemorrhage), it was estimated that, at the time of the first visit, the mean duration of LAM had been 5.6 ± 0.3 years.

Pulmonary Function Tests and Rate of Decline in Lung Function
The average number of tests per patient was 6.0 ± 0.2 (range, 2 to 14). Initial pulmonary function test results are shown in Table 1 . After an average follow-up time of, respectively, 3.9 ± 0.2 years and 4.0 ± 0.2 years, DLCO had declined from 15.9 ± 0.4 mL/min/mm Hg (72.7 ± 1.6% predicted) to 13.5 ± 0.3 mL/min/mm Hg (65.2 ± 1.5% predicted), and FEV1 from 2.09 ± 0.04 L (75.2 ± 1.4% predicted) to 1.83 ± 0.05 L (69.5 ± 0.6% predicted). The mean yearly declines in DLCO and FEV1 were 2.4 ± 0.4% predicted (0.69 ± 0.07 mL/min/mm Hg) and 1.7 ± 0.4% predicted (75.0 ± 9.0 mL), respectively.


View this table:
[in this window]
[in a new window]

  		Table 1. Initial Pulmonary Function in 275 Patients With LAM*

 
Of the 275 patients, 161 were premenopausal and 114 were postmenopausal. As shown in Table 2 , postmenopausal patients were significantly older and had lower initial DLCO and a longer follow-up time than premenopausal patients. Despite these differences between groups, the rates of decline in percentage of predicted DLCO were not significantly different (p = 0.236). There was a trend toward a lower rate of decline in FEV1 in the postmenopausal patients, but the difference was not statistically significant (p = 0.090).


View this table:
[in this window]
[in a new window]

  		Table 2. Yearly Decline in DLCO and FEV1 in Premenopausal and Postmenopausal Patients*

 
Predictors of Decline in Lung Function
Since lung function declines with age, we used the percentage of predicted DLCO and FEV1, which are adjusted for age, rather than the actual values, to adjust for age-dependent changes in function. In addition, we further adjusted the multivariate models for significant predictive variables that included age, initial lung function, and length of follow-up. Finally, we also incorporated in the analysis the duration of disease, estimated by years since first diagnosis and years since development of first LAM-related symptoms, as a predictor of lung function decline.

Predictors of Decline in DLCO
Of the potential predicting variables (initial DLCO and FEV1, age, duration of disease, time under observation, menopausal state, treatment or no treatment with progesterone, and route of administration of progesterone), only initial DLCO (r = 0.25, p < 0.0001) and FEV1 (r = 0.12, p = 0.039) were significantly correlated with the decline in DLCO. Patients with higher initial DLCO and FEV1, ie, with less severe disease, tended to have a greater rate of decline in DLCO.

Predictors of Decline in FEV1
The rate of decline in FEV1 was negatively correlated with the initial DLCO (r = –0.17, p = 0.004) and age (r = – 0.22, p = 0.0003). That is, older patients and patients with higher DLCO and FEV1 had a lower rate of decline in FEV1. Follow-up time, ie, the time under observation, was not correlated with the yearly rate of decline in DLCO (p = 0.257) or FEV1 (p = 0.835).

In a multivariate regression analysis, we confirmed that initial DLCO (p < 0.001) was a significant predictor of the rate of decline in DLCO. Both initial DLCO (p < 0.001) and the patient age (p < 0.001) were significant predictors of the rate of decline in FEV1.

Duration of disease was not a significant predictor of the decline in DLCO and FEV1 except in the group of patients who were treated with progesterone. Using a cluster analysis, where variables are clustered into groups based on their intercorrelations, we confirmed that length of disease falls into the same variable cluster as time of follow-up, which is a better predictor of the rate of lung function change.

Decline in DLCO and FEV1 in Patients Treated With and Without Progesterone: Adjusted Analysis
Of the 275 patients, 139 were treated with progesterone (67 po and 72 IM). The mean duration of progesterone therapy for all was 56 ± 4 months, and the average monthly dose was 580 ± 37 mg. The mean duration of therapy for patients treated with oral progesterone was 48 ± 5 months, and the average monthly dose was 714 ± 68 mg. For patients treated with IM progesterone, the mean duration of therapy was 63 ± 6 months and the average monthly dose was 462 ± 29 mg. The monthly dose of progesterone was significantly lower (p < 0.001) in the IM group, but the cumulative totals of administered drug were not significantly different: 40,600 ± 9,810 (po) vs 30,440 ± 3,660 mg (IM), p = 0.313.

Differences among the three groups of patients in age, initial lung function, years since diagnosis, and observation time (follow-up time) are shown in Table 3 . Progesterone-treated patients had lower initial DLCO and FEV1 than did nontreated patients, and they also tended to have a longer time of follow-up. Additionally, patients treated with IM progesterone were significantly younger. Consequently, to test for a treatment effect adjusted for baseline differences between the three groups, a multivariate regression model was used, adjusting for one or more of these significant variables: initial lung function, age, duration of disease (where significant), and route of therapy.


View this table:
[in this window]
[in a new window]

  		Table 3. Yearly Decline in DLCO and FEV1 in Patients Not Treated With Progesterone and Patients Treated With po or IM Progesterone*

 
Progesterone vs No Progesterone
We found that after adjusting for initial percentage of predicted DLCO, the rate of decline of percentage of predicted DLCO was higher in the progesterone-treated group, regardless of the route of administration, than in the nontreated group (3.2 ± 0.5% predicted and 1.6 ± 0.6% predicted, respectively; p = 0.001). After adjusting for initial percentage of predicted DLCO and age, the difference in rates of decline in FEV1 in progesterone-treated and untreated patients was not statistically significant (2.5 ± 0.5% predicted vs 0.8 ± 0.5% predicted, p = 0.473).

No Progesterone vs po Progesterone
The rate of decline of percentage of predicted DLCO, after adjusting for initial DLCO, was significantly lower (p = 0.002) in the untreated group than in the group treated with po progesterone (Table 3, Fig 1 ). After adjusting for initial FEV1 and age, the rate of decline of percentage of predicted FEV1 in the untreated group was lower than that of patients treated with po progesterone, but the difference was not statistically significant (p = 0.064) [Table 3, Fig 1].



View larger version (29K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1. Yearly rates of decline in percentage of predicted DLCO and FEV1 in patients not treated with progesterone (white bars), patients treated with po progesterone (black bars), and patients treated with IM-administered progesterone (cross-hatched bars). The rates of decline in DLCO of untreated patients (white bar, marked with asterisk) are significantly lower than those of patients treated by the po (p = 0.002) or IM routes (p = 0.022). There is no significant difference in FEV1 rates of decline between untreated patients and patients treated by either route of administration; p values are adjusted for initial lung function, age, and duration of disease, where significant.

 
No Progesterone vs IM Progesterone
After adjusting for initial FEV1 and age, we found no significant difference between untreated patients and patients treated with IM progesterone in the rates of decline of percentage of predicted FEV1 (p = 0.520) [Table 3, Fig 1]. However, the rate of decline of percentage of predicted DLCO, after adjusting for initial DLCO, was significantly lower (p = 0.022) in the untreated group than in the group treated with IM progesterone (Table 3, Fig 1).

IM vs po Progesterone
In this analysis, duration of disease, initial FEV1, and age were significant predictors of rates of decline in DLCO and FEV1. Patients with greater duration of disease had a lower rate of decline in lung function. After adjusting for age, duration of disease, and initial lung function, we found a tendency toward a lower rate of decline of percentage of predicted FEV1 in the IM progesterone group (1.9 ± 0.6% predicted vs 3.2 ± 0.8% predicted). However, the difference was not statistically significant (p = 0.081). There was no significant difference between these two groups in the rates of decline of percentage of predicted DLCO (2.8 ± 0.5% vs 3.6 ± 0.9%, p = 0.800) [Table 3, Fig 1].


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We report here a retrospective analysis of the decline in lung function in a large population of patients with LAM, focusing on patients who were treated with progesterone by the po or IM route vs those who did not receive hormonal therapy. To quantify the decline in lung function, we selected the DLCO and FEV1 because these tests correlate well with disease severity defined by CT scans and LAM histology scores.101124 Initial DLCO and FEV1 and age were the most important predictors of rates of decline in function. After adjusting for differences between groups, we found a significantly greater rate of decline in DLCO in patients treated with progesterone than in those who were not treated. In addition, we found no significant difference in the rates of decline in FEV1 between patients treated with progesterone by either route of administration, and untreated patients.

Postmenopausal patients tended to have lower rates of decline in FEV1 than premenopausal patients, although the difference in rates of FEV1 decline was not statistically significant. This was seen despite the fact that postmenopausal patients had a significantly lower DLCO (p = 0.037) than premenopausal patients that, based on our data, should have been associated with a higher rate of decline in FEV1. Conversely, postmenopausal patients were significantly older than premenopausal patients, and the rate of decline in FEV1 decreases with age. Thus, age and menopause, or a combination of both factors, could have accounted for a lower rate of decline in FEV1 in postmenopausal patients.

Our data demonstrate the difficulties encountered in evaluating retrospectively the effects of therapeutic interventions on lung function in heterogeneous patient populations. Although the multivariate analysis attempted to adjust for factors found to correlate with decline in lung function, it is still possible that treated and untreated patient populations may have been substantially different in the actual rates of disease progression. It is also conceivable that patients who appeared to be sicker were more likely to be treated by their physicians, whereas those with milder disease chose not to receive or were not offered progesterone therapy.

The efficacy of hormonal therapy with progesterone in slowing the progression of lung disease in LAM has not been established. Reports of success, based on few patients, or without objective data, are matched by reports2526272829303132333435 of therapeutic failures. In one study36 of premenopausal patients, the yearly decline in DLCO was less in 16 patients treated with progesterone than in 13 untreated patients. However, the initial DLCO was lower in the treated group, which, according to our data, was associated with a lower rate of decline in DLCO. In five patients for whom pretreatment and posttreatment decline rates for FEV1 and DLCO were available, it was found that progesterone decreased the rate of decline in lung function. In this analysis, it was assumed that there was a constant rate of decline in lung function that was diminished by progesterone. This assumption is probably incorrect because our study suggests that the rate of decline in lung function may not be constant over time, ie, as the DLCO declines, the rate of decline in DLCO decreases, and the rate of decline in FEV1 increases. Therefore, any comparison of rates of decline in lung function between LAM patient groups needs to adjust for initial function to ensure that the initial severity and rate of progression of disease are reasonably similar in all groups.

After adjusting for initial lung function and age, we found no benefit of progesterone in decreasing the rate of decline in lung function. We observed a trend toward a lower rate of decline in FEV1 in patients treated with IM progesterone than in those treated with po progesterone. Presumably, the lower bioavailability of po progesterone3738394041 could account for the tendency for higher rates of decline in FEV1 in patients treated po than in those treated by the IM route. However, the finding that patients treated with progesterone po had a greater rate of decline in FEV1 than untreated patients cannot be explained by a lower drug availability. Conversely, the possibility that po progesterone might actually produce adverse effects on FEV1 cannot be excluded. In addition, since treatment with IM progesterone was not significantly better than no treatment, it appears that treatment with this hormone by either route of administration offers no benefit to patients with LAM.

Our data raise questions about the justification for committing a patient with LAM to prolonged treatment of a chronic disease with an agent of questionable benefit and significant side effects.424344454647484950 However, because this was a retrospective study and the patient populations were heterogeneous, our findings have to be interpreted with caution. The question of whether treatment with progesterone is of benefit to patients with LAM may never be completely answered unless a prospective therapeutic trial comparing IM progesterone with a placebo is undertaken. Our observations should provide useful information for designing therapeutic trials in LAM.


   Acknowledgements
 
We thank Dr. Martha Vaughan for discussions and critical review, and Xiaoling Chen for assistance in compilation and analysis of the data. We also thank the LAM Foundation and the Tuberous Sclerosis Alliance for their assistance in recruiting patients. This study would not have been possible without the cooperation of patients with LAM, who, in many cases, traveled great distances to participate in our clinical research protocols.


   Footnotes
 
Abbreviations: DLCO = diffusion capacity of the lung for carbon monoxide; LAM = lymphangioleiomyomatosis; NHLBI = National Heart, Lung, and Blood Institute; TSC = tuberous sclerosis complex.

Supported by the NHLBI, Division of Intramural Research.

Ms. Xiaoling Chen was supported in part by a grant from the LAM Foundation.

Received for publication January 12, 2004. Accepted for publication July 23, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Kitaichi, M, Nishimura, K, Harumi, I, et al (1995) Pulmonary lymphangioleiomyomatosis: a report of 46 patients including a clinicopathologic study of prognostic factors. Am J Respir Crit Care Med 151,527-533[Abstract]
  2. Sullivan, EJ Lymphangioleiomyomatosis: a review. Chest 1998;114,1689-1703[ISI][Medline]
  3. Chu, SC, Horiba, K, Usuki, J, et al Comprehensive evaluation of 35 patients with lymphangioleiomyomatosis. Chest 1999;115,1041-1052[CrossRef][Medline]
  4. Urban, TJ, Lazor, R, Lacronique, J, et al Pulmonary lymphangioleiomyomatosis: a study of 69 patients. Medicine 1999;78,321-337[CrossRef][Medline]
  5. Costello, LC, Hartman, TE, Ryu, JH High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clin Proc 2000;75,591-594[ISI][Medline]
  6. Moss, J, Avila, NA, Barnes, PM, et al Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med 2001;163,669-671
  7. 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 Respir Crit Care Med 2001;164,661-668[Abstract/Free Full Text]
  8. Strizheva, GD, Carsillo, T, Kruger, W, et al The spectrum of mutations in TSC1 and TSC2 in women with tuberous sclerosis and lymphangioleiomyomatosis. Am J Respir Crit Care Med 2001;163,253-258[Abstract/Free Full Text]
  9. Osborne, JP, Fryer, A, Webb, D Epidemiology of tuberous sclerosis. Ann NY Acad Sci 1991;615,125-127[Medline]
  10. Taveira-DaSilva, AM, Hedin, CJ, Stylianou, MP, et al Reversible airflow obstruction, proliferation of abnormal smooth muscle cells and impairment of gas exchange as predictors of outcome in lymphangioleiomyomatosis. Am J Respir Crit Care Med 2001;164,1072-1076[Abstract/Free Full Text]
  11. Taveira-DaSilva, AM, Stylianou, MP, Hedin, CJ, et al Maximal oxygen uptake and severity of disease in lymphangioleiomyomatosis. Am J Respir Crit Care Med 2003;168,1427-1431[Abstract/Free Full Text]
  12. Yockey, CC, Riepe, RE, Ryan, K Pulmonary lymphangioleiomyomatosis complicated by pregnancy. Kansas Med 1986;87,277-278
  13. Brunelli, A, Catalini, G, Fianchini, A Pregnancy exacerbating unsuspected mediastinal lymphangioleiomyomatosis and chylothorax. Int J Gynaecol Obstet 1996;52,289-290[CrossRef][Medline]
  14. Shen, A, Iseman, MD, Waldron, JA, et al Exacerbation of pulmonary lymphangioleiomyomatosis by exogenous estrogens. Chest 1987;91,782-785[Medline]
  15. Yano, S Exacerbation of pulmonary lymphangioleiomyomatosis by exogenous oestrogen used for infertility treatment. Thorax 2002;57,1085-1086[Abstract/Free Full Text]
  16. Oberstein, EM, Fleming, LE, Gomez-Marin, O, et al Pulmonary lymphangioleiomyomatosis (LAM): examining oral contraceptive pills and onset of disease. J Womens Health 2003;12,81-85
  17. Colley, MH, Geppert, E, Franklin, WA Immunohistochemical detection of steroid receptors in a case of lymphangioleiomyomatosis. Am J Surg Pathol 1989;13,803-807[ISI][Medline]
  18. Berger, U, Khaghani, A, Pomerance, A, et al Pulmonary lymphangioleiomyomatosis and steroid receptors. Am J Clin Pathol 1990;93,609-614[ISI][Medline]
  19. Ohori, NP, Yousem, SA, Sonmez-Alpan, E, et al Estrogen and progesterone receptors in lymphangioleiomyomatosis, epithelioid hemangioendothelioma, and sclerosing hemangioma of the lung. Am J Clin Pathol 1991;96,529-535[ISI][Medline]
  20. Matsui, K, Takeda, K, Zu-Xi, Y, et al Downregulation of estrogen and progesterone receptors in the abnormal smooth muscle cells in pulmonary lymphangioleiomyomatosis following therapy: an immunochemical study. Am J Respir Crit Care Med 2000;161,1002-1009[Abstract/Free Full Text]
  21. American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 1991;144,1202-1218[ISI][Medline]
  22. American Thoracic Society. Standardization of spirometry, 1994 update. Am Rev Respir Crit Care Med 1994;152,1107-1136[ISI]
  23. American Thoracic Society. Single-breath carbon monoxide diffusing capacity (transfer factor): recommendations for a standard technique, 1995 update. Am Rev Respir Crit Care Med 1995;152,2185-2198[ISI][Medline]
  24. Matsui, K, Takeda, K, Yu, Z, et al Prognostic significance of pulmonary lymphangioleiomyomatosis histologic score. Am J Surg Pathol 2001;25,479-484[CrossRef][ISI][Medline]
  25. Svendsen, TL, Viskum, K, Hansborg, N, et al Pulmonary lymphangioleiomyomatosis: a case of progesterone receptor positive lymphangioleiomyomatosis treated with medroxyprogesterone, oophorectomy and tamoxifen. Br J Dis Chest 1984;78,264-270[ISI][Medline]
  26. Sawicka, EH, Morris, JR A report of two long-surviving cases of pulmonary lymphangioleiomyomatosis and the response to progesterone therapy. Br J Dis Chest 1985;79,400-406[CrossRef][ISI][Medline]
  27. Ten Brock, E, Votto, JJ Lymphangioleiomyomatosis: treatment with hormonal manipulation. N Y State J Med 1986;86,533-536[ISI][Medline]
  28. Eliasson, AH, Phillips, YY, Tenholder, MF Treatment of lymphangioleiomyomatosis: a meta-analysis. Chest 1989;196,1352-1355
  29. Taylor, JR, Ryu, J, Colby, T, et al Lymphangioleiomyomatosis: clinical course in 32 patients. N Engl J Med 1990;323,1254-1260[ISI][Medline]
  30. van Milligen de Wit, AWM, Meilof-Planteydt, MNM Successful treatment of lymphangioleiomyomatosis with oophorectomy and medroxyprogesterone-acetate: report of a case and brief review of the literature. Netherlands J Med 1990;36,246-251[ISI][Medline]
  31. Rajjoub, S, Blatt, MW, Ritterspach, J Response to treatment with progesterone in a patient with pulmonary lymphangioleiomyomatosis. West Virginia Med J 1995;91,322-323
  32. Zanella, A, Toppan, P, Nitti, D, et al Pulmonary lymphangioleiomyomatosis: a case report in postmenopausal woman treated with pleurodesis and progesterone (medroxyprogesterone acetate). Tumori 1996;82,96-98[ISI][Medline]
  33. Yigla, M, Bentur, L, Ben Izhak, O, et al Pulmonary lymphangioleiomyomatosis: prolonged survival despite multiple pregnancies and no hormonal therapy. Respirology 1996;3,213-215
  34. Denoo, X, Hermans, G, Degives, R, et al Successful treatment of pulmonary lymphangioleiomyomatosis with progestins. Chest 1999;115,276-279[Medline]
  35. Seyama, K, Kira, S, Takahashi, H, et al Longitudinal follow-up study of 11 patients with pulmonary lymphangioleiomyomatosis: diverse clinical courses of LAM allow some patients to be treated without anti-hormone therapy. Respirology 2001;6,331-340[CrossRef][Medline]
  36. Johnson, S, Tattersfield, AE Decline in lung function in lymphangioleiomyomatosis: relation to menopause and progesterone treatment. Am J Respir Crit Care Med 1999;160,628-633[Abstract/Free Full Text]
  37. Stockdale, AD, Rostom, AY Clinical significance of differences in bioavailability of medroxyprogesterone acetate preparations. Clin Pharmacol 1989;16,129-133
  38. Fotherby, K Pharmacokinetics of progestational compounds. Maturitas 1986;8,123-132[CrossRef][ISI][Medline]
  39. Victor, A, Johansson, EDB Pharmacokinetic observations on MPA administered orally and intravaginally. Contraception 1976;14,319-329[CrossRef][ISI][Medline]
  40. Fotherby, K Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy. Contraception 1996;54,59-69[CrossRef][ISI][Medline]
  41. Fotherby, K, Koetsawang, S, Shrimander, K, et al A preliminary pharmacokinetic and pharmacodynamic evaluation of depo-medroxyprogesterone acetate and norethisterone enantate. Fertil Steril 1980;34,131-139[ISI][Medline]
  42. Depo-Provera Sterile Aqueous Suspension [package insert], medroxyprogesterone. Kalamazoo MI: The Upjohn Company, 1999
  43. Wassertheil-Smoller, S, Hendrix, SL, Limacher, M, et al Effect of estrogen plus progestin on stroke in postmenopausal women. JAMA 2003;289,2673-2684[Abstract/Free Full Text]
  44. Amatayakul, K, Sivasomboon, B, Thanangkul, O A study of the mechanism of weight gain in medroxyprogesterone acetate users. Contraception 1980;22,605-622[CrossRef][ISI][Medline]
  45. Civic, D, Scholes, D, Ichikawa, L, et al Depressive symptoms in users and non-users of depot medroxyprogesterone acetate. Contraception 2000;61,385-890[CrossRef][ISI][Medline]
  46. Dux, S, Bishara, J, Marom, D, et al Medroxyprogesterone acetate-induced secondary adrenal insufficiency [letter]. Ann Pharmacotherapy 1998;32,134[Free Full Text]
  47. Siminoski, K, Goss, P, Drucker, DJ The Cushing syndrome induced by medroxyprogesterone acetate. Ann Intern Med 1989;111,758-760[ISI][Medline]
  48. Kim, C, Seidel, K, Begier, E, et al Diabetes and depot medroxyprogesterone contraception in Navajo women. Arch Intern Med 2001;161,1766-1771[Abstract/Free Full Text]
  49. Riippa, P, Kauppila, A, Sundstrom, H, et al Hepatic impairment during simultaneous administration of medroxyprogesterone acetate and tamoxifen in the treatment of endometrial and ovarian carcinoma. Anticancer Res 1984;4,109-112[ISI][Medline]
  50. Moss, J, DeCastro, R, Patronas, N, et al Meningiomas in lymphangioleiomyomatosis. JAMA 2001;286,1879-1891[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 ChestHome page
F. X. McCormack
Lymphangioleiomyomatosis: A Clinical Update
Chest, February 1, 2008; 133(2): 507 - 516.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
S. Harari, R. Cassandro, J. Chiodini, A. M. Taveira-DaSilva, and J. Moss
Effect of a Gonadotrophin-Releasing Hormone Analogue on Lung Function in Lymphangioleiomyomatosis
Chest, February 1, 2008; 133(2): 448 - 454.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
J. H. Ryu, J. Moss, G. J. Beck, J.-C. Lee, K. K. Brown, J. T. Chapman, G. A. Finlay, E. J. Olson, S. J. Ruoss, J. R. Maurer, et al.
The NHLBI Lymphangioleiomyomatosis Registry: Characteristics of 230 Patients at Enrollment
Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 105 - 111.
[Abstract] [Full Text] [PDF]

Home page
 RadioGraphicsHome page
G. F. Abbott, M. L. Rosado-de-Christenson, A. A. Frazier, T. J. Franks, R. D. Pugatch, and J. R. Galvin
From the Archives of the AFIP: Lymphangioleiomyomatosis: Radiologic-Pathologic Correlation
RadioGraphics, May 1, 2005; 25(3): 803 - 828.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (16)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Taveira-DaSilva, A. M.
Right arrow Articles by Moss, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Taveira-DaSilva, A. M.
Right arrow Articles by Moss, J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS