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ABSTRACT: OBJECTIVE: This study aims to investigate venous thromboembolism (VTE) risk in relation to age at menopause, age at menarche, parity, bilateral oophorectomy, and time since menopause, as well as any interaction with randomized hormone therapy (HT) assignment, among postmenopausal women. METHODS: Using pooled data from the Women's Health Initiative HT clinical trials including 27,035 postmenopausal women aged 50 to 79 years who had no history of VTE, we assessed the risk of VTE in relation to age at menopause, age at menarche, parity, bilateral oophorectomy, and time since menopause by Cox proportional hazards models. Linear trends, quadratic relationships, and interactions of reproductive life characteristics with HT on VTE risk were systematically tested. RESULTS: During follow-up, 426 women reported a first VTE, including 294 non-procedure-related events. No apparent interaction of reproductive life characteristics with HT assignment on VTE risk was detected, and there was not a significant association between VTE and age at menarche, age at menopause, parity, oophorectomy, or time since menopause. However, analyses restricted to non-procedure-related VTE showed a U-shaped relationship between age at menopause and thrombotic risk that persisted after multivariable analysis (P < 0.01). Compared with women aged 40 to 49 years at menopause, those who had early menopause (age <40 y) or late menopause (age >55 y) had a significantly increased VTE risk (hazard ratio [95% CI]: 1.8 [1.2-2.7] and 1.5 [1.0-2.4], respectively). CONCLUSIONS: Reproductive life characteristics have little association with VTE and do not seem to influence the effect of HT on thrombotic risk among postmenopausal women. Nevertheless, early and late onset of menopause might be newly identified risk factors for non-procedure-related VTE.
Menopause (New York, N.Y.) 06/2013; · 3.08 Impact Factor
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ABSTRACT: The cardiovascular safety of widely used combined hormonal contraceptives is still debated. Newer generations of oral formulations as well as non-oral contraceptives (transdermal and vaginal) have been recently evaluated in the context of cardiovascular disease. This review provides a summary of the association between combined oral contraceptives (COCs) and arterial diseases, with an emphasis on new formulations of hormonal contraceptives, as well as routes of administration. A systematic search of the Medline database was performed to find all relevant articles which included women who had widely use third generation pills, and the development of new progestins. Eligible articles published in English and reporting risk of arterial events (myocardial infarction [MI] and stroke) among users of hormonal contraceptives were reviewed. A quantitative assessment was made from included studies. Overall, current use of oral combined contraceptives increased the risk of MI and ischemic stroke (pooled OR: 1.7; 95% confidence interval [95% CI]: 1.2-2.3 and OR: 1.8; 95% CI: 1.2-2.8, respectively), but this was not associated with the risk of hemorrhagic stroke (OR: 1.1; 95% CI: 0.7-1.9). The increase in ischemic arterial disease was higher among first generation pill users compared with second or third generation pill users. In contrast, risk of ischemic arterial disease among current users of second or third generation pill was similar (p = 0.23 for MI risk and 0.99 for ischemic stroke). In conclusion, newer generation formulations of COCs, as well as the non-oral hormonal contraceptive, do not seem to be safer than second generation hormonal contraceptives.
Best practice & research. Clinical endocrinology & metabolism. 02/2013; 27(1):35-45.
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Pierre Gourdy,
Anne Bachelot,
Sophie Catteau-Jonard,
Nathalie Chabbert-Buffet,
Sophie Christin-Maître,
Jacqueline Conard,
Alexandre Fredenrich,
Anne Gompel,
Françoise Lamiche-Lorenzini,
Caroline Moreau, Geneviève Plu-Bureau,
Anne Vambergue,
Bruno Vergès,
Véronique Kerlan
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ABSTRACT: Hormonal contraceptive methods are widely used in France, including not only oral estrogen-progestin combinations but also non-oral estrogen-progestin delivery methods (patches, vaginal rings), as well as oral forms, implants and intra-uterine devices that deliver only a progestin. Hormonal contraception has only a modest impact on lipid and carbohydrate metabolism, but estrogen-progestin contraceptives have been linked to a variety of vascular risks. Overall, the risk of venous thrombosis is multiplied by a factor of about 4, depending on age, the compounds used, and other risk factors (including biological thrombophilia and a personal history of thrombosis), whereas the risk of arterial events is only increased in women with risk factors. Available data suggest there is no excess risk with progestin-based contraceptives, but far fewer studies have been conducted. At the initiative of the French Society of Endocrinology, an expert group met in 2010 in order to reach a consensus on the use of hormonal contraceptive methods in women with vascular or metabolic risk factors, based on available data and international guidelines published by WHO in 2009 and subsequently adapted to the United States context. The following text, intentionally limited to hormonal contraception, is intended to serve as a guide when prescribing in specific clinical situations, such as a family or personal history of arterial or venous thromboembolism, or the existence of cardiovascular risk factors (hypertension, smoking, diabetes, dyslipidemia, obesity).
Annales d Endocrinologie 10/2012; · 0.74 Impact Factor
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ABSTRACT: Hormone therapy (HT) is the most effective treatment for correcting menopausal symptoms after menopause. HT initially consisted of estrogens alone and progestogens were secondly added to estrogens for preventing the risk of endometrial cancer associated to estrogens use. Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is a major harmful effect of HT. It is now well known that oral and transdermal estrogens are differentially associated with VTE risk but progestogens may be another important determinant of the thrombotic risk among HT users. Both randomized controlled trials and meta-analysis of observational studies suggested that the VTE risk was higher among users of estrogens plus progestogens than among users of estrogens alone. With respect to the different pharmacological classes of progestogens, there is evidence for a deleterious effect of medroxyprogesterone acetate on VTE risk. In addition, observational studies showed that norpregnane derivatives were significantly associated with an increased VTE risk whereas micronized progesterone could be safe with respect to thrombotic risk. The effect of tibolone on VTE risk remains uncertain. In conclusion, progestogens may have differential effects on VTE risk according to the molecules and therefore represent an important potential determinant of the thrombotic risk among postmenopausal women using estrogens.
Maturitas 12/2011; 70(4):354-60. · 2.77 Impact Factor
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ABSTRACT: Catamenial pneumothorax and thoracic endometriosis (TE) are still under diagnosed. The purpose of this study is to increase the diagnostic accuracy for these conditions in patients with spontaneous pneumothorax and to identify their risk factors.
We conducted a retrospective study on all consecutive women of reproductive age referred to our Centre for surgical treatment of spontaneous pneumothorax between July 2000 and January 2009.
The study population comprised 156 premenopausal women of whom 49 (31.4%) had catamenial and/or TE-related pneumothorax. Over a quarter of these 49 patients had a previous history of recurrent thoracic or scapular catamenial pain. They experienced their first pneumothorax episode at an older age (mean ± SD) (34.0 years ± 6.7) than women with idiopathic pneumothorax (28.7 ± 6.1 years, P < 0.001). Pelvic endometriosis was found in 51% of women with catamenial and/or TE-related pneumothorax. After adjustment for confounding factors by multiple logistic regression analysis, the results show that, infertility [odd ratio (OR) = 4.21, 95% confidence interval (CI) = 1.28-13.88] and a history of pelvic surgery with a uterine procedure and/or uterine scraping (OR = 2.85, 95% CI = 1.12-7.26) were the strongest predictors of catamenial and/or TE-related pneumothorax.
Infertility and uterine procedures are significantly associated with catamenial and/or TE-related pneumothorax. Scapular or thoracic pain during menses often precedes the occurrence of pneumothorax and is highly specific for the diagnosis of TE. Our results suggest that in women with pelvic endometriosis, these symptoms should be systematically investigated for an earlier diagnosis of TE.
Human Reproduction 06/2011; 26(9):2322-9. · 4.47 Impact Factor
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The Lancet 03/2011; 377(9771):1072; author reply 1073-4. · 38.28 Impact Factor
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ABSTRACT: The association between combined oral contraceptives (OC) and the risk of myocardial infarction (MI) has been intensively studied, and conclusions are controversial. While progestogen-only contraceptives (POC) are commonly used worldwide, their impact on cardiovascular diseases is poorly investigated and remains unclear.
We carried out a meta-analysis based on EMBASE- and MEDLINE-referenced literature corresponding to OC marketed since 1960.
Eligible articles published in English language describing OC or POC use and MI outcome were reviewed, and relevant ones were extracted. All types of POC and route of administration were considered.
Six case-control studies were identified. The combined odds ratio showed no increase in the MI risk with POC use (odds ratio = 1.07; 95% confidence interval, 0.62-1.84). This result was similar according to the route of administration, including implant, injectable, and oral POC.
Data from observational studies suggest no increase in risk of MI with POC use. However, these results are based on limited data. Further investigations are needed, especially among women at high MI risk.
The Journal of clinical endocrinology and metabolism 02/2011; 96(4):1169-74. · 6.50 Impact Factor
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ABSTRACT: The route of estrogen administration is an important determinant of the risk of the first venous thromboembolism (VTE) event in postmenopausal women using hormone therapy (HT). However, the impact of transdermal estrogens on VTE recurrence risk has not been investigated. The aim of our study was to assess the impact of HT by route of estrogen administration on the risk of recurrent VTE.
A total of 1,023 consecutive postmenopausal women aged 45 to 70 years with a confirmed first VTE were recruited from an outpatient clinic of a hemostasis hospital unit between January 2000 and December 2008 and were followed for an average of 79 months after discontinuation of anticoagulation therapy.
Recurrent VTE occurred in 77 women (1.1% per year). During the follow-up, 130 women used HT (12.7%), including 103 transdermal estrogen users (10.0%) and 10 oral estrogen users (1.0%). After adjustment for potential confounders, there was no significant association between recurrent VTE and use of transdermal estrogens (hazard ratio, 1.0; 95% CI, 0.4-2.4), with the nonusers as a reference group. In contrast, women using oral estrogens had an increased risk of recurrent VTE (hazard ratio, 6.4; 95% CI, 1.5-27.3). Consistently, no subgroup of women had evidence of a risk of recurrent VTE with transdermal HT that significantly differed from that observed for all women.
Oral but not transdermal estrogens are associated with a higher risk of recurrent VTE among postmenopausal women. This result provides further epidemiological evidence that transdermal estrogens may be safe with respect to VTE risk.
Menopause (New York, N.Y.) 12/2010; 18(5):488-93. · 3.08 Impact Factor
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The Lancet 01/2010; 375(9709):117; author reply 118-9. · 38.28 Impact Factor
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ABSTRACT: Oral estrogen therapy increases venous thromboembolism risk among postmenopausal women. Although recent data showed transdermal estrogens may be safe with respect to thrombotic risk, the impact of the route of estrogen administration and concomitant progestogens is not fully established.
We used data from the E3N French prospective cohort of women born between 1925 and 1950 and biennially followed by questionnaires from 1990. Study population consisted of 80 308 postmenopausal women (average follow-up: 10.1 years) including 549 documented idiopathic first venous thromboembolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional models. Compared to never-users, past-users of hormone therapy had no increased thrombotic risk (HR=1.1; 95% CI: 0.8 to 1.5). Oral not transdermal estrogens were associated with increased thrombotic risk (HR=1.7; 95% CI: 1.1 to 2.8 and HR=1.1; 95% CI: 0.8 to 1.8; homogeneity: P=0.01). The thrombotic risk significantly differed by concomitant progestogens type (homogeneity: P<0.01): there was no significant association with progesterone, pregnanes, and nortestosterones (HR=0.9; 95% CI: 0.6 to 1.5, HR=1.3; 95% CI: 0.9 to 2.0 and HR=1.4; 95% CI: 0.7 to 2.4). However, norpregnanes were associated with increased thrombotic risk (HR=1.8; 95% CI: 1.2 to 2.7).
In this large study, we found that route of estrogen administration and concomitant progestogens type are 2 important determinants of thrombotic risk among postmenopausal women using hormone therapy. Transdermal estrogens alone or combined with progesterone might be safe with respect to thrombotic risk.
Arteriosclerosis Thrombosis and Vascular Biology 10/2009; 30(2):340-5. · 6.37 Impact Factor
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ABSTRACT: The association between combined oral contraceptives (OC) use and increased risk of stroke has been reported. While progestogen-only contraceptives (POC) are commonly used worldwide, their impact on cardiovascular disease remains unclear.
A meta-analysis based on EMBASE and MEDLINE referenced literature corresponding to OCs marketed since 1960 was carried out. Eligible articles assessing the risk of stroke in relation to OC or POC were reviewed, and relevant studies were extracted. All types of POC and routes of administration were taken into account in the meta-analysis.
Six case-control studies were identified. The combined odd ratio (OR) showed no increase in the risk of stroke among POC users (OR=0.96; 95% confidence interval: 0.70 to 1.31). This result was similar according to the route of administration (either implant or injectable or oral POC).
Data from observational studies show that POC use is not associated with an increased risk of stroke. However, these results are based on limited data. Further investigations are needed in women with risk factors of stroke.
Stroke 03/2009; 40(4):1059-62. · 5.73 Impact Factor
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Sandra Dupouy,
Véronique Viardot-Foucault,
Marco Alifano,
Frédérique Souazé, Geneviève Plu-Bureau,
Marc Chaouat,
Anne Lavaur,
Danielle Hugol,
Christian Gespach,
Anne Gompel,
Patricia Forgez
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ABSTRACT: The neurotensin (NTS) and its specific high affinity G protein coupled receptor, the NT1 receptor (NTSR1), are considered to be a good candidate for one of the factors implicated in neoplastic progression. In breast cancer cells, functionally expressed NT1 receptor coordinates a series of transforming functions including cellular migration and invasion.
we investigated the expression of NTS and NTSR1 in normal human breast tissue and in invasive ductal breast carcinomas (IDCs) by immunohistochemistry and RT-PCR. NTS is expressed and up-regulated by estrogen in normal epithelial breast cells. NTS is also found expressed in the ductal and invasive components of IDCs. The high expression of NTSR1 is associated with the SBR grade, the size of the tumor, and the number of metastatic lymph nodes. Furthermore, the NTSR1 high expression is an independent factor of prognosis associated with the death of patients.
these data support the activation of neurotensinergic deleterious pathways in breast cancer progression.
PLoS ONE 02/2009; 4(1):e4223. · 4.09 Impact Factor
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ABSTRACT: To assess the risk of venous thromboembolism in women using hormone replacement therapy by study design, characteristics of the therapy and venous thromboembolism, and clinical background.
Systematic review and meta-analysis.
Medline.
Eight observational studies and nine randomised controlled trials.
Studies on hormone replacement therapy that reported venous thromboembolism. REVIEW MEASURES: Homogeneity between studies was analysed using chi(2) and I(2) statistics. Overall risk of venous thromboembolism was assessed from a fixed effects or random effects model.
Meta-analysis of observational studies showed that oral oestrogen but not transdermal oestrogen increased the risk of venous thromboembolism. Compared with non-users of oestrogen, the odds ratio of first time venous thromboembolism in current users of oral oestrogen was 2.5 (95% confidence interval 1.9 to 3.4) and in current users of transdermal oestrogen was 1.2 (0.9 to 1.7). Past users of oral oestrogen had a similar risk of venous thromboembolism to never users. The risk of venous thromboembolism in women using oral oestrogen was higher in the first year of treatment (4.0, 2.9 to 5.7) compared with treatment for more than one year (2.1, 1.3 to 3.8; P<0.05). No noticeable difference in the risk of venous thromboembolism was observed between unopposed oral oestrogen (2.2, 1.6 to 3.0) and opposed oral oestrogen (2.6, 2.0 to 3.2). Results from nine randomised controlled trials confirmed the increased risk of venous thromboembolism among women using oral oestrogen (2.1, 1.4 to 3.1). The combination of oral oestrogen and thrombogenic mutations or obesity further enhanced the risk of venous thromboembolism, whereas transdermal oestrogen did not seem to confer additional risk in women at high risk of venous thromboembolism.
Oral oestrogen increases the risk of venous thromboembolism, especially during the first year of treatment. Transdermal oestrogen may be safer with respect to thrombotic risk. More data are required to investigate differences in risk across the wide variety of hormone regimens, especially the different types of progestogens.
BMJ (Clinical research ed.). 05/2008; 336(7655):1227-31.
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ABSTRACT: The use of combined hormonal contraceptives with ethinyl estradiol (EE) and a progestin results in alterations in potential biomarkers of venous thromboembolism risk. Evaluation of the impact of delivery route on these changes is difficult due to an interaction between EE and the progestin component.
The aim of the study was to compare the impact of oral and vaginal administration of EE alone on hemostatic variables and estrogen-sensitive liver proteins.
This was a single-center, randomized, crossover study with two treatment cycles separated by a washout cycle.
The study was conducted in an academic outpatient center.
Fourteen healthy postmenopausal women were enrolled; 13 completed the study and were included in the analyses.
Participants were randomized to receive EE (15 microg/d) delivered by oral tablet or vaginal ring for 21 d in one of two treatment sequences.
Changes in plasma concentration or activity of 10 hemostatic variables and six estrogen-sensitive liver proteins between baseline and d 21 of treatment were the primary outcomes.
Prothrombin fragment 1 + 2 plasma level was unaffected by treatment or delivery route. Angiotensinogen (expressed as plasma level of angiotensin I) increased similarly with oral and vaginal delivery; mean (sd) increases were 2757 (1033) and 2864 (893) ng /ml, respectively (P = 0.0002). Alterations in other study variables, except total cholesterol, were similar with oral and vaginal administration.
Our results provide evidence that the customary effects of combined hormonal contraceptives on hemostatic variables and estrogen-sensitive liver proteins are largely related to EE and independent of delivery route during short-term treatment.
Journal of Clinical Endocrinology & Metabolism 07/2007; 92(6):2074-9. · 6.50 Impact Factor
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Marianne Canonico,
Emmanuel Oger, Geneviève Plu-Bureau,
Jacqueline Conard,
Guy Meyer,
Hervé Lévesque,
Nathalie Trillot,
Marie-Thérèse Barrellier,
Denis Wahl,
Joseph Emmerich,
Pierre-Yves Scarabin
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ABSTRACT: Oral estrogen therapy increases the risk of venous thromboembolism (VTE) in postmenopausal women. Transdermal estrogen may be safer. However, currently available data have limited the ability to investigate the wide variety of types of progestogen.
We performed a multicenter case-control study of VTE among postmenopausal women 45 to 70 years of age between 1999 and 2005 in France. We recruited 271 consecutive cases with a first documented episode of idiopathic VTE (208 hospital cases, 63 outpatient cases) and 610 controls (426 hospital controls, 184 community controls) matched for center, age, and admission date. After adjustment for potential confounding factors, odds ratios (ORs) for VTE in current users of oral and transdermal estrogen compared with nonusers were 4.2 (95% CI, 1.5 to 11.6) and 0.9 (95% CI, 0.4 to 2.1), respectively. There was no significant association of VTE with micronized progesterone and pregnane derivatives (OR, 0.7; 95% CI, 0.3 to 1.9 and OR, 0.9; 95% CI, 0.4 to 2.3, respectively). In contrast, norpregnane derivatives were associated with a 4-fold-increased VTE risk (OR, 3.9; 95% CI, 1.5 to 10.0).
Oral but not transdermal estrogen is associated with an increased VTE risk. In addition, our data suggest that norpregnane derivatives may be thrombogenic, whereas micronized progesterone and pregnane derivatives appear safe with respect to thrombotic risk. If confirmed, these findings could benefit women in the management of their menopausal symptoms with respect to the VTE risk associated with oral estrogen and use of progestogens.
Circulation 03/2007; 115(7):840-5. · 14.74 Impact Factor
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ABSTRACT: Cardiovascular disease has emerged as a leading cause of death in women. In recent years, significant attention has been paid to the potential benefits of hormone therapy on chronic diseases such as cardiovascular disease. Large prevention trials failed to confirm the cardioprotective effect of estrogen. The divergent findings from observational and randomized clinical studies are summarized and reasons for the different results are postulated. Use of estrogen alone or estrogen opposed with progestins is not indicated for the prevention of cardiovascular disease and may even increase the risk of stroke. Oral estrogen increases venous thromboembolism events. Recent data suggest that transdermal estrogens are safe with respect to venous thromboembolism. Current data have limited ability to investigate the wide variety of hormone treatments available. Clinical research should be continued to assist patients and clinicians in making treatment decisions on the basis of an individual's benefits and risks.
Maturitas 08/2006; 54(4):372-9. · 2.77 Impact Factor
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ABSTRACT: Cyclical mastalgia is a common complaint, with a potentially important relationship to breast cancer risk. In the last decade, case-control studies have reported that cyclical mastalgia could be considered as an independent risk factor for breast cancer. The subjectivity of a retrospectively collected symptom questioned the validity of this finding. We have examined the association between cyclical mastalgia and breast cancer risk in the French cohort study of women with benign breast disease diagnosed in two breast clinics between 1976 and 1979 and followed-up until 1997. The present study was restricted to the women free of any hormonal treatment (n = 247). The mean follow-up was 16 +/- 5 years, and a total of 22 breast cancers occurred during the follow-up. Using a Cox model with duration of cyclical mastalgia as a time-varying variable, the adjusted relative risk of breast cancer increased with the duration of cyclical mastalgia (P = 0.006). The corresponding relative risk for 37 months of cyclical mastalgia was 5.31 (95% confidence interval, 1.92-14.72). We show here that the conclusion still holds when the symptom cyclical mastalgia was collected prospectively in a cohort study, bringing additional evidence that cyclical mastalgia may represent an independent and useful clinical marker of increased breast cancer risk. It might be a confounding factor when assessing the effects of hormonal treatments on breast cancer risk such as hormonal replacement therapy or oral contraceptives.
Cancer Epidemiology Biomarkers & Prevention 07/2006; 15(6):1229-31. · 4.12 Impact Factor
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Céline Straczek,
Emmanuel Oger,
Marianne Beau Yon de Jonage-Canonico, Geneviève Plu-Bureau,
Jacqueline Conard,
Guy Meyer,
Martine Alhenc-Gelas,
Hervé Lévesque,
Nathalie Trillot,
Marie-Thérèse Barrellier,
Denis Wahl,
Joseph Emmerich,
Pierre-Yves Scarabin
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ABSTRACT: Oral estrogen increases the risk of venous thromboembolism (VTE) in postmenopausal women, particularly in those with a prothrombotic mutation. Transdermal estrogen may be safe with respect to VTE. We investigated the impact of the route of estrogen administration on the association between a prothrombotic mutation (factor V Leiden or prothrombin G20210A mutation) and VTE risk.
We performed a multicenter case-control study of VTE among postmenopausal women who were enrolled in 1999 through 2004 at 7 clinical centers in France. We recruited 235 consecutive patients with a first documented episode of idiopathic VTE and 554 controls. Factor V Leiden was associated with a 3.4-fold-increased risk of VTE (95% confidence interval [CI], 2.0 to 5.8), and a prothrombin mutation was associated with a 4.8-fold-increased risk of VTE (95% CI, 2.5 to 9.4). Oral but not transdermal estrogen was associated with an increased risk of VTE (odds ratio [OR], 4.3; 95% CI, 2.6 to 7.2; and OR, 1.2; 95% CI, 0.8 to 1.7, respectively). After adjustment for potential confounding factors, the combination of either factor V Leiden or prothrombin G20210A mutation and oral estrogen gave a 25-fold-increased risk of VTE compared with nonusers without mutation (95% CI, 6.9 to 95.0). However, the risk for women with prothrombotic mutation using transdermal estrogen was similar to that of women with a mutation who were not using estrogen (OR, 4.4; 95% CI, 2.0 to 9.9; and OR, 4.1; 95% CI, 2.3 to 7.4, respectively).
In contrast to oral estrogen, transdermal estrogen does not confer additional risk on women who carry a prothrombotic mutation. The safety of transdermal estrogen has to be confirmed in randomized trials.
Circulation 12/2005; 112(22):3495-500. · 14.74 Impact Factor
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JAMA The Journal of the American Medical Association 04/2005; 293(11):1322; author reply 1322-3. · 30.03 Impact Factor
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ABSTRACT: The objective of the study was to evaluate the venous impact of a progestogen-only contraception on women at high risk of venous thromboembolism (VTE). In this retrospective cohort study, 204 consecutive women at high risk of VTE were recruited between January 1992 and June 1997 and were prospectively followed. Women using chlormadinone acetate (CMA) at antigonadotropic doses (n=102) were matched by age and date of referral and history of venous thrombosis with women who had no hormonal contraception (n=102). During follow-up (mean of 33 months), nine episodes of VTE were observed: three in women receiving CMA and six in nontreated women. Using the Cox model to adjust for confounding variables such as age, thrombophilia and body mass index, the relative risk of VTE associated with the use of CMA was not significant [relative risk: 0.8 (0.2-3.9)]. These reassuring results need to be confirmed in other prospective studies.
Contraception 12/2004; 70(6):437-41. · 2.72 Impact Factor
