Association between premenopausal progestogen use and postmenopausal hormonal therapy in the GAZEL cohort

doi:10.1016/j.maturitas.2007.08.008

Maturitas

Volume 58, Issue 3, 20 November 2007, Pages 216-225

https://doi.org/10.1016/j.maturitas.2007.08.008 Get rights and content

Abstract

Objectives

The aim of this work was to verify the existence of and characterise the relationship between premenopausal progestogen use, subsequent use of estrogen–progestogen therapy (EPT) and risk factors for breast cancer, and to describe and analyse premenopausal progestogen use among women participating in a longitudinal study.

Methods

Data came from self-administered questionnaires mailed to 2254 pre- or peri-menopausal women aged 45 years or older participating in the French GAZEL cohort and followed for 10 years. Bivariate and multivariate analyses first examined the association between progestogen use and women's and physicians’ characteristics. A generalised linear model was then used to analyse the association between progestogen use and EPT use, while taking into account factors associated with progestogen use.

Results

Thirty-six percent of the women had used progestogens before menopause: 56% of them 19-norpregnane derivatives, and 13% 17α hydroxyprogesterone derivatives. They were more likely to report breast pain, a family history of breast cancer and mood changes, to be thin, to consult a gynaecologist rather than a general practitioner, to consult a female physician, and to consult often. Of the 1756 women who had reached menopause, EPT users were more likely to have used progestogens premenopausally (adjusted RR: 1.2; 95% CI: 1.1–1.3).

Conclusions

Physician characteristics play an important role in the use of progestogens before menopause. Our results also suggest that women using progestogens may have a higher risk of breast cancer, that is, that progestogen use may be a confounding rather than causal factor. The analyses concerning the relationship between EPT use and breast cancer risk must take progestogen use before menopause into account, as they do other confounding factors, such as age at menarche, parity, and use of oral contraceptives.

Introduction

Progestogen hormones are used for oral contraception, treatment of premenopausal symptoms [1], and estrogen–progestogen therapy (EPT) [2]. The increased risk of breast cancer associated with the use of combined estrogen–progestogen contraceptives and with the use of postmenopausal EPT remains an open question [3], [4], [5]. The Women's Health Initiative (WHI), a large randomised trial, showed an increased risk of breast cancer among EPT users (hazard ratio, HR: 1.24; 95% CI: 1.01–1.54) [6], but no increased risk has been demonstrated among users of estrogen alone (HR: 0.77; 95% CI: 0.59–1.01). The progestogen used in combination with conjugated estrogens in the WHI was medroxyprogesterone acetate, and the precise effect on breast cancer risk of other progestogens added to estrogen therapy remains uncertain, with in vitro [7] and observational cohort findings [8] supporting the hypothesis that breast cancer risk may vary according to the type of progestogen combined with estrogens in EPT.

Epidemiological studies of progestogen use before menopause (frequency and determinants) are rare, and no published studies investigate the association between progestogen use during the pre- and peri-menopausal periods and subsequent EPT.

Our study accordingly sought to confirm three hypotheses: first, that women using progestogens before menopause differ from women not using this treatment, second, that these user characteristics may be risk factors for breast cancer, and third, that women using progestogens before menopause are more likely to take EPT afterwards. If these hypotheses are confirmed, assessment of the relationship between EPT and breast cancer must take premenopausal use of progestogens into account. Our main objective was therefore to verify the existence of and characterise the relationship between premenopausal progestogen use, subsequent use of EPT and risk factors for breast cancer. We also wanted to describe and analyse premenopausal progestogen use among women who have participated since 1990 in the GAZEL cohort.

Section snippets

Population and methods

Our population was part of the French GAZEL cohort, set up in 1989. This cohort includes 20,046 men and women employed by the French national power company (EDF-GDF) who volunteered to participate in epidemiological research [9]. Since 1989, the INSERM (French Institute for Health and Medical Research) unit managing the cohort has mailed a general self-administered questionnaire each year to all members (http://www.gazel.inserm.fr). Within this cohort, a prospective survey (entitled “Women and

Statistical methods

First, to analyse the factors associated with progestin use among the 2254 premenopausal women, we compared ever-users with never-users in a bivariate analysis, using Pearson's χ² test for the qualitative variables and Student's t-test for the quantitative variables. Those associated (p < 0.10) with ever-use in the bivariate analysis were then included in a forward stepwise logistic regression.

We then used a generalised linear model to analyse the association between EPT use and premenopausal

Results

The mean age of the 2254 women in this overall sample was 46.8 (±1.56) years at inclusion. Most had not passed the baccalaureate examination (Table 1). More than half (65.5%) lived in a home with two or more people, and most (83%) lived in municipalities with more than 2000 inhabitants. Only 15.2% smoked, 23% reported occasional or no alcohol use at all, and 44.2% reported weekly or occasional physical exercise. The women in our sample were generally not overweight, with a mean body mass index

Discussion

In this sample of French working women participating in a cohort study, more than one-third of the premenopausal women had used progestogens at some point during the study between the age of 45 and menopause. They were more likely to report risk factors for breast cancer (breast tenderness or pain and a family history of breast cancer) and mood changes, to be thin, to consult a gynaecologist (rather than a general practitioner), to consult a female physician, and to consult often. Follow-up

Conclusion

We observed a high prevalence of progestin use among premenopausal women in our population. The reasons for their use are consistent with the indications during the premenopausal period found in the literature. Characteristics of the physician (specialisation and gender) play an important role in the use of this treatment. Our main results suggest that women using progestogens before menopause may have a higher risk of breast cancer, because they are more likely to experience mastalgia and to

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Cited by (6)

Characteristics and determinants of initiation of premenopausal use of oral progestagens in the French E3N cohort
2010, Journal de Gynecologie Obstetrique et Biologie de la Reproduction
Décrire les caractéristiques et les déterminants de l’initiation d’un traitement progestatif seul – i.e. non associé à un estrogène – parmi des femmes françaises en préménopause.
Nos analyses incluent 41 603 femmes de la cohorte française E3N. La prévalence d’utilisation a été calculée de 1992 à 2005. Les déterminants de l’initiaition d’un traitement progestatif ont été analysés de manière prospective entre 1992 et 2005 à l’aide de modèles de Cox, multivariés à risque proportionnels.
Cinquante-huit pour cent des femmes ayant atteint leur ménopause entre 1992 et 2005 ont été utilisatrices de progestatifs seuls durant leur préménopause. Entre 1992 et la fin des années 1990, l’augmentation de la prévalence d’utilisation de progestatifs seuls dans notre cohorte était proche de 50 %. L’initiation de traitements progestatifs était significativement associée à un niveau d’étude élevé (≥ bac + 5 vs < bac : hazard ratio [HR] : 1,09, intervalle de confiance [IC] : 1,01–1,18), à un indice de masse corporelle (IMC) normal (femmes en surpoids et obèses vs femmes d’IMC normal : HR = 0,84, IC : 0,79–0,90 et HR = 0,79, IC : 0,69–0,89 respectivement), à un antécédent de troubles gynécologiques (mastodynies, maladies bénignes du sein, maladies bénignes de l’utérus ou de l’ovaire [HR = 1,38, IC : 1,27–1,49, HR = 1,18, IC : 1,13–1,24 et HR = 1,60, IC : 1,52–1,68 respectivement]) et à un suivi gynécologique récent (correspondant à une mammographie ou un frottis récent [HR = 1,11, IC : 1,05–1,17 and HR = 1,38, CI : 1,27–1,49 respectivement]).
Étant donné que, au moins en France, l’utilisation de progestatifs seuls en préménopause est fréquente, l’évaluation de ses risques et bénéfices est d’importance en termes de santé publique.
To describe the characteristics and determinants of initiation of use of progestagens alone – i.e. without concomitant use of estrogen – among French premenopausal women.
Forty-one thousand six hundred and three women from the French E3N cohort were included in our analyses. Prevalence of use was calculated from 1992 to 2005. Determinants of progestagens alone initiation were investigated prospectively from 1992 to 2005, using multivariable Cox proportional hazards models.
Fifty-eight per cent of women who had reached menopause between 1992 and 2005 ever used progestagens alone during their premenopause. Between 1992 and the end of 1990s, the increase in the prevalence of progestagens alone use in our cohort was close to 50%. Initiation of progestagens alone was significantly associated with a high level of education (postgraduate compared to high-school graduate: Hazard ratio [HR]: 1.09 95% confidence interval [CI]: 1.01–1.18), with a normal body mass index (overweight and obese women compared to normal-weight women: HR = 0.84, 95% CI: 0.79–0.90 and HR = 0.79, 95% CI: 0.69–0.89 respectively), history of gynecological disorders (mastalgia, benign breast disease and benign uterine or ovarian disease [HR = 1.38, 95% CI: 1.27–1.49, HR=1.18, 95% CI: 1.13–1.24 and HR = 1.60, 95% CI: 1.52–1.68 respectively]) and with recent gynaecological screening (as measured by recently performed mammogram or Pap smear HR = 1.11, 95% CI: 1.05–1.17 and HR = 1.38, 95% CI: 1.27–1.49 respectively).
Since, at least in France, use of progestagens alone at premenopause is common, evaluation of its risks and benefits is of public health importance.
The French GAZEL Cohort Study: 20 years of epidemiologic research
2009, Advances in Life Course Research
The GAZEL Cohort Study was set up in 1989 among Électricité de France-Gaz de France (EDF-GDF) workers. It is an open epidemiologic laboratory characterized by a broad coverage of health problems and determinants and accessible to the community of researchers. At inception in 1989, the GAZEL Cohort Study included 20 625 volunteers working at EDF-GDF then aged from 35 to 50 years (15 011 men and 5614 women). The cohort is broadly diverse in terms of social, economic, and occupational status, health, and health-related behavior. The data collected routinely cover diverse dimensions and come from different sources: annual self-administered questionnaire (morbidity, lifestyles, life events, etc.); personnel department of EDF-GDF for social, demographic, and occupational characteristics; EDF-GDF Special Social Insurance fund (for sickness absences and cancer and ischemic heart disease registries), occupational medicine (occupational exposure and working conditions), Social Action Fund (healthcare utilization), Health Screening Centers for standardized health examination and the constitution of a biobank, and the National Death Register (causes of death). Follow-up has been excellent, and the number of subjects lost to follow-up was exceptionally low; active participation by the self-administered questionnaire is also elevated.
Today, more than 40 projects on diversified themes have been set up in the GAZEL Cohort Study by some 30 French and foreign teams. Different health problems taking into account behavioral, social, psychological and medical occupational risk factors have been the object of research projects in the cohort. A substantial proportion of the research work has focused on social inequalities in health. Here, we present a brief panorama of the main fields covered by research in the GAZEL Cohort Study that have already been published over the years.
Progestogen use in women approaching the menopause and breast cancer risk
2009, Maturitas
Progestogens, particularly synthetic progestins, are widely used to contrast the clinical consequences of the relative hyperestrogenism that characterizes the years preceding the menopause. As a large body of data on postmenopausal hormone therapy (HT) demonstrates that the addition of synthetic progestins to estrogen increases the breast cancer risk compared to estrogen alone, it is important to evaluate if the use of progestogens in premenopausal years is associated with the risk of breast cancer.
Main literature data on the association with breast cancer risk of progestogens, either used alone in premenopausal years or added to estrogen in postmenopausal HT, were reviewed.
Available data suggest that long-term current use of progestogens in premenopausal women after the age of 40 years can increase the risk of breast cancer. Consistently with the data on postmenopausal HT, the risk increase is higher for lobular cancer than for ductal cancer.
The most important and widely accepted indications to the use of progestogens in the years preceding the menopause are anovulatory menstrual disorders, for which a limited period of treatment is generally sufficient. Awaiting for further data, when using progestogens for longer periods to treat other problems (endometriosis, cyclical mastalgia, etc.), the possibility of increased breast cancer risk and clinical benefits have to be weighed. Anyway, as micronized progesterone and dydrogesterone, at least when they were used in postmenopausal HT, seem to have, according to a large observational study, a safer risk profile on the breast, the preferential use of these preparations could be suggested.
Premenopausal Use of Progestogens and Cutaneous Melanoma Risk: A French Prospective Cohort Study
2020, American Journal of Epidemiology
Progestogens and breast cancer
2015, Progestogens in Obstetrics and Gynecology
Progestatives: Do we still have the choice?
2009, Reproduction Humaine et Hormones

View full text

Association between premenopausal progestogen use and postmenopausal hormonal therapy in the GAZEL cohort

Abstract

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Population and methods

Statistical methods

Results

Discussion

Conclusion

Lancet Oncol

Baillieres Best Pract Res Clin Obstet Gynaecol

Fertil Steril

Soc Sci Med

Fertil Steril

Using progestins in clinical practice

Am Fam Physician

Role of progestogen in hormone therapy for postmenopausal women: position statement of The North American Menopause Society

Menopause

Oral contraceptives and the risk of breast cancer

N Engl J Med

Oral contraceptive use and risk of early-onset breast cancer in carriers and noncarriers of BRCA1 and BRCA2 mutations

Cancer Epidemiol Biomarkers Prev

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomised controlled trial

JAMA

Differential effects of progestogens on breast cancer cell lines

Maturitas