Depot-medroxyprogesterone acetate (DMPA) and risk of invasive adenocarcinomas and adenosquamous carcinomas of the uterine cervix

doi:10.1016/0010-7824(95)00215-V

Contraception

Volume 52, Issue 5, November 1995, Pages 307-312

https://doi.org/10.1016/0010-7824(95)00215-V Get rights and content

Abstract

A hospital-based case-control study was conducted in two hospitals in Bangkok, Thailand, and in one hospital each in Chiang Mai, Thailand, Mexico City, Mexico and Nairobi, Kenya. One purpose of this study was to determine whether the long-acting progestational contraceptive, depot-medroxyprogesterone acetate (DMPA), alters risk of invasive cervical carcinomas with adenomatous histological features. Information on prior use of DMPA, screening for cervical cancer, and the suspected risk factors for this disease was ascertained from interviews of 239 women with adenocarcinomas and 85 women with adenosquamous carcinomas, as well of from a large pool of controls, 2534 of whom were matched to the cases included in this report. For selected subsets of these women, a smoking history was also elicited, blood specimens were collected for measurement of antibodies against herpes simplex and cytomegalovirus, and information on sexual behavior was obtained from interviews of their husbands. The relative risk (and 95% confidence interval) of adenomatous cervical carcinomas in women who ever used DMPA was estimated to be 0.75 (0.51, 1.11). No trends in risk were observed with duration of DMPA use, times since first or last use, or age at first use. The results provide reassurance that use of DMPA for over four years does not enhance risk of adenomatous cervical carcinomas, and risk is not increased after a potential latent period of over 12 years since initial exposure.

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Cited by (20)

Disparities in Cervical Cancer Incidence and Mortality: Can Epigenetics Contribute to Eliminating Disparities?
2017, Advances in Cancer Research
Citation Excerpt :
We and others, as well as meta-analyses involving 24 epidemiological studies with 16,573 cases and 35,509 controls, have reported an up to twofold increase in CIN2 + risk in women reporting oral contraceptive use, and the strength of this association increased with increasing duration of use (Beral, Hannaford, & Kay, 1988; Brinton et al., 1987; de Villiers, 2003; Gram, Macaluso, & Stalsberg, 1992; Hoyo et al., 2005; McFarlane-Anderson, Bazuaye, Jackson, Smikle, & Fletcher, 2008; Moreno et al., 2002; Munoz et al., 2002; Smith et al., 2003; Vanakankovit & Taneepanichskul, 2008). Others report no association (Castle et al., 2002; Green et al., 2003; Hoyo et al., 2005; La Vecchia et al., 1994; Thiry et al., 1993; Thomas & Ray, 1995) or an inverse association between oral contraceptive use and cervical dysplasia (Becker, Wheeler, McGough, Parmenter, et al., 1994). However, NHANES data suggest that oral contraceptive use is lower in African Americans than European Americans (Lee et al., 2005; Phares et al., 2004), suggesting that differences in the prevalence of hormonal contraceptive use are unlikely to account for race/ethnic differences observed in ICC and CIS incidence.
Screening for uterine cervical intraepithelial neoplasia (CIN) followed by aggressive treatment has reduced invasive cervical cancer (ICC) incidence and mortality. However, ICC cases and carcinoma in situ (CIS) continue to be diagnosed annually in the United States, with minorities bearing the brunt of this burden. Because ICC peak incidence and mortality are 10–15 years earlier than other solid cancers, the number of potential years of life lost to this cancer is substantial. Screening for early signs of CIN is still the mainstay of many cervical cancer control programs. However, the accuracy of existing screening tests remains suboptimal. Changes in epigenetic patterns that occur as a result of human papillomavirus infection contribute to CIN progression to cancer, and can be harnessed to improve existing screening tests. However, this requires a concerted effort to identify the epigenomic landscape that is reliably altered by HPV infection specific to ICC, distinct from transient changes.
Canadian Contraception Consensus (part 3 of 4): Chapter 8 - Progestin-only contraception
2016, Journal of Obstetrics and Gynaecology Canada
Citation Excerpt :
Son utilisation ne semble pas engendrer une hausse des risques de cancer du sein197–200. Les résultats d’études récentes quant au cancer du col utérin sont rassurants et indiquent que ce cancer est associé au tabagisme plutôt qu’à l’utilisation d’AMPR201–204. Déclaration sommaire
Fournir des lignes directrices aux fournisseurs de soins quant à l’utilisation de modes de contraception pour la prévention de la grossesse et quant à la promotion d’une sexualité saine.
Orientation des praticiens canadiens en ce qui concerne l’efficacité globale, le mécanisme d’action, les indications, les contre-indications, les avantages n’étant pas liés à la contraception, les effets indésirables, les risques et le protocole de mise en œuvre des modes de contraception abordés; planification familiale dans le contexte de la santé sexuelle et du bien-être général; méthodes de counseling en matière de contraception; et accessibilité et disponibilité des modes de contraception abordés au Canada.
La littérature publiée a été récupérée par l’intermédiaire de recherches menées dans MEDLINE et The Cochrane Library entre janvier 1994 et janvier 2015 au moyen d’un vocabulaire contrôlé (p. ex. contraception, sexuality, sexual health) et de mots clés (p. ex. contraception, family planning, hormonal contraception, emergency contraception) appropriés. Les résultats ont été restreints aux analyses systématiques, aux études observationnelles et aux essais comparatifs randomisés / essais cliniques comparatifs publiés en anglais entre janvier 1994 et janvier 2015. Les recherches ont été mises à jour de façon régulière et intégrées à la directive clinique jusqu’en juin 2015. La littérature grise (non publiée) a été identifiée par l’intermédiaire de recherches menées dans les sites Web d’organismes s’intéressant à l’évaluation des technologies dans le domaine de la santé et d’organismes connexes, dans des collections de directives cliniques, dans des registres d’essais cliniques et auprès de sociétés de spécialité médicale nationales et internationales.
La qualité des résultats a été évaluée au moyen des critères décrits dans le rapport du Groupe d’étude canadien sur les soins de santé préventifs (Tableau 1).
Déclarations sommaires
- 15.
  Les implants de progestatif comptent des taux d’échec aussi faibles que ceux de la contraception permanente. (II-2)
- 16.
  L’insertion d’un implant immédiatement à la suite d’un accouchement ou d’un avortement constitue une façon efficace d’abaisser les taux de nouvelle grossesse chez les adolescentes et de nouvel avortement. (II-2)
- 17.
  Les perturbations du cycle menstruel constituent l’effet indésirable le plus courant des modes de contraception à progestatif seul. (II-2) L’aménorrhée est très courante dans le cadre de l’utilisation d’acétate de médroxyprogestérone-retard et d’implants de progestatif. (II-2)
- 18.
  L’utilisation de progestatifs administrés selon des doses contraceptives ne semble pas accroître le risque de thromboembolie veineuse, d’infarctus du myocarde ou d’accident vasculaire cérébral. (II-2)
- 19.
  L’efficacité des implants de progestatif (ou de l’acétate de médroxyprogestérone) n’est pas amoindrie chez les femmes obèses ou présentant une surcharge pondérale. (II-2)
- 20.
  La constatation d’un gain pondéral précoce dans le cadre de l’utilisation d’acétate de médroxyprogestérone-retard permet de prédire la poursuite du gain pondéral. (II-2)
- 21.
  L’utilisation d’acétate de médroxyprogestérone-retard est associée à un délai quant à la reprise de l’ovulation. (II-2)
- 22.
  L’utilisation d’acétate de médroxyprogestérone-retard est associée à une baisse de la densité minérale osseuse. Cette baisse atteint sa rapidité maximale au cours des deux premières années d’utilisation et semble être largement réversible à la suite de l’abandon du traitement à l’acétate de médroxyprogestérone-retard. (I) Nous ne disposons pas de données probantes solides indiquant que l’utilisation d’acétate de médroxyprogestérone-retard cause l’ostéoporose (II-2) ou qu’elle entraîne une hausse du risque de fracture. (II-2)
- 23.
  Il n’a pas été démontré que l’utilisation de préparations à progestatif seul entraîne une baisse de la production de lait maternel. (I) Les petites quantités d’hormones stéroïdiennes sécrétées dans le lait maternel n’exercent pas un effet indésirable sur la croissance et le développement du nouveau-né. (II-2)
- 24.
  L’utilisation d’acétate de médroxyprogestérone-retard est associée à une baisse des risques de cancer de l’endomètre et de cancer de l’ovaire. (II-2)
Recommandations
- 12.
  Le recours à des modes de contraception à progestatif seul devrait être envisagé chez les femmes qui présentent des troubles médicaux dans le cadre desquels la prise d’œstrogènes est contre-indiquée ou moins souhaitable, comme dans le cas des femmes qui ont récemment connu un accouchement, qui allaitent ou qui fument et qui sont âgées de plus de 35 ans. (III-A)
- 13.
  Aucune restriction ne devrait être imposée quant à l’utilisation d’acétate de médroxyprogestérone-retard (y compris en ce qui a trait à la durée d’utilisation) chez les femmes en âge de procréer qui sont autrement admissibles à l’utilisation de ce mode de contraception. Les risques et les avantages globaux de la poursuite de l’utilisation d’acétate de médroxyprogestérone-retard devraient faire l’objet de discussions avec les utilisatrices à intervalles réguliers tout au long du traitement. (III-A)
- 14.
  Des services de counseling traitant des perturbations du cycle menstruel devraient être offerts avant la mise en œuvre d’un mode de contraception à progestatif seul. (I-A)
- 15.
  Les fournisseurs de soins devraient aviser leurs patientes des effets potentiels de l’acétate de médroxyprogestérone-retard sur la densité minérale osseuse et leur offrir des conseils en matière de « santé osseuse » (y compris en ce qui concerne la supplémentation en calcium et en vitamine D, l’abandon du tabagisme, la pratique d’exercices de port de poids et l’atténuation de la consommation d’alcool et de caféine). (III-A)
- 16.
  En présence de saignements prolongés et/ou fréquents chez des utilisatrices de contraceptifs à progestatif seul, la présence d’une grossesse, d’une infection transmissible sexuellement ou d’une pathologie génitale devrait être écartée. (III-B)
- 17.
  La possibilité d’une grossesse ectopique doit être écartée lorsqu’une grossesse en vient à se manifester chez une femme qui utilise un mode de contraception à progestatif seul. (III-A)
Canadian Contraception Consensus (Part 3 of 4): Chapter 8 - Progestin-Only Contraception
2016, Journal of Obstetrics and Gynaecology Canada
Citation Excerpt :
There does not appear to be an increased risk of breast cancer with DMPA use.197–200 Recent studies regarding cervical cancer are reassuring and show that cervical cancer is associated with smoking status rather than DMPA use.201–204 Summary Statement
To provide guidelines for health care providers on the use of contraceptive methods to prevent pregnancy and on the promotion of healthy sexuality.
Overall efficacy of cited contraceptive methods, assessing reduction in pregnancy rate, safety, ease of use, and side effects; the effect of cited contraceptive methods on sexual health and general well-being; and the relative cost and availability of cited contraceptive methods in Canada.
Published literature was retrieved through searches of Medline and The Cochrane Database from January 1994 to January 2015 using appropriate controlled vocabulary (e.g., contraception, sexuality, sexual health) and key words (e.g., contraception, family planning, hormonal contraception, emergency contraception). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from January 1994 to January 2015. Searches were updated on a regular basis in incorporated in the guideline to June 2015. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.
The quality of the evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1).
Summary Statements
- 15.
  Progestin implants have failure rates as low as permanent contraception. (II-2)
- 16.
  The use of a progestin implant immediately postpartum and post-abortion is an effective way of decreasing repeat pregnancy in adolescents and repeat abortions. (II-2)
- 17.
  The most common side effect of progestin-only contraceptive methods is menstrual cycle disturbances. (II-2) Amenorrhea is very common with depot medroxyprogesterone acetate and progestin implant use. (II-2)
- 18.
  The use of progestins given at contraceptive doses does not appear to increase the risk of venous thromboembolism, myocardial infarction, or stroke. (II-2)
- 19.
  The efficacy of progestin implants or depot medroxyprogesterone acetate is not decreased in overweight and obese women. (II-2)
- 20.
  Early weight gain with depot medroxyprogesterone acetate use is predictive of continued weight gain. (II-2)
- 21.
  Depot medroxyprogesterone acetate use is associated with a delay in resumption of ovulation. (II-2)
- 22.
  The use of depot medroxyprogesterone acetate (DMPA) is associated with a decrease in bone mineral density. This decrease is most rapid in the first 2 years of use and appears to be largely reversible once DMPA is discontinued. (I) There is no strong evidence that the use of DMPA causes osteoporosis (II-2) or increases the risk of fracture. (II-2)
- 23.
  The use of progestin-only preparations has not been shown to decrease breast milk production. (I) The small amounts of steroid hormones secreted in breast milk do not have an adverse effect on infant growth and development. (II-2)
- 24.
  Depot medroxyprogesterone acetate use is associated with a decreased risk of endometrial and ovarian cancer. (II-2)
Recommendations
- 12.
  Progestin-only methods of contraception should be considered in women with medical conditions where estrogen is contraindicated or less appropriate, such as women who are recently postpartum, breastfeeding, or in smokers over age 35. (III-A)
- 13.
  There should be no restriction on the use of depot medroxy-progesterone acetate (DMPA), including duration of use, among women of reproductive age who are otherwise eligible to use the method. The overall risks and benefits of continuing DMPA use should be discussed with DMPA users at regular intervals throughout the course of treatment. (III-A)
- 14.
  Counselling regarding menstrual cycle disturbances should be done prior to initiating a progestin-only method of contraception. (I-A)
- 15.
  Health care providers should inform patients of the potential effects of depot medroxyprogesterone acetate on bone mineral density and counsel them on “bone health,” including calcium and vitamin D supplementation, smoking cessation, weight-bearing exercise, and decreased alcohol and caffeine consumption. (III-A)
- 16.
  If prolonged and/or frequent bleeding occurs in users of progestin-only contraceptives, pregnancy, sexually transmitted infection, and genital pathology should be ruled out. (III-B)
- 17.
  Ectopic pregnancy should be ruled out if a pregnancy occurs in a woman using a progestin-only method of contraception. (III-A)
The contraception needs of the perimenopausal woman
2014, Best Practice and Research: Clinical Obstetrics and Gynaecology
Citation Excerpt :
Some studies looking at the effect of DMPA on ovarian cancer had shown no benefit: it may be that these were carried out in areas of the world where injectable contraception is used too rarely to demonstrate an effect [56]. Any effect of DMPA on risk of cervical cancer is probably minimal [57]. Oestrogen inhibits osteoclast activity and reduces bone resorption.
Perimenopausal women have low fertility but must still be advised to use contraception until natural sterility is reached if they are sexually active. Patterns of contraceptive use vary in different countries worldwide. Long-acting reversible contraceptive methods offer reliable contraception that may be an alternative to sterilisation. Hormonal methods confer significant non-contraceptive benefits, and each individual woman should weigh up the benefits and risks of a particular method. No method of contraception is contraindicated by age alone, although combined hormonal contraception and injectable progestogens are not recommended for women over the age of 50 years. The intrauterine system has particular advantages as a low-dose method of effective hormonal contraception, which also offers control of menstrual dysfunction and endometrial protection in women requiring oestrogen replacement. Condoms are recommended for personal protection against sexually transmitted infections in new relationships. Standard hormone replacement therapy is not a method of contraception.
Progesterone signaling inhibits cervical carcinogenesis in mice
2013, American Journal of Pathology
Human papillomavirus is the main cause of cervical cancer, yet other nonviral cofactors are also required for the disease. The uterine cervix is a hormone-responsive tissue, and female hormones have been implicated in cervical carcinogenesis. A transgenic mouse model expressing human papillomavirus oncogenes E6 and/or E7 has proven useful to study a mechanism of hormone actions in the context of this common malignancy. Estrogen and estrogen receptor α are required for the development of cervical cancer in this mouse model. Estrogen receptor α is known to up-regulate expression of the progesterone receptor, which, on activation by its ligands, either promotes or inhibits carcinogenesis, depending on the tissue context. Here, we report that progesterone receptor inhibits cervical and vaginal epithelial cell proliferation in a ligand-dependent manner. We also report that synthetic progestin medroxyprogesterone acetate promotes regression of cancers and precancerous lesions in the female lower reproductive tracts (ie, cervix and vagina) in the human papillomavirus transgenic mouse model. Our results provide the first experimental evidence that supports the hypothesis that progesterone signaling is inhibitory for cervical carcinogenesis in vivo.
Contraception
2013, Women and Health

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Depot-medroxyprogesterone acetate (DMPA) and risk of invasive adenocarcinomas and adenosquamous carcinomas of the uterine cervix

Abstract

Lancet

Contraception

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Oral contraceptive use and risk of invasive cervical cancer

Int J Epidemiol

Long-term use of oral contraceptives and risk of invasive cervical cancer

Int J Cancer

Hormonal content of combined oral contraceptives in relation to the reduced risk of endometrial carcinoma

Int J Cancer