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. Author manuscript; available in PMC: 2022 Jul 14.
Published in final edited form as: Cancer Epidemiol Biomarkers Prev. 2021 Feb 22;30(5):927–935. doi: 10.1158/1055-9965.EPI-20-1355

Depot-medroxyprogesterone acetate use is associated with decreased risk of ovarian cancer: the mounting evidence of a protective role of progestins

Minh Tung Phung 1, Alice W Lee 2, Anna H Wu 3, Andrew Berchuck 4, Kathleen R Cho 5, Daniel W Cramer 6,7, Jennifer Anne Doherty 8, Marc T Goodman 9, Gillian E Hanley 10, Holly R Harris 11, Karen McLean 12, Francesmary Modugno 13,14, Kirsten B Moysich 15, Bhramar Mukherjee 1,16, Joellen M Schildkraut 17, Kathryn L Terry 6,7, Linda J Titus 18; Ovarian Cancer Association Consortium, Susan J Jordan 19, Penelope M Webb 20; Australian Ovarian Cancer Study Group and the Ovarian Cancer Association Consortium, Malcolm C Pike 3,21, Celeste Leigh Pearce 1; Ovarian Cancer Association Consortium
PMCID: PMC9281627  NIHMSID: NIHMS1677456  PMID: 33619020

Abstract

Background

Combined oral contraceptive use is associated with a decreased risk of invasive epithelial ovarian cancer (ovarian cancer). There is suggestive evidence of an inverse association between progestin-only contraceptive use and ovarian cancer risk, but studies have been underpowered.

Methods

The current study used primary data from 7,977 women with ovarian cancer and 11,820 control women in seven case-control studies from the Ovarian Cancer Association Consortium to evaluate the association between use of depot-medroxyprogesterone acetate (DMPA), an injectable progestin-only contraceptive, and ovarian cancer risk. Logistic models were fit to determine the association between ever use of DMPA and ovarian cancer risk overall and by histotype. A systematic review of the association between DMPA use and ovarian cancer risk was conducted.

Results

Ever use of DMPA was associated with a 35% decreased risk overall (OR=0.65, 95% CI 0.50–0.85). There was a statistically significant trend of decreasing risk with increasing duration of use (p-trend<0.001). The systematic review yielded six studies, four of which showed an inverse association and two showed increased risk.

Conclusions

DMPA use appears to be associated with a decreased risk of ovarian cancer in a duration-dependent manner based on the preponderance of evidence. Further study of the mechanism through which DMPA use is associated with ovarian cancer is warranted.

Impact

The results of this study are of particular interest given the rise in popularity of progestin-releasing intrauterine devices which have a substantially lower progestin dose than that in DMPA, but may have a stronger local effect.

Keywords: ovarian cancer, progestin, injectable contraceptive, depot-medroxyprogesterone acetate, progestin-only contraceptive

INTRODUCTION

Combined oral contraceptives (COCs), which include both an estrogen and progestin component, have been shown to reduce risk of invasive epithelial ovarian cancer by approximately 20% per five years of COC use (1, 2). It has long been hypothesized that progestins in particular are associated with reduced risk of ovarian cancer (3). However, the relationship between progestin-only contraceptives and ovarian cancer risk is not well understood.

Injectable progestin-only contraceptives, depot-medroxyprogesterone acetate (DMPA) and norethisterone oenanthate (NET-EN), are long-acting (4). Both have been available in some countries since the 1960s for contraception, but not until 1992 in the U.S. (5–7) and 1994 in Australia (8). Previous studies of the association between DMPA use and ovarian cancer risk have been small and the results were equivocal (9–12). Understanding the relationship between DMPA use and ovarian cancer may provide a broader understanding of the role of progestins in ovarian cancer risk, has significant value given its wide-spread use in some populations, and may be informative with respect to the potential for progestin-releasing intrauterine devices (IUDs) as chemopreventive for the disease.

We used data from seven studies from the international Ovarian Cancer Association Consortium (OCAC) to conduct a pooled analysis examining the association between use of DMPA and ovarian cancer risk. The number of women with ovarian cancer using DMPA in this study is greater than in previous studies, thus our analysis presented here is the largest to date. The association between ovarian cancer risk with duration of DMPA use was examined and compared to the association with duration of COC use and number of births. We also conducted a systematic review to identify previously published studies that have examined the relationship between DMPA use and ovarian cancer risk to put the results of our analysis in context with the existing literature.

MATERIAL AND METHODS

All studies included in this analysis obtained institutional ethics committee approval and followed recognized ethnical guidelines including the Declaration of Helsinki, the Belmont Report, and/or the U.S. Common Rule. All participants provided written informed consent.

OCAC Pooled Analysis

We used data from seven case-control studies participating in the OCAC that had DMPA use information available - six in the U.S. and one in Australia: the Diseases of the Ovary and their Evaluation Study (DOV) (13), the Hawaii Ovarian Cancer Study (HAW) (14), the Hormones and Ovarian Cancer Prediction Study (HOP) (15), the North Carolina Ovarian Cancer Study (NCO) (16), the New England Case Control Study (NEC) (17), the University of Southern California Study of Lifestyle and Women’s Health (USC) (18, 19), and the Australian Ovarian Cancer Study (AUS) (20). Data were self-reported and collected by in-person or telephone interviews using structured questionnaires. Data were sent to the OCAC data-coordinating center (Duke University) for central harmonization (21). The OCAC Epidemiology Working Group created a codebook which was distributed to each study site. The Working Group reviewed the data that were received, carried out logic checks and queried sites to resolve inconsistencies. Cases were women with invasive epithelial ovarian cancer (hereafter referred to as ovarian cancer). Controls were women without a personal history of ovarian cancer who had at least one intact ovary.

Ever/never use of DMPA was available for all seven studies, and duration of DMPA use was available from four of these studies (DOV, NCO, USC and AUS). Duration of DMPA use was provided by each study in three-month intervals (i.e., 3, 6, 9, etc.).

The association between DMPA and ovarian cancer risk overall and by histotype was modeled using conditional logistic regression. All models were conditioned on age at diagnosis for cases/reference age for controls (<40, five-year age groups to 74, 75+ years), race/ethnicity (Non-Hispanic White, Hispanic White, Black, Asian, other) and OCAC study site (n=7). Education level (less than high school, high school, some college, college graduate), COC use (never use, <1 year, 1–4 years, 5–9 years, 10+ years of use), parity (0, 1, 2, 3+ births), and breastfeeding (never, <12 months, 12–23 months, 24+ months) were considered important confounders a priori and were included in all models. The inclusion of duration of COC use and parity allowed us to compare the effects of these hormonal exposures to DMPA use on ovarian cancer risk.

The impact of additional potential confounders, including a personal history of endometriosis (yes/no), first-degree family history of ovarian cancer (yes/no), body mass index (<25, 25-<30, 30+ kg/m2), incomplete pregnancies (0, 1, 2+), and smoking (never, current, former), on the association between DMPA use and ovarian cancer risk were considered. None of these exposures changed the beta-coefficients for the DMPA use-ovarian cancer risk association by >10%; they were not included in the final models.

Of the total of 20,446 participants, only women with complete data were included; 649 (3.2%) had missing data on at least one variable in the final model and were excluded. The variables with the most missing values were education level (1.7%), breastfeeding (1.0%), COC use (0.9%), and race/ethnicity (0.3%).

Based on age at diagnosis and year of birth, many women who participated in the study would have been post-menopausal at the time DMPA was approved for contraception in the U.S. (1992) or Australia (1994). Although it was possible for women in the U.S. to receive DMPA for contraception at least as early as 1967 as some care providers received approval to use it as an investigational new drug (9), we conducted a sensitivity analysis which excluded women who were post-menopausal or >45 years of age in 1992 for the U.S. studies and 1994 for the Australian study to ensure that they could have used DMPA for contraception.

We also carried out multinomial logistic regression to determine whether the results by histotype were statistically different from each other.

Statistical significance was defined as pࣘ0.05 using 2-sided tests. Data were analyzed using R studio 1.1.463.

Systematic Review

A systematic search in PubMed was conducted to look for original research that reported the association between use of injectable DMPA as a contraception method and ovarian cancer risk. The search terms used were “ovarian cancer”, “depot-medroxyprogesterone acetate”, “progestin”, “contraceptive” and their synonyms. A manual search of the references provided in the selected articles was also conducted. Studies had to be published in English before August 1st, 2019 and be available in full text. Studies on DMPA use for other purposes (such as cancer treatment), review studies, in vitro studies, and studies conducted in animals were excluded. After duplicates were removed, publications were screened based on titles, abstracts, and full texts, using Rayyan (22) as the analysis system. For articles that met the inclusion criteria, we extracted information about authors, year of publication, study design, time and place of recruitment, number and characteristics of participants, and the findings related to the objectives of this review.

RESULTS

Pooled Analysis

We included 7,977 women with ovarian cancer and 11,820 control women in our analysis (Table 1). Ninety women with ovarian cancer (1.1%) and 252 control women (2.1%) had ever used DMPA (Table 1). The prevalence of DMPA use in control women ranged from 0.8% to 3.5% across the seven studies.

Table 1:

Description of study participants by case/control status and DMPA use in a pooled analysis of the association between DMPA use and ovarian cancer risk in seven OCAC studies

Cases Controls
DMPA Users (%) n = 90 Non-Users (%) n = 7,887 DMPA Users (%) n = 252 Non-Users (%) n = 11,568
Study Site Location Years recruited
AUS Australia 2001–2005 15 (16.7%) 1,184 (15.0%) 48 (19.0%) 1,389 (12.0%)
DOV western Washington, USA 2002–2009 19 (21.1%) 1,117 (14.2%) 47 (18.7%) 1,794 (15.5%)
HAW Hawaii, USA 1993–2008 9 (10.0%) 700 (8.9%) 33 (13.1%) 1,070 (9.2%)
HOP western Pennsylvania, northeast Ohio, western New York, USA 2003–2009 11 (12.2%) 705 (8.9%) 42 (16.7%) 1,760 (15.2%)
NCO North Carolina, USA 1999–2008 16 (17.8%) 899 (11.4%) 37 (14.7%) 1,011 (8.7%)
NEC New Hampshire, eastern Massachusetts, USA 1992–2008 12 (13.3%) 1,473 (18.7%) 26 (10.3%) 2,053 (17.7%)
USC Los Angeles County, California, USA 1993–2010 8 (8.9%) 1,809 (22.9%) 19 (7.5%) 2,491 (21.5%)
Age
Mean (SD) 46.6 (11.4) 57.3 (11.1) 42.9 (10.4) 55.8 (12.1)
Median 44 58 43 56
Range 24–76 20–91 22–77 18–94
Education Level
< High school 6 (6.7%) 1,018 (12.9%) 22 (8.7%) 963 (8.3%)
High school 19 (21.1%) 1,986 (25.2%) 70 (27.8%) 2,700 (23.3%)
Some College 40 (44.4%) 2,369 (30.0%) 82 (32.5%) 3,587 (31.0%)
College Graduate 25 (27.8%) 2,514 (31.9%) 78 (31.0%) 4,318 (37.3%)
Race/Ethnicity
Non-Hispanic White 66 (73.3%) 6,492 (82.3%) 198 (78.6%) 9,717 (84%)
Hispanic White 6 (6.7%) 319 (4.0%) 8 (3.2%) 413 (3.6%)
Black 8 (8.9%) 275 (3.5%) 12 (4.8%) 370 (3.2%)
Asian 6 (6.7%) 481 (6.1%) 6 (2.4%) 570 (4.9%)
Other 4 (4.4%) 320 (4.1%) 28 (11.1%) 498 (4.3%)
Oral Contraceptive Use
Never 16 (17.8%) 3,347 (42.4%) 16 (6.3%) 3,545 (30.6%)
<1 year 17 (18.9%) 940 (11.9%) 25 (9.9%) 1,198 (10.4%)
1–4.99 years 23 (25.6%) 1,804 (22.9%) 79 (31.3%) 2,892 (25.0%)
5–9.99 years 20 (22.2%) 1,027 (13.0%) 68 (27.0%) 1,994 (17.2%)
10+ years 14 (15.6%) 769 (9.8%) 64 (25.4%) 1,939 (16.8%)
Parity
0 30 (33.3%) 1,931 (24.5%) 40 (15.9%) 1,871 (16.2%)
1 14 (15.6%) 1,107 (14.0%) 46 (18.3%) 1,557 (13.5%)
2 28 (31.1%) 2,228 (28.2%) 90 (35.7%) 3,687 (31.9%)
3+ 18 (20.0%) 2,621 (33.2%) 76 (30.2%) 4,453 (38.5%)
Breastfeeding
Never 51 (56.7%) 4,335 (55.0%) 98 (38.9%) 5,037 (43.5%)
<12 months 27 (30.0%) 2,173 (27.6%) 77 (30.6%) 3,636 (31.4%)
12–23 months 6 (6.7%) 796 (10.1%) 38 (15.1%) 1,513 (13.1%)
24+ months 6 (6.7%) 583 (7.4%) 39 (15.5%) 1,382 (11.9%)
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Overall, ever-use of DMPA was associated with a 35% reduction in risk of ovarian cancer (OR = 0.65, 95% CI 0.50–0.85). This inverse association was observed in all seven OCAC studies (Figure 1). When restricting to women who were pre-menopausal and ≤45 at the time DMPA use was approved for contraception (56 users/2,660 cases and 197 users/4,884 control women), a similar association was observed; women who used DMPA had a 42% reduction in risk of ovarian cancer compared to never users (OR=0.58, 95% CI 0.42–0.81). DMPA use was inversely associated with all histotypes except low-grade serous where the odds ratio was 1.0 (Figure 2). Likely due to small numbers, only the association with high-grade serous was statistically significant (OR=0.60, 95% CI 0.41–0.88). The results across histotypes were not statistically significantly different from each other (p>0.05 for all comparisons).

Figure 1:

Figure 1:

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OCAC study-specific results of ever use of DMPA and ovarian cancer risk. The models are conditioned on race/ethnicity, and age and adjusted for education level, oral contraceptive use duration, parity and breastfeeding. The pooled analysis of the studies showed that ever-use of DMPA was associated with a 35% reduction in risk of ovarian cancer (OR = 0.65, 95% CI 0.50–0.85).

Figure 2:

Figure 2:

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Ever use of DMPA and risk of individual histotypes of ovarian cancer in OCAC. The sum of high-grade serous, low-grade serous, mucinous, endometrioid and clear cell is lower than the total number of cases due to some cases not being classified as one of those five histotypes. The models are conditioned on OCAC study site, race/ethnicity, and age and adjusted for education level, oral contraceptive use duration, parity and breastfeeding.

As the duration of DMPA use increased, the magnitude of the inverse association with ovarian cancer became stronger (p for trend<0.001; Table 2). Compared to never users, women who used DMPA for 3–9 months (1–3 injections) had an 8% reduced risk of ovarian cancer (OR= 0.92, 95% CI 0.54–1.57; Table 2). Women who used DMPA for 12–18 months (4–6 injections) had a 44% reduced risk (OR=0.56, 95% CI 0.29–1.07), and those who had used DMPA for 21+ months had a 56% reduced risk (OR=0.44, 95% CI 0.26–0.77) (Table 2). In the same model, women who used COCs for 12–59 months had a 24% risk reduction compared to never users (OR=0.76, 95% CI 0.68–0.84); and women with two births had a 35% risk reduction compared to nulliparous women (OR=0.65, 95% CI 0.57–0.74) (Table 2).

Table 2:

Odds ratios (ORs) and 95% confidence intervals (CIs) for duration of use (four studies) of DMPA use, oral contraceptive use, parity and ovarian cancer risk

Cases (%) n=5,064 Controls (%) n=6,831 Odds ratio* 95% Confidence interval
DMPA use
  Never use 5,009 (98.9%) 6,685 (97.9%) 1.0
  3–9 months (1–3 shots) 24 (0.5%) 42 (0.6%) 0.92 0.54–1.57
  12–18 months (4–6 shots) 13 (0.3%) 41 (0.6%) 0.56 0.29–1.07
  21+ months (7+ shots) 18 (0.4%) 63 (0.9%) 0.44 0.26–0.77
p-trend<0.001
Oral contraceptive use
  Never use 1,956 (38.6%) 1,889 (27.7%) 1.0
  1–11 months 580 (11.5%) 613 (9.0%) 1.01 0.88–1.16
  12– 59 months 1,202 (23.7%) 1,701 (24.9%) 0.76 0.68–0.84
  60–119 months 724 (14.3%) 1,249 (18.3%) 0.59 0.52–0.67
  120+ months 602 (11.9%) 1,379 (20.2%) 0.42 0.37–0.48
p-trend<0.001
Parity
  0 1,158 (22.9%) 1,129 (16.5%) 1.0
  1 734 (14.5%) 944 (13.8%) 0.81 0.70–0.94
  2 1,457 (28.8%) 2,224 (32.6%) 0.65 0.57–0.74
  3+ 1,715 (33.9%) 2,534 (37.1%) 0.60 0.52–0.68
p-trend<0.001
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*

Single model fit with DMPA use, oral contraceptive use, and parity; conditioned on OCAC study site, race/ethnicity, and age; adjusted for education level and breastfeeding.

Systematic Review

From the 4,702 records found through the PubMed search, 4,696 were removed for the following reasons: duplicates (n=34), DMPA use for different purposes (e.g., stimulating drugs for infertility; n=2,181), non-ovarian cancer outcomes (e.g., other cancer types; n=1,879), not original research (i.e., review articles; n=320), studies in animals (n=162), no English full texts (n=74), in vitro studies (n=45), or no full text available (n=1). The summary of the remaining six studies which met the a priori review criteria is presented in Table 3.

Table 3:

Summary of the articles included in a systematic review of the associations between invasive ovarian cancer risk and use of injectable depot-medroxyprogesterone acetate (DMPA).

No. First Author Year of publication Study design Time period and country of recruitment Duration of follow-up Sample size Participants’ characteristics Outcome Exposure Adjustment factors Results
1 Liang et al. 1983 (9) Retrospective cohort study of women receiving DMPA for contraception 1967–1976 in the U.S. Until Dec 31, 1980 (4–13 years) 5,003 Black women given DMPA during 1967–1976 under FDA Investigational New Drug approval. Not clear if invasive or borderline or both DMPA Age, year, race SIR=0.86 (0.0–4.6) Observed 1 case of ovarian cancer.
Compared to an expected 1.16 cases based on national rates for black women (adjusted for lost to follow-up),
2 WHO 1991 (10) Hospital-based case-control 1979–1986 in Mexico
1979–1988 in Thailand		 224 cases (9.8% used DMPA)
1,781 controls (12.9% used DMPA)		 Cases and controls were matched on age, hospital and year of interview. Invasive and borderline DMPA Age, hospital, year of interview, number of live births and use of COCs. OR=0.81 (95% CI 0.36–1.8) for invasive.
3 Wilailak et al. 2012 (11) Hospital-based case-control 2006–2008
Thailand		 330 cases (17.9% used DMPA)
982 controls (25.7% used DMPA)		 Cases and controls were matched on age and hospital. Invasive DMPA COC use, breastfeeding, parity and family history of gynecological cancer. OR=0.52 (95% CI 0.33–0.88)
4 Urban et al. 2012 (23) Hospital-based case-control 1995–2006
South Africa		 182 cases (5.5% ever used injectable and never used oral contraceptives) 1,492 controls (16.7% ever used injectable and never used oral contraceptives). Black females
18–79 years old		 Invasive Injectable contraceptives Age at diagnosis, year of diagnosis, education, tobacco smoking, alcohol consumption, parity/age at first birth, number of sexual partners, urban/rural residence, and province of birth. OR for Ever use of injectable and Never use of oral contraceptives compared to Never use of both: 0.35 (95% CI 0.17–0.71).
5 Huang et al. 2015 (24) Population-based cohort 1997–2000
China		 12.6 years follow-up on average. 174 cases (3.4% used contraceptive shots) 70,259 participants (2.6% used contraceptive shots) 40–70 years old. Invasive Contraceptive shots Age at recruitment, education, years of ovulation, irregular ovulatory cycles, first-degree family history of cancer, regular physical activity within 5 years, other contraceptive methods (never/ever) HR= 1.33 (0.58–3.04)
6 Iversen et al. 2018 (12) Prospective, nationwide cohort 1995–2015
Denmark		 Up to 20 years. 1,249 cases/ (3 of them had used DMPA and had not switched their contraceptives) 1,879,227 participants Aged 15–49 years. Invasive DMPA Calendar year, parity, age, education, tubal sterilization, hysterectomy, endometriosis, polycystic ovary syndrome, and family history of breast or ovarian cancer Among women who had not switched their hormonal contraceptives, hazard ratio for DMPA use compared to never use of any hormonal contraceptives HR= 6.56 (95% CI 2.11–20.40)
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Of the six studies identified, four specifically studied the association between DMPA use and ovarian cancer risk; the other two did not distinguish between DMPA and NET-EN use. A cohort study of 5,003 Black women in the U.S. who used DMPA for an average of ~18 months and were followed for an average of 8.6 years observed only one ovarian cancer case compared to an expected 1.16 cases (SIR=0.86, 95% CI 0.1–4.6) (9). Two hospital-based case-control studies, one carried out by the World Health Organization (WHO) in Mexico and Thailand (22 DMPA users/224 invasive and borderline ovarian cancer cases) (10) and a second conducted in Thailand (59 DMPA users/330 invasive ovarian cancer cases) (11), observed inverse associations between DMPA use and invasive ovarian cancer risk (OR= 0.81, 95% CI 0.36–1.8 and OR=0.52, 95% CI 0.33–0.88, respectively). In contrast, a population-linkage study carried out in Denmark observed a six-fold increase in ovarian cancer risk among DMPA users (n=3 cases) (RR=6.56, 95% CI 2.11–20.40) (12).

Of the two studies that did not specify the type of injectable contraceptive used, one found an inverse association and the other found a positive association. Urban and colleagues, in their hospital-based case-control study in South Africa, found that ever use of injectable progestin-only contraceptives with no use of oral contraceptives (n=10 cases), was associated with reduced risk of invasive ovarian cancer compared to never use of either (OR=0.35, 95% CI 0.17–0.71) (23). A cohort study in Shanghai, China observed a positive association between injectable contraceptive use and ovarian cancer risk (HR=1.33, 95% CI 0.58–3.04) (24).

DISCUSSION

In the pooled OCAC data, we observed a 35% reduced risk of ovarian cancer among women who had used DMPA; this decreased risk was consistently observed in all seven OCAC studies included. We also observed a dose-response relationship with greater risk reduction associated with longer duration of DMPA use when we pooled data across the four of the OCAC studies with this information. The results were broadly consistent across histotype, robust to sensitivity analysis restricted to women who were pre-menopausal and <46 years of age at the time DMPA was approved for contraception in the U.S. and Australia, and not likely to be confounded given that we were able to take COC use, parity, breastfeeding, education level, race/ethnicity, age, and other factors into account in the analysis.

Six previous studies on DMPA use and ovarian cancer were identified through our systematic review; four of these studies found inverse associations with effect estimates ranging from 0.35 to 0.86 (9–11, 23). Of the two studies that did not find an inverse association, one also did not observe the expected inverse association with combined oral contraceptive (COC) use or tubal ligation (24); systematic bias may have been introduced by only measuring contraceptive exposures at baseline in this 12 year follow-up study (24). . Further, these two studies also had the lowest prevalence of DMPA use among cases (six users out of 174 cases (24) and three users out of 1,249 cases (12)), making these results particularly susceptible to uncontrolled confounding. Overall, based on the results of our pooled analysis and systematic review, the preponderance of evidence indicates an inverse association between DMPA use and ovarian cancer risk.

Our results are also consistent with studies that examined the association between ovarian cancer and progestin-releasing IUDs, another progestin-only long-acting contraceptive (12, 25, 26). The prevalence of progestin-releasing IUD use has increased significantly, but because these types of IUDs were not marketed until 2000 in the U.S. and Australia (27), there are limited data on their association with ovarian cancer risk. However, the three studies that have examined the relationship between progestin-releasing IUD use and ovarian cancer found an inverse association (RR=0.84, 95% CI 0.53–1.35 (12),RR=0.53, 95% CI 0.32–0.88 (25), and SIR=0.59, 95% CI 0.47–0.73 (26)), however the last of these studies did not adjust for potential confounders. In the literature, prevalence of progestin-only pill use ranged from 2.1% to 9.3% among controls in the four case-control studies that have reported this information; the prevalence of exclusive use of progestin-only pills ranged from 0.2%−1.8%. Based on these four studies, the association between progestin-only pill use and ovarian cancer risk is equivocal (28–31).

COC use and parity are two other exposures that are associated with higher progestin/progesterone exposure compared to normal cycling. The average serum progestin concentration produced by DMPA is 5.1-fold higher than that produced by a COC with the same duration of use (32–34), whereas the progesterone exposure during pregnancy is approximately equivalent to the progestin dose in DMPA. In our data, the OR for 12–59 months of COC use was 0.76 compared to 0.56 for 10–18 months of DMPA use (Table 2) which is suggestive of a stronger magnitude of effect for DMPA use. The DMPA OR is similar to that observed with parity (two births OR=0.65; Table 2). A DMPA injection is associated with residual anovulatory effects that last as long as nine months after the injection which may explain the stronger inverse association with ovarian cancer compared to COCs (35–37). Also, the high levels of estrogen and other hormones during pregnancy may affect the magnitude of the inverse association between parity and ovarian cancer risk. The DMPA duration data are sparse making firm conclusions impossible, but it does appear that DMPA is at least as protective as COCs and parity.

The mechanisms underlying the protective effect of progestins are unclear. A simple explanation of blocking ovulation is possible, but if this were the only mechanism, the effect of all such exposures would be the same, which is not what has been observed. It is also possible that there is a direct hormonal effect (3). These direct effects may be due to the induction of cell death, thus preventing oncogenic transformation of precursor cancer cells. Indeed, it was found that progesterone induces necroptotic cell deaths in transformation-related protein 53 (Trp53) mouse oviduct epithelium and in immortalized human p53-defective fallopian tube epithelial cells (38). Possibly more importantly, in a randomized study of women undergoing risk-reducing bilateral salpingo-oophorectomy, women who received levonorgestrel had statistically significantly lower cell proliferation (Ki-67) in the ovarian surface epithelium (OSE) compared to women who received placebo (p=0.011) (39), but OSE is not considered to be the cell of origin for most ovarian cancers. There was some suggestion in this study that progestins cleared genetically abnormal cells in the fallopian tube fimbriae based on karyometic results (39). In addition, several in vitro studies have demonstrated that progestins induce apoptosis in human ovarian carcinoma cell lines (40–42).

A major strength of this study is the large sample size which included 90 women with ovarian cancer who used DMPA. The results of this study are widely generalizable as we included participants in many locations in the U.S. and Australia. This allowed us to explore histotype-specific associations as well as the overall association by duration on a subset of studies. It is possible there is misclassification of duration of DMPA use as a woman may find it difficult to remember precisely how many shots she received. However, there is little reason to expect this misclassification to be differential as DMPA use is not a stigmatized exposure, thus the impact of any non-differential recall error would be toward the null. It is possible that participants may have misreported NET-EN use as DMPA use. However, DMPA is used every three months while NET-EN is used every two months. We had duration of use data from four OCAC studies and the durations were in multiples of three suggesting that this is not NET-EN use.

Overall, the results from this study of DMPA use build on the body of evidence of a protective role for progestins/progesterone for ovarian cancer. Further investigation is warranted to understand the mechanism underlying the decreased risk. This is particularly relevant given the increasingly popularity of progestin-releasing IUDs.

Acknowledgements

We would like to thank all of the women who participated in this research. We are grateful to the family and friends of Kathryn Sladek Smith for their generous support of the Ovarian Cancer Association Consortium through their donations to the Ovarian Cancer Research Fund. We thank the doctors, nurses, clinical and scientific collaborators, health care providers and health information sources who have contributed to the many studies contributing to this manuscript. We also wish to thank Marjorie Riggan for her great assistance and with managing the OCAC database.

The AOCS also acknowledges the cooperation of the participating institutions in Australia, and the contribution of the study nurses, research assistants and all clinical and scientific collaborators. The complete AOCS Study Group can be found at www.aocstudy.org.

Support for the Ovarian Cancer Association Consortium was provided by donations from family and friends of the Kathryn Sladek Smith to the Ovarian Cancer Research Fund. In addition, these studies were supported by the NIH (R01-CA054419 and P50-CA105009, to D.W. Cramer; R01-CA112523 and R01-CA087538, to J.A. Doherty; R01-CA058598, N01-CN-55424 and N01- PC-67001, to M.T. Goodman; R01-CA095023, to F. Modugno and K.B. Moysich; P50-CA159981 and R01-CA126841, to K.B. Moysich; K07-CA080668, to F. Modugno; R01-CA076016, to J.M. Schildkraut; P01-CA17054, to A.H. Wu, M.C. Pike and C.L. Pearce; P30-CA14089, to A.H. Wu and M.C. Pike; R01-CA061132 and P30CA008748, to M.C. Pike; R03-CA113148, P30CA046592 and R03-CA115195, to C.L. Pearce); NIH/National Center for Research Resources/General Clinical Research Center (M01-RR000056, to F. Modugno); U.S. Army Medical Research and Material Command (DAMD17–01-1–0729, to the Australian Ovarian Cancer Study Group); the U.S. Department of Defense (DAMD17–02-1–0669, to F. Modugno; DAMD17–02-1–0666, to A. Berchuck; W81XWH-10–1-02802, to K.L. Terry), National Health & Medical Research Council of Australia (199600, 400413 and 400281, to P.M. Webb), Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia (multi-state applications 191, 211, and 182, to P.M. Webb); and the California Cancer Research Program (00–01389V-20170, to C.L. Pearce and M.C. Pike; 2II0200, to A.H. Wu); University of Pittsburgh School of Medicine Dean’s Faculty Advancement Award (to F. Modugno). AOCS gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation. Cases ascertainment for the University of Southern California Study of Lifestyle and Women’s Health was supported by the NIH (N01-PC67010, N01-CN025403).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funders.

LIST OF ABBREVIATIONS

AUS

The Australian Ovarian Cancer Study

CI

Confidence interval

COC

Combined oral contraceptive

DMPA

Depot-medroxyprogesterone acetate

DOV

The Disease of the Ovary and their Evaluation Study

FDA

Food and Drug Administration

HAW

The Hawaii Ovarian Cancer Study

HOP

The Hormones and Ovarian Cancer Prediction Study

HR

Hazard ratio

IUD

Intrauterine device

NCO

The North Carolina Ovarian Cancer Study

NEC

The New England Case Control Study

NET-EN

Norethisterone oenanthate

OCAC

Ovarian Cancer Association Consortium

OR

Odds ratio

RR

Risk ratio

SD

Standard deviation

SIR

Standardized incidence ratio

Trp53

Transformation-related protein 53

U.S

United States

USA

The United States of America

USC

The University of Southern California Study of Lifestyle and Women’s Health

WHO

World Health Organization

Footnotes

Conflict of interest disclosure statement

No conflicts of interest were reported beyond grant funding to carry out research as described above. Dr. Webb received grant funding from Astra Zeneca for an unrelated study of ovarian cancer.

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