American Journal of Obstetrics & Gynecology
Volume 200, Issue 5 , Pages 489.e1-489.e8, May 2009

Depot-medroxyprogesterone acetate and combined oral contraceptive use and cervical neoplasia among women with oncogenic human papillomavirus infection

Presented in part at the 35th Annual Meeting of the Society for Epidemiologic Research, Palm Desert, CA, June 18-21, 2002.

  • Tiffany G. Harris, PhD

      Affiliations

    • Department of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, WA
    • Corresponding Author InformationReprints: Tiffany Harris, PhD, New York City Department of Health and Mental Hygiene, 253 Broadway, Room 602, New York, NY 10007
    • ,
  • Leslie Miller, MD

      Affiliations

    • Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA
    • ,
  • Shalini L. Kulasingam, PhD

      Affiliations

    • Department of Obstetrics and Gynecology, University of Minnesota, Minneapolis, MN
    • ,
  • Qinghua Feng, PhD

      Affiliations

    • Department of Pathology, University of Washington School of Medicine, Seattle, WA
    • ,
  • Nancy B. Kiviat, MD

      Affiliations

    • Department of Pathology, University of Washington School of Medicine, Seattle, WA
    • ,
  • Stephen M. Schwartz, PhD

      Affiliations

    • Department of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, WA
    • Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA
    • ,
  • Laura A. Koutsky, PhD

      Affiliations

    • Department of Epidemiology, University of Washington School of Public Health and Community Medicine, Seattle, WA

Received 18 July 2008; received in revised form 13 October 2008; accepted 16 January 2009.

Article Outline

Objective

The objective of the study was to examine the relationship of depot-medroxyprogesterone acetate (DMPA) and combined oral contraceptive (COC) use with cervical intraepithelial neoplasia (CIN).

Study Design

Two case-control studies of women who presented for gynecologic care and underwent cytologic and human papillomavirus (HPV) testing were performed. The first included oncogenic HPV-positive women grouped based on histology: negative (n = 152), CIN1 (n = 133), and CIN2-3 or greater (n = 173). For the second, 2 groups were identified: negative HPV/negative histology (n = 107) and positive oncogenic HPV/negative histology (n = 152).

Results

Among oncogenic HPV-positive women, DMPA use was inversely associated with CIN2-3 or greater (adjusted odds ratio [ORadj], 0.4; 95% confidence interval [CI], 0.2-1.1) and CIN1 (ORadj, 0.1; 95% CI, 0.01-0.6); COC use was not associated with either. Among histologically negative women, DMPA use was associated with oncogenic HPV (ORadj, 4.7; 95% CI, 1.4-15.8).

Conclusion

Among women with oncogenic HPV, hormonal contraceptive use was not associated with an increased risk of CIN2-3 or greater. Longer-term DMPA use may attenuate the colposcopic and histologic features of CIN because women reporting such use were more likely than others to have cervical oncogenic HPV without evidence of CIN.

Key words: cervical intraepithelial neoplasia, depot-medroxyprogesterone acetate, hormonal contraception, oncogenic human papillomavirus infection

 

Hormonal contraceptives are used by millions of women worldwide to prevent pregnancy. Many studies have evaluated the relationship between oral contraceptives and cervical cancer and have found that the highest risk of cervical cancer was associated with long-term (≥ 10 years) use.1, 2 Studies evaluating the association with human papillomavirus (HPV) infection have mixed findings.3, 4, 5, 6, 7, 8, 9 Limitations with many of these previous studies include the following: (1) no measure of HPV status; (2) confounding by history of cytologic screening; and (3) disease status in the cases and controls was determined by different methods (histology vs cytology). In addition, because different formulations and doses of combined oral contraceptives (COCs) are being used in the United States today, the results may not be applicable to current methods. Few studies have evaluated the relationship between depot-medroxyprogesterone acetate (DMPA; Depo-Provera; Pfizer, Inc, New York, NY), a progestin-only injectable contraceptive, and cervical neoplasia.1, 8, 10 A recent metaanalysis found only a slight increase in cervical neoplasia risk associated with long-term DMPA use (≥ 5 years).1

The present study was designed to determine whether DMPA and COC use increase the risk for: (1) cervical intraepithelial neoplasia (CIN) grade 2-3 or greater or CIN1 among oncogenic HPV-positive women or (2) acquisition or detection of HPV among women with no histologic evidence of cervical neoplasia. Unlike previous studies, disease status for both cases and controls was based on histology.

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Materials and Methods 

Study subjects and data collection 

The University of Washington Human Subjects Division approved all protocols and consent forms. As described previously, women presenting from December 1997 through August 2002 for routine gynecologic care at 3 Planned Parenthood clinics who met the following criteria were eligible for cytologic and HPV screening with the study: were 18-50 years old; had no history of treatment for cervical neoplasia or hysterectomy; were not planning to continue a current pregnancy; and did not report being HIV-positive or having another immunosuppressive condition.11, 12, 13

During this time period, 4975 women were enrolled, and after providing written, informed consent, participants completed a brief questionnaire that included demographic, reproductive, and sexual history questions. A pelvic examination was performed and a cervical specimen was collected using a cytobrush and a plastic spatula for liquid cytology (ThinPrep; Cytyc Corp, Boxborough, MA). A Dacron-tipped swab sample from the endo- and ectocervix was obtained for HPV DNA testing by polymerase chain reaction (PCR).

Women with the following findings were contacted and offered colposcopy and biopsy with the study (median time between screening and colposcopy-biopsy was 60 days): (1) atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion, or high-grade squamous intraepithelial lesion on Papanicolaou test; (2) negative Papanicolaou test and a positive oncogenic HPV test; and (3) a random sample of women with negative Papanicolaou and negative HPV tests.11, 12

At the colposcopy-biopsy visit, a detailed questionnaire regarding demographic, reproductive/gynecologic, sexual history, and general medical information was administered. The brand, duration, and the month and year of last use for the 4 most recent hormonal contraception methods was obtained via the questionnaire without the use of recall aids. Very few women reported 4 hormonal contraceptive methods. A pelvic examination was performed and cervical specimens were collected as described for the screening visit. A colposcopic examination of the cervix was performed using acetic acid, and punch biopsies were taken from the most abnormal appearing areas. If none were seen, a cervical biopsy was taken at the 12 o'clock position. Women with lesions that extended into the endocervical canal or women with squamous intraepithelial lesion on screening cytology and no colposcopically visible lesions also underwent endocervical curettage (ECC).

Women with negative results or low-grade disease (atypia or CIN1) were referred back to Planned Parenthood for follow-up. Women with high-grade disease (CIN2-3 or greater) were offered a loop electrosurgical excision procedure (LEEP). Women with cancer were referred to a gynecologic oncologist. At the clinician's discretion, some women were referred for repeat colposcopies and biopsies and/or ECCs. HPV testing was not performed at these repeat visits.

HPV DNA detection 

All HPV DNA testing was performed at the Harborview Medical Center HPV DNA Laboratory (Seattle, WA).11, 12, 13 First, the cervical swab sample was digested with proteinase K and the DNA precipitated with ethanol. Then the HPV L1 consensus primer (MY09/MY11 and HMB01) PCR amplification assay and Roche line blot assay (Alameda, CA) were used for amplification and typing of HPV DNA.14 This system allowed for the detection and typing of oncogenic HPV types 16/18/26/31/33/35/39/45/51/52/55/56/58/59/68/73/82/83 and nononcogenic HPV types 6/11/40/42/53/54/57/66/84. The primers PC04 and GH20 were used for beta-globin detection (control for DNA quality).14

Cytology and histology 

All cytology and histology specimens were processed and reviewed at Harborview Medical Center. The cytology slides were screened by a cytotechnologist and reviewed by pathologists without knowledge of the colposcopy or HPV results; findings were recorded in terms of the 1991 Bethesda System.15 A random 10% sample of all slides read as negative was rescreened manually. Histology was classified as negative, atypia, CIN1, CIN2, CIN3, carcinoma in situ, adenocarcinoma in situ (AIS), microinvasive cancer, or invasive cancer.

Statistical analysis 

To evaluate the association between hormonal contraception and CIN, the analysis was restricted to women positive for at least 1 oncogenic HPV type at colposcopy-biopsy (n = 591). To minimize misclassification by case-control status, oncogenic HPV-positive women with negative histology whose cytology was abnormal (n = 60) or unsatisfactory (n = 7) and oncogenic HPV-positive women with atypia on histology (n = 66) were excluded.

Of the remaining 458 women, 3 outcome groups were defined based on the most severe histologic diagnosis from a biopsy, an ECC, or a LEEP specimen. The first was composed of women who were histologically negative and had negative or ASC-US cytology at both screening and colposcopy-biopsy (n = 152). The second group was composed of women with CIN1 (n = 133). The third was composed of women with CIN2-3 or greater (including AIS or greater) (n = 173).

Women were categorized separately as to their DMPA and COC use (ie, 2 separate variables) at colposcopy-biopsy: never user, former user, recent user who had been using that method for < 2 years, or recent user who had been using that method for ≥ 2 years. Former use was defined as having stopped using that method at least 1 year before colposcopy-biopsy, and recent use was defined as having used that method within 1 year of colposcopy-biopsy. The time intervals were chosen based on the observation that at least 50% of CIN develops within 2 years of detecting cervical HPV infection.16 Women who had used both DMPA and COC within 1 year of colposcopy-biopsy were categorized as recent users for both methods.

A third variable was created to ascertain the association between use of a COC with higher amounts of estrogen (≥ 35 μg) and CIN: never used a COC with 35 μg or greater of estrogen, former user of 35 μg or greater of estrogen COC, recent user of 35 μg or greater of estrogen COC who had been using for < 2 years, and recent user of 35 μg or greater of estrogen COC who had been using for ≥ 2 years.

For all hormonal contraceptive variables, if the month of last use was missing, it was imputed as the midpoint of the possible months of use. Seven women's (2 negative, 1 CIN1, and 4 CIN2-3) month of last use for former COC use was imputed, and 14 women's (6 negative, 5 CIN1, and 3 CIN2-3) month of last use for former DMPA use was imputed.

Multinomial logistic regression was used to evaluate the association between hormonal contraception and CIN. The DMPA and COC variables were always included in the same model, and all models were adjusted for age (18-19, 20-24, 25-29, and 30-50 years), parity (0, 1, ≥ 2), and lifetime number of male partners (1, 2-4, 5-14, ≥ 15). One woman with negative histology was excluded from the logistic regression analysis because of missing information on lifetime number of male partners. Other variables (eg, smoking, screening history) were not included because they did not confound the association between hormonal contraception and CIN.

To evaluate the association between hormonal contraception and oncogenic HPV detection, cases were women who were positive for an oncogenic HPV type at colposcopy-biopsy, were histologically negative, and had normal or ASC-US cytology at both visits (controls from the CIN analysis; n = 152). Controls were HPV-negative women with negative histology and cytology at both visits (n = 107). Cases were compared with controls using logistic regression, and all models were adjusted for age, parity, and lifetime number of male partners. One HPV DNA–negative woman and 1 HPV DNA–positive woman were excluded from the logistic regression analysis because of missing information on the lifetime number of male partners.

Variables for COC use, DMPA use, and COC use of 35 μg or greater were created similarly to that for the CIN analysis, but the time intervals for defining recent use and duration of use were halved because new HPV infections are generally detectable within 1 year of exposure.5 One case's month of last use for former DMPA use was imputed as described above.

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Results 

Hormonal contraception and CIN 

Of the 458 subjects in the analysis who were oncogenic HPV–positive at colposcopy-biopsy, 377 (83%) were also oncogenic HPV–positive at screening, and of these, 345 (92%) were positive for the same type. At colposcopy-biopsy, HPV16 was detected in specimens from 43 (28%) of the women with negative histology, 27 (20%) of the women with CIN1, and 90 (52%) of the women with CIN2-3 or greater. CIN cases were more likely than controls to have 2 or more oncogenic HPV types detected at colposcopy-biopsy and to have the same type detected at both visits (Table 1). Cases were slightly less likely to have undergone cytologic screening before study enrollment. Among those previously screened, cases with CIN2-3 or greater were more likely to have a history of an abnormal cytologic result.

TABLE 1. Distribution of demographic, gynecologic, sexual behavior, and HPV characteristics for oncogenic HPV DNA-positive women with negative, CIN1, and ≥ CIN2-3 histology
CharacteristicHPV-positive, negative histology (n = 152), n (%)HPV-positive, CIN1 histology (n = 133), n (%)PaHPV-positive, ≥ CIN2-3 histology (n = 173), n (%)Pa
Age (y) .10 .88
18-1923(15)34(26) 24(14)
20-2474(49)64(48) 79(46)
25-2937(24)25(19) 46(26)
30-5018(12)10(7) 24(14)
Race/ethnicity .36 .47
White99(65)97(73) 123(71)
African American20(13)14(10) 21(12)
Other33(22)22(17) 29(17)
Education .86 .34
< 12th grade17(11)14(11) 14(8)
≥ 12th grade135(89)119(89) 159(92)
Ever had a cytologic test before study .02 .03
No1(1)7(5) 8(5)
Yes151(99)126(95) 165(95)
History of abnormal cytologyb .81 <.001
No98(65)80(63) 66(40)
Yes53(35)46(37) 99(60)
Parity .06 .15
0100(66)87(65) 96(55)
129(19)36(27) 46(27)
≥ 223(15)10(8) 31(18)
Age at first sexual intercourse(y)c .23 .50
≤ 1320(13)21(16) 19(12)
14-17104(70)79(60) 108(66)
≥ 1826(17)32(24) 37(22)
Lifetime number of male partnersd .13 .48
15(3)12(9) 5(3)
2-437(25)29(22) 32(19)
5-1476(50)71(53) 101(58)
≥ 1533(22)21(16) 35(20)
Cigarette smoking status .11 .35
Never smoker53(35)34(25) 50(29)
Former smoker26(17)34(26) 39(22)
Current smoker73(48)65(49) 84(49)
Number of oncogenic HPV types at colposcopy-biopsy .04 <.001
1122(80)93(70) 108(62)
≥ 230(20)40(30) 65(38)
Type-specific oncogenic HPV repeat positivitye .01 <.001
No56(38)31(23) 20(12)
Yes92(62)102(77) 151(88)

CIN1, cervical intraepithelial neoplasia 1; ≥ CIN2-3, cervical intraepithelial neoplasia 2-3 or greater; HPV, human papillomavirus.

Harris. DMPA and combined OC use and CIN in women with oncogenic HPV. Am J Obstet Gynecol 2009.

aP value (2-sided) for Pearson's χ2 test of the null hypothesis that the CIN1 histology group or ≥ CIN2-3 histology group are different from the negative histology group with respect to the distribution of the listed characteristics;

bAmong those who had at least 1 cytologic test and does not include cytologic result from study screening visit;

cTwo women in the negative histology group, 1 woman in the CIN1 histology group, and 9 women in the ≥ CIN2-3 histology group were missing information on age at first sexual intercourse;

dOne woman in the negative histology group was missing information on lifetime number of male partners;

eFour women in the negative histology group and 2 women in the ≥ CIN2-3 histology group had insufficient PCR results from screening; therefore, type-specific oncogenic HPV repeat positivity could not be determined.

Recent use of DMPA for 2 years or longer was inversely associated with CIN2-3 or greater, although this association was not significant (adjusted odds ratio [ORadj], 0.4; 95% confidence interval [CI], 0.2-1.1; Table 2). Recent use of DMPA for 2 years or longer was also inversely associated with CIN1 (ORadj, 0.1; 95% CI, 0.01-0.6). However, there was only 1 woman with CIN1 with this exposure. When both of the recent DMPA use categories were combined, recent use remained inversely associated with CIN1 (ORadj, 0.5; 95% CI, 0.2-0.98; P = .046).

TABLE 2. Odds ratios and confidence intervals for the associations between hormonal contraception use and CIN among oncogenic HPV DNA-positive women
HPV-positive, -negative (n = 151)a n (%)HPV-positive, CIN1 (n = 133) n (%)HPV-positive, CIN1 vs HPV-positive, -negativeHPV-positive, ≥ CIN2-3 (n = 173) n (%)HPV-positive, ≥ CIN2-3 vs HPV-positive, -negative
Contraceptive typeORadjb95% CIORadjb95% CI
DMPA
Recent userc35(23)16(12)0.50.2-0.9835(20)0.70.4-1.3
≥ 2 y of use15(10)1(1)0.10.01-0.613(8)0.40.2-1.1
< 2 y of use20(13)15(11)0.60.3-1.522(12)0.70.4-1.6
Former user18(12)17(13)0.80.4-1.819(11)0.70.4-1.5
Never user98(65)100(75)1.0 119(69)1.0
COC
Recent userc94(62)101(76)1.50.7-3.1105(60)0.90.5-1.7
≥ 2 y of use37(24)31(23)1.10.5-2.644(25)0.90.4-1.9
< 2 y of use57(38)70(53)1.40.7-3.061(35)0.80.4-1.6
Former user26(17)14(10)1.10.4-2.832(19)1.00.5-2.1
Never user31(21)18(14)1.0 36(21)1.0

CIN1, cervical intraepithelial neoplasia 1; ≥ CIN2-3, cervical intraepithelial neoplasia 2-3 or greater; COC, combined oral contraceptives; DMPA, depot-medroxyprogesterone acetate; HPV, human papillomavirus.

Harris. DMPA and combined OC use and CIN in women with oncogenic HPV. Am J Obstet Gynecol 2009.

aOne woman in the negative histology group was excluded from the analysis because of missing information on lifetime number of male partners;

bAdjusted for age at colposcopy-biopsy (18-19, 20-24, 25-29, 30-50 years), lifetime number of male partners (1, 2-4, 5-14, ≥ 15), and parity (0, 1, ≥ 2);

cRecent use was defined as using that method within 1 year of the colposcopy-biopsy visit. The most recent COC brand reported was Ortho Tri-Cyclen (38%) followed by Ortho-Cyclen (19%) and Ortho-Novum 7/7/7 (10%; all manufactured by Ortho-McNeil Pharmaceuticals, Inc [Raritan, NJ]); 6% could not recall the brand of COC they most recently used.

Recent use of a COC for 2 years or longer was not associated with CIN2-3 or greater (ORadj, 0.9; 95% CI, 0.4-1.9) or CIN1 (ORadj, 1.1; 95% CI, 0.5-2.6). When women who had used COCs for 5 years or longer were compared with never users, there was no association with CIN2-3 or greater (ORadj, 1.0; 95% CI, 0.4-2.6) or CIN1 (ORadj, 1.1; 95% CI, 0.4-3.2). Recent use of an estrogen COC of 35 μg or greater for 2 years or longer was not associated with CIN2-3 or greater (ORadj, 1.1; 95% CI, 0.5-2.7).

The main analysis was repeated separating women with CIN3 from women with CIN2. The estimates for CIN3 were not significantly (all P > .13) different from those for CIN2 (data not shown). Likewise, when the main analysis was restricted to HPV16-positive women, results were similar (data not shown).

Hormonal contraception and oncogenic HPV 

Oncogenic HPV–positive women were younger and more likely to be nulliparous than HPV-negative women (data not shown). Among histologically negative women, recent use of DMPA for 1 year or longer was significantly associated with oncogenic HPV detection (ORadj, 4.7; 95% CI, 1.4-15.8), but recent COC use was not (Table 3). When cases were restricted to HPV16-positive women, the OR for recent DMPA use for 1 year or longer increased slightly (ORadj, 5.5; 95% CI, 0.9-34.5).

TABLE 3. Odds ratios and confidence intervals for the associations between hormonal contraception use and oncogenic HPV DNA positivity
Contraceptive typeHPV DNA–negative (n = 106)a n (%)HPV DNA–positive (n = 151)a n (%)ORadjb95% CI
DMPA
Recent userc17(16)32(21)1.60.7-3.7
≥ 1 y of use5(5)20(13)4.71.4-15.8
<1 y of use12(11)12(8)0.70.3-2.1
Former user12(11)21(14)1.30.6-3.1
Never user77(73)98(65)1.0
COC
Recent userc66(62)87(58)0.60.3-1.5
≥ 1 y of use32(30)48(32)0.80.3-2.0
< 1 y of use34(32)39(26)0.50.2-1.2
Former user23(22)33(22)0.90.3-2.3
Never user17(16)31(20)1.0

COC, combined oral contraceptives; DMPA, depot-medroxyprogesterone acetate; HPV, human papillomavirus.

Harris. DMPA and combined OC use and CIN in women with oncogenic HPV. Am J Obstet Gynecol 2009.

aOne HPV DNA-negative woman and 1 HPV DNA-positive woman were excluded from the logistic regression analysis because of missing information on lifetime number of male partners;

bAdjusted for age at colposcopy-biopsy (18-19, 20-24, 25-29, 30-50 years), lifetime number of male partners (1, 2-4, 5-14, ≥ 15), and parity (0, 1, ≥ 2);

cRecent use was defined as using that method within 6 months of the colposcopy-biopsy visit. The most recent COC brand reported was Ortho Tri-Cyclen (39%) followed by Ortho-Cyclen (19%) and Ortho-Novum 7/7/7 (11%; all manufactured by Ortho-McNeil Pharmaceuticals, Inc [Raritan, NJ]); 4% could not recall the brand of COC they most recently used.

To further explore the association of DMPA use with oncogenic HPV, 2 additional analyses were performed. First, among 142 histologically negative women who were HPV-negative at screening, DMPA use for 1 year or longer was associated with being oncogenic HPV positive at colposcopy-biopsy (ORadj, 7.3; 95% CI, 1.5-35.5). Adjusting for the number of new male partners since screening did not change the estimate to an important degree. Second, among 163 histologically negative women who were oncogenic HPV–positive at screening and did not have any new male partners between visits (women most likely not acquiring a new HPV infection), DMPA use for 1 year or longer was not associated with being positive for the same oncogenic HPV type at colposcopy-biopsy (ORadj, 1.1; 95% CI, 0.3-3.7).

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Comment 

Among women with oncogenic HPV, those with CIN were slightly less likely than women with negative histology to report ever use of DMPA in the previous year (borderline statistical significance for CIN2-3 or greater). COC use was not associated with CIN2-3 or greater or with CIN1. Recent use of DMPA for 1 year or longer was positively associated with detection of oncogenic HPV. This relationship did not appear to be caused by HPV persistence as measured by type-specific repeat oncogenic HPV positivity; however, DMPA was associated with new HPV infection. COC use was not associated with oncogenic HPV detection.

One study that specifically addressed the risk of cervical cancer associated with DMPA among oncogenic HPV-positive women found no association,10 but Castle et al8 found a small increased risk of CIN2 and CIN3 with current injectable contraceptive use. This is in contrast to our findings of an inverse association between DMPA use and both CIN1 and CIN2-3 or greater among oncogenic HPV–positive women. Unlike our study, neither of these previous studies used a control group free of cervical disease, which could lead to associations that are spuriously closer to the null or positive.

Several recent,1, 2, 3, 17, 18, 19, 20, 21 but not all,10 studies among HPV-positive women have found an increased risk of cervical neoplasia for longer durations (≥ 10 years) of oral contraceptive use. We did not find a positive association between 2 years or longer or 5 years or longer of COC use and cervical neoplasia, although the estimates from recent metaanalyses by Smith et al1 (medium-duration use OR, 1.3) and Appleby et al2 (≥ 5 years of use risk ratio, 1.45) are well inside our CI. However, these results were largely driven by studies conducted outside of the United States and subjects likely used very different hormonal contraceptive formulations than those used by women in the United States in recent years. Previous studies among HPV-positive women conducted in the United States and other industrialized countries did not find an association.3, 17, 18, 21 We found no association between COC use and HPV detection, which is similar to other studies.3, 6, 9

There are a number of mechanisms through which use of hormonal contraceptives might affect the development of HPV infection and risk of cervical neoplasia. First, hormones may inhibit the immune response to HPV infection.22, 23 Our findings that HPV persistence and CIN2-3 or greater were not positively associated with DMPA or COC use do not support this mechanism; however, the interactions between HPV, hormones, and the immune system are not completely understood.

A second hypothesis is based on findings that HPV gene expression and cellular proliferation is increased by estrogen and progestin in vitro.24, 25, 26 Our preliminary work assessing levels of HPV16 E7 DNA using quantitative PCR suggests that DMPA users have slightly higher levels than non-DMPA users (Long Fu Xi, personal communication, July 10, 2008). However, our finding that DMPA was not associated with type-specific repeat oncogenic HPV positivity does not support promoter effects of progestin on the viral genome as the reason for the observed positive association seen between DMPA and detection of oncogenic HPV. Up-regulation of HPV gene expression by hormones may occur before viral integration,27, 28 and other evidence suggests that once HPV is integrated, hormones may have various effects, depending on the placement of the hormone response elements.29 The fact that we did not find a positive association between hormonal contraception and CIN2-3 or greater may be explained, in part, by differences in the physical state of the virus (integrated versus episomal) in these lesions.

And third, hormones influence cervical epithelial differentiation and maturation.30, 31, 32 DMPA decreases cell maturation and promotes the appearance of atrophic epithelium,30, 32 which could make histologic features of CIN more difficult to detect among DMPA users because the loss of glycogen and hydration will shrink the cytoplasm lessening the effect of acetic acid.33 If the colposcopist cannot see an acetowhite lesion, then she/he is not likely to do a directed biopsy. This may explain why among women with oncogenic HPV infection, DMPA use was inversely associated with CIN detection. However, this may not translate into an increased risk of developing invasive cervical cancer because the inverse association between DMPA and CIN was strongest for CIN1 lesions and most CIN1 lesions regress spontaneously.

Lastly, atrophic epithelium may be more susceptible to damage, making it more vulnerable to HPV infection and could explain our finding that DMPA use was positively associated with oncogenic HPV infection. We have found that DMPA use does result in thinning of the vaginal epithelium, perhaps reflecting the loss of glycogen.34 However, this association was not found in other studies.35, 36, 37

A limitation of this analysis is the use of self-reported data on hormonal contraceptive use, but there is no reason to suspect that accuracy differed between women with and without CIN because these data were obtained before colposcopy-biopsy. In addition, studies comparing self-reported information to data from other sources have found good agreement for the current method and for total duration of use.38 We did not have information on the number of DMPA injections or whether COC use was continuous during the time interval women reported using the method.

Because of the young age of our population and their fewer years of contraceptive use, we had limited power to assess the association between long-term (≥ 10 years) hormonal contraceptive use and CIN and for several of the subanalyses. Because women mostly used 2 similar types of COCs, we were also unable to look at the risk associated with specific formulations. In addition, we did not have complete information on barrier contraception use. However, the use of barrier contraception has not been consistently associated with protection from HPV infection.39, 40

There are several strengths of the current analysis. All subjects were ascertained from the same clinic population, and misclassification of disease status was minimized by: (1) cases and controls being diagnosed in the same manner (by cytology and histology) and (2) requiring that the oncogenic HPV-positive/histologically negative group have negative and/or ASC-US cytology at both screening and colposcopy-biopsy. Lastly, we collected detailed information (brand/type, duration, date of last use) on the 4 most recent hormonal contraceptive methods. Only 5 women reported 4 methods, so we are fairly confident that we sufficiently captured usage.

In summary, the hormonal contraception formulations used by women in this study do not appear to increase risk of CIN2-3 or greater or CIN1. Although women who use DMPA may be at an increased risk for HPV acquisition, neither the risk for persistent infection nor CIN was increased. Because of the tendency of DMPA to promote the appearance of an atrophic epithelium, it is also possible that the colposcopic and histologic features of HPV-related cervical lesions are less pronounced among women who use DMPA. If others find that DMPA use makes lesions less visible, it will be important to consider other approaches, such as including a Papanicolaou test, when performing colposcopies on women using this contraceptive method. It will also be important for future studies to evaluate the effects of long-term DMPA use and the current formulations of COC on HPV infection and cervical neoplasia.

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Acknowledgment 

We thank Planned Parenthood, Kim Tomlinson, Akhila Balasubramanian, and Connie Nelson for their work on the Evaluation of Screening Methods for Cervical Cancer Study and Dr Thomas Lumley for his participation on Dr Harris's dissertation committee.

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References 

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 Dr Harris is currently affiliated with the New York City Department of Health and Mental Hygiene, New York, NY.

 This study was supported in part by Public Health Service Grant CA34493 from the National Cancer Institute.

 Cite this article as: Harris TG, Miller L, Kulasingam SL, et al. Depot-medroxyprogesterone acetate and combined oral contraceptive use and cervical neoplasia among women with oncogenic human papillomavirus infection. Am J Obstet Gynecol 2009;200:489.e1-489.e8.

PII: S0002-9378(09)00088-X

doi:10.1016/j.ajog.2009.01.030

American Journal of Obstetrics & Gynecology
Volume 200, Issue 5 , Pages 489.e1-489.e8, May 2009

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