Pelvic inflammation has been implicated in the genesis of ovarian cancer. We conducted serologic measurements of
Ovarian cancer
is an often fatal disease with an uncertain etiology. We suggested that pelvic
inflammation may play a role in the development of ovarian cancer [
One quarter to
three quarters of proven cases of PID are caused by
Chlamydia serology is a relatively specific marker of past chlamydial PID,
particularly of more severe infections [
We previously
reported pilot results from a population-based case-control study (117 cases and 170 controls)
of ovarian cancer showing that ovarian cancer was significantly associated with
high IgG antibody titers to chlamydia [
Subjects for this serologic analysis were part of a population-based case-control study conducted in a contiguous region comprising Western Pennsylvania, Eastern Ohio, and Southwestern New York State. Cases were residents of this geographic region with histologically confirmed, primary, epithelial ovarian, fallopian tube, or peritoneal cancer diagnosed between February 2003 and July 2006. Both invasive and borderline tumors were included. Women were referred from hospital tumor registries, clinical practices, or pathology databases and contacted with the permission of their gynecologists. Eligible women were at least 25 years of age and within 9 months of initial diagnosis.
Controls consisted of women at least age 25 who lived in telephone exchanges wherein cases resided. Random digit dialing was used to identify age-eligible women, and these were further screened by the study team to ensure that they had not had a previous oophorectomy or diagnosis of ovarian cancer. Eligible women were then invited to participate. Potential controls were frequency matched by 5-year age group and telephone exchange to cases in an approximately 2:1 ratio.
Women were interviewed in their homes by trained interviewers. The questionnaire included a reproductive and gynecological history, a contraceptive history, a medical history, a family history, and information on lifestyle practices.
We were able to draw blood on 92.5% of the interviewed cases and 84.4% of the interviewed controls. Blood samples were processed within 2 hours of collection by a laboratory technician. For this analysis, we selected the first 521 cases and 766 controls with complete questionnaires, tumor registry (e.g., histology) information, and adequate serum samples.
Serologic testing for IgG antibodies to serovar D of
Each of the antibody levels tested was measured in optical density (OD) units (range 0.0–0.4+). We log transformed all OD units to reduce
skewing when considering these as continuous measures and categorized OD units
into neat whole number categories when considering these as discrete
measures. These cut points corresponded
to those in our published pilot study [
About one
quarter of women were younger
than the age of 50 and half
were age 50 to 65 (see Table
Frequencies of demographic and reproductive characteristics by case/control status.
Variable | Case subjects no. (%) | Control subjects no. (%) | |
---|---|---|---|
Age group, years | |||
24–49 | 135 (25.9) | 204 (26.6) | 9.29 (.026) |
50–56 | 111 (21.3) | 208 (27.2) | |
57–66 | 129 (24.8) | 187 (24.4) | |
≥67 | 146 (28.0) | 167 (21.8) | |
Ethnic group | |||
White | 495 (95.0) | 736 (96.1) | 1.14 (.57) |
Black | 19 (3.6) | 20 (2.6) | |
Other | 7 (1.3) | 10 (1.3) | |
Education | |||
Less than high school | 46 (8.8) | 37 (4.8) | 13.56 (.001) |
High school | 180 (34.5) | 229 (29.9) | |
Posthigh school | 295 (56.6) | 500 (65.3) | |
Family history of ovarian cancer | |||
No | 487 (95.3) | 731 (97.3) | 3.74 (.053) |
Yes | 24 (4.7) | 20 (2.7) | |
Live births | |||
None | 124 (23.8) | 104 (13.6) | 22.23 (.000) |
Any | 397 (76.2) | 662 (86.4) | |
Tubal ligation | |||
No | 389 (78.3) | 490 (65.0) | 25.3 (.000) |
Yes | 108 (21.7) | 264 (35.0) | |
Oral Contraception, years | |||
0 | 223 (42.8) | 214 (27.9) | 40.02 (.000) |
<1–4 | 205 (39.3) | 321 (41.9) | |
5–9 | 59 (11.3) | 134 (17.5) | |
≥10 | 34 (6.5) | 97 (12.7) | |
Menopausal status | |||
Premenopausal | 142 (30.4) | 194 (29.9) | .028 (.87) |
Postmenopausal | 325 (69.6) | 454 (70.1) | |
Self-report PID | |||
No | 515 (98.8) | 759 (99.1) | .18 (.68) |
Yes | 6 (1.2) | 7 (0.9) | |
Self-report gonococcal or chlamydial cervicitis | |||
No | 502 (96.4) | 736 (96.1) | .062 (.80) |
Yes | 19 (3.6) | 30 (3.9) |
After adjustment
for possible confounding factors and based on our previous antibody titer cut points
[
Frequencies and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for chlamydial elementary bodies optical density (OD) units, in cases and controls, categorized by previously defined cut points. (ORs were adjusted for age, education, family history of ovarian cancer, tubal ligation, nulliparity/any parity, and years of oral-contraceptive use).
Chlamydia EB | |||
---|---|---|---|
OD units | Case subjects | Control subjects | OR (95% CI) |
<0.10 | 248 | 342 | 1.0 |
0.10–0.199 | 138 | 173 | 1.1 (0.8–1.5) |
0.20–0.399 | 73 | 113 | 0.9 (0.6–1.2) |
≥0.40 | 62 | 138 | 0.6 (0.4–0.9) |
Frequencies and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for chlamydial elementary bodies, categorized by quartiles, in case and control subjects. (ORs were adjusted for age, education, family history of ovarian cancer, tubal ligation, nulliparity/any parity, and years of oral-contraceptive use.)
Chlamydia EB | |||
---|---|---|---|
EB quartiles | Case subjects | Control subjects | OR (95% CI) |
<0.06 | 133 | 189 | 1.0 |
0.06–0.11 | 133 | 189 | 1.1 (0.8–1.5) |
0.11–0.24 | 146 | 176 | 1.2 (0.9–1.7) |
≥0.25 | 109 | 212 | 0.7 (0.5–1.1) |
In age-stratified analyses, we continued to find the chlamydia antibodies that reduced
ovarian cancer risk (see Table
Frequencies and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for chlamydial elementary bodies optical-density (OD) units, in case and control subjects stratified by age.
OD units | Case subjects | Control subjects | OR (95% CI) | |
---|---|---|---|---|
Age 24–49 | <0.10 | 69 | 82 | 1.0 |
0.10–0.199 | 32 | 42 | 0.9 (0.5–1.6) | |
0.20–0.399 | 18 | 37 | 0.6 (0.3–1.1) | |
≥0.40 | 16 | 43 | 0.4 (0.2–0.9) | |
Trend = .007 | ||||
Age 50–56 | <0.10 | 55 | 103 | 1.0 |
0.10–0.199 | 22 | 47 | 0.9 (0.5–1.6) | |
0.20–0.399 | 15 | 20 | 1.4 (0.7–3.0) | |
≥0.40 | 19 | 38 | 0.9 (0.5–1.8) | |
Trend = .908 | ||||
Age 57–66 | <0.10 | 58 | 88 | 1.0 |
0.10–0.199 | 41 | 38 | 1.6 (0.9–2.8) | |
0.20–0.399 | 19 | 31 | 0.9 (0.5–1.8) | |
≥0.40 | 11 | 30 | 0.6 (0.3–1.2) | |
Trend = .227 | ||||
Age ≥67 | <0.10 | 66 | 69 | 1.0 |
0.10–0.199 | 43 | 46 | 1.0 (0.6 –1.7) | |
0.20–0.399 | 21 | 25 | 0.9 (0.4 –1.7) | |
≥0.40 | 16 | 27 | 0.6 (0.3 –1.3) | |
Trend = .217 |
We found that women with ovarian cancer were less likely to have high levels of IgG to
Our current finding is the reverse of the link between chlamydia and ovarian cancer in our previous
analysis [
Explanations for a lack of association include the long
period between exposure to chlamydia (in the reproductive period) and blood
collection (generally after the age of 50) in our population. If titers fall significantly over time, they
may have become undetectable in some women. Data from a Dutch study suggested that 18% of women had a decline of
twofold in chlamydia titers over four years [
Another explanation is the lack of sensitivity of antichlamydial antibody serologic testing. Only about 60% of women with PID develop detectable serology, and the test does not detect gonorrhea, another cause of PID. This lack of sensitivity would have resulted in erroneously missing some women with prior PID and would have resulted in an odds ratio biased toward the null. Moreover, it is possible that ovarian cancer itself or its treatment might acutely reduce chlamydia titers, and therefore mask an association.
Strengths of this study include the population-based ascertainment of cases and controls, the standardized collection and storage of bloods, the measurement of chlamydia EB antibodies at a reference, research laboratory, with laboratory personnel masked to case-control status, and evidence of an independent effect after adjustment for potentially confounding factors.
In summary, our findings do not support previous evidence of a link between chronic persistent chlamydia infection, the most common cause of PID, and risk for ovarian cancer.
The authors thank the women with ovarian cancer and those without cancer who participated in this study as well as their dedicated physicians, in particular Drs. Michael Hopkins and Eric Jennison. They also thank a dedicated team of staff including Katie Farrow, Ya Du, Jenny Lo, Sheri Hutchison, Tammy DeBruce, Tamara Cursio, Briana Mayle, and Elizabeth Hallman.