Abstract
This cohort study of Swedish register data examines the association between polycystic ovary syndrome and cancer risk in females aged 15 to 50 years between 1985 and 2009.
Inconsistent results have been reported for the association between polycystic ovary syndrome (PCOS) and risks of ovarian and breast cancers.1 Few studies had sufficient sample sizes, well-defined diagnostic criteria, or reasonable confounding adjustment.1,2 Even fewer studies have addressed the risks of other cancers. Thus, we conducted a large, population-based cohort study with a long follow-up period and rather sufficient confounding adjustment.
Methods
Using Swedish register data, we established a cohort including all females aged 15 to 50 years between 1985 and 2009 (N = 3 511 357). Those with cancers before entry (n = 17 750) and PCOS diagnosed when they were younger than 9 years (n = 3) were excluded. All eligible participants (n = 3 493 604) were followed up until cancer, emigration, death, or December 31, 2009, whichever came first. The present study was conducted from October 1, 2014, to March 21, 2018. Ethical approval for study was granted by the Regional Ethics Vetting Board in Stockholm, Sweden, with waiver of informed consent.
Exposure of interest was a diagnosis of PCOS. The outcome measure was histologically verified primary cancer. Cancer diagnosed within 1 year from exposure was considered occurring in the unexposed period. The cohort was cross-linked to other registers to identify information on exposure, outcome, and covariates (including the highest achieved educational level, parity, parental cancer history, use of medications, and diabetes). Hazard ratios (HRs) for cancers among PCOS vs non-PCOS individuals were derived from Cox proportional hazards regression models with 2-tailed 95% CIs. The significance level was set at α = .05. Proportionality assumption was tested and no obvious deviation was found. To address influence of menopause, HRs over attained age younger than 51 and 51 or older years (median menopause age in Sweden3) were estimated separately.
We further analyzed the interaction between PCOS and covariates and performed sensitivity analyses by excluding individuals with missing educational level data or by additionally adjusting for use of medications (metformin, oral contraceptives, and hormone replacement therapy) with follow-up constrained to 2005-2009 (the Prescribed Drug Register became available July 1, 2005). SAS, version 9.4 (SAS Institute) and Stata, version 14.0 (StataCorp LP) were used for all statistical analyses.
Results
Among 14 764 women with diagnosed PCOS (mean [SD] age at study entry, 28.5 [6.9] years), 182 had primary cancers. Polycystic ovary syndrome was positively associated with an increased overall cancer risk (fully adjusted HR, 1.15; 95% CI, 1.00-1.33) (Table 1). Excess cancer risks observed at specific sites determined from fully adjusted models were as follows: endometrium (HR, 2.62; 95% CI, 1.58-4.35), ovary (HR, 2.16; 95% CI, 1.30-3.59), endocrine gland (HR, 1.92; 95% CI, 1.21-3.06), pancreas (HR, 3.40; 95% CI, 1.41-8.20), kidney (HR, 3.07; 95% CI, 1.27-7.39), and skeletal and hematopoietic system (HR, 1.69; 95% CI, 1.05-2.72).
Table 1. Cancer Association With PCOS Overall.
| Cancera | PCOS | Minimally Adjusted HR (95% CI)b | Fully Adjusted HR (95% CI)c |
|---|---|---|---|
| Primary cancers | 182 | 1.21 (1.05-1.40) | 1.15 (1.00-1.33) |
| Digestive system | 19 | 1.44 (0.92-2.27) | 1.37 (0.88-2.16) |
| Colon and rectum | 10 | 1.17 (0.63-2.17) | 1.13 (0.61-2.11) |
| Pancreas | 5 | 3.88 (1.61-9.34) | 3.40 (1.41-8.20) |
| Respiratory system | 4 | 0.66 (0.25-1.75) | 0.64 (0.24-1.72) |
| Skin | 17 | 0.99 (0.61-1.59) | 1.00 (0.62-1.61) |
| Melanoma | 14 | 0.95 (0.56-1.60) | 0.97 (0.58-1.64) |
| Nonmelanoma | 3 | 1.28 (0.41-3.99) | 1.24 (0.40-3.85) |
| Breast | 48 | 0.87 (0.66-1.15) | 0.85 (0.64-1.13) |
| Female genital systemd | 40 | 1.76 (1.29-2.40) | 1.54 (1.13-2.11) |
| Cervix | 8 | 0.76 (0.38-1.51) | 0.74 (0.37-1.48) |
| Endometrium | 15 | 3.32 (2.00-5.52) | 2.62 (1.58-4.35) |
| Ovary | 15 | 2.42 (1.46-4.02) | 2.16 (1.30-3.59) |
| Urinary system | 6 | 1.91 (0.86-4.25) | 1.80 (0.81-4.01) |
| Kidney | 5 | 3.20 (1.33-7.71) | 3.07 (1.27-7.39) |
| Endocrine gland | 18 | 2.07 (1.30-3.30) | 1.92 (1.21-3.06) |
| Thyroid | 6 | 1.31 (0.59-2.92) | 1.29 (0.58-2.87) |
| Other endocrine glands | 12 | 2.85 (1.62-5.03) | 2.55 (1.45-4.50) |
| Skeletal and hematopoietic system | 17 | 1.78 (1.10-2.86) | 1.69 (1.05-2.72) |
| Brain cancer | 6 | 0.71 (0.32-1.58) | 0.67 (0.30-1.49) |
| Other cancers | 7 | 1.09 (0.52-2.29) | 1.03 (0.49-2.16) |
Abbreviations: HR, hazard ratio; PCOS, polycystic ovary syndrome.
Only primary cancers within each system are shown.
Univariable Cox regression model using attained age as the time scale and adjusted for calendar year in 5-year intervals.
Multivariable Cox regression model further adjusted for (1) achieved educational level indicating social economic status as well as levels of smoking and alcohol consumption, (2) parity indicating fertility of a woman, (3) history of parental cancer as inheritance factors, and (4) diabetes as metabolic profile. The proportional hazards assumption was tested and satisfied by all covariates.
Individuals who underwent hysterectomy or salpingo-oophorectomy were censored because they had no risk of gynecologic cancers after surgery.
We further performed analysis by menopause status (Table 2). The excess risks were prominent only before menopause. The HR for overall cancer was 1.22 (95% CI, 1.03-1.44); endometrial cancer, 6.45 (95% CI, 3.65-11.40); ovarian cancer, 2.55 (95% CI, 1.45-4.50); pancreatic cancer, 6.68 (95% CI, 2.49-17.91); kidney cancer, 4.57 (95% CI, 1.71-12.22); and endocrine gland cancers (except thyroid cancer), 2.90 (95% CI, 1.56-5.40).
Table 2. Cancer Association With PCOS by Menopausal Statusa.
| Cancerb | Premenopausal | Postmenopausal | ||
|---|---|---|---|---|
| PCOS No. | HR (95% CI) | PCOS No. | HR (95% CI) | |
| Primary cancers | 133 | 1.22 (1.03-1.44) | 49 | 1.01 (0.76-1.33) |
| Digestive system | 12 | 1.60 (0.91-2.82) | 7 | 1.11 (0.53-2.33) |
| Colon and rectum | 6 | 1.22 (0.55-2.72) | 4 | 1.02 (0.38-2.73) |
| Pancreas | 4 | 6.68 (2.49-17.91) | 1 | 1.15 (0.16-8.19) |
| Respiratory system | 2 | 0.72 (0.18-2.88) | 2 | 0.58 (0.15-2.34) |
| Skin | 15 | 1.09 (0.65-1.80) | 2 | 0.64 (0.16-2.55) |
| Breast | 35 | 0.91 (0.65-1.27) | 13 | 0.72 (0.42-1.24) |
| Female genital system | 32 | 1.72 (1.21-2.43) | 8 | 1.10 (0.55-2.20) |
| Cervix | 8 | 0.80 (0.40-1.60) | 0 | 0 |
| Endometrium | 12 | 6.45 (3.65-11.40) | 3 | 0.78 (0.25-2.41) |
| Ovary | 12 | 2.55 (1.45-4.50) | 3 | 1.34 (0.43-4.15) |
| Urinary system | 4 | 2.30 (0.86-6.14) | 2 | 1.25 (0.31-5.02) |
| Kidney | 4 | 4.57 (1.71-12.22) | 1 | 1.33 (0.19-9.45) |
| Endocrine gland | 14 | 1.83 (1.08-3.09) | 4 | 2.36 (0.88-6.29) |
| Thyroid | 4 | 0.94 (0.35-2.52) | 2 | 4.58 (1.14-18.37) |
| Other endocrine glands | 10 | 2.90 (1.56-5.40) | 2 | 1.60 (0.40-6.38) |
| Skeletal and hematopoietic system | 12 | 1.61 (0.91-2.84) | 5 | 1.92 (0.80-4.61) |
| Brain cancer | 3 | 0.42 (0.14-1.30) | 3 | 1.64 (0.53-5.08) |
| Other cancers | 4 | 0.91 (0.34-2.43) | 3 | 1.24 (0.40-3.86) |
Abbreviations: HR, hazard ratio; PCOS, polycystic ovary syndrome.
Multivariable Cox regression model using attained age as the time scale and adjusted for calendar year, achieved educational level, parity, history of parental cancer, and diabetes (<51 vs ≥51 years; 51 years is median menopause age in Sweden).
Melanoma and nonmelanoma were not listed owing to too few cases.
No significant interaction between PCOS and covariates was observed. In sensitivity analyses, excluding patients with missing educational level data or further adjusting for use of medications did not change the results materially.
Discussion
Several carcinogenic processes are associated with PCOS, including dyslipidemia, hyperinsulinemia, and chronic inflammation.4 However, studies on risk of all types of cancer are scarce (except for endometrial, ovarian, and breast cancers). To our knowledge, only Gottschau et al5 reported a higher risk of kidney, colon, and brain cancer without adjusting for confounding factors. Our study indicates that cancer may need to be added to the spectrum of long-term health consequences of PCOS and warrants increased surveillance among these patients.
The limitations of the study include underestimated PCOS prevalence from the National Patient Register (patients in primary care, private clinics, or outpatient care before 2001 could not be identified) and the variation of PCOS morbidity owing to differing diagnostic criteria. Further studies are needed to define the cancer risk pattern among patients with PCOS more clearly.
References
- 1.Barry JA, Azizia MM, Hardiman PJ. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2014;20(5):748-758. doi: 10.1093/humupd/dmu012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Harris HR, Terry KL. Polycystic ovary syndrome and risk of endometrial, ovarian, and breast cancer: a systematic review. Fertil Res Pract. 2016;2:14. doi: 10.1186/s40738-016-0029-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Falconer H, Yin L, Bellocco R, Altman D. Thyroid cancer after hysterectomy on benign indications: Findings from an observational cohort study in Sweden. Int J Cancer. 2017;140(8):1796-1801. [DOI] [PubMed] [Google Scholar]
- 4.Kelly CC, Lyall H, Petrie JR, Gould GW, Connell JM, Sattar N. Low grade chronic inflammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab. 2001;86(6):2453-2455. doi: 10.1210/jcem.86.6.7580 [DOI] [PubMed] [Google Scholar]
- 5.Gottschau M, Kjaer SK, Jensen A, Munk C, Mellemkjaer L. Risk of cancer among women with polycystic ovary syndrome: a Danish cohort study. Gynecol Oncol. 2015;136(1):99-103. doi: 10.1016/j.ygyno.2014.11.012 [DOI] [PubMed] [Google Scholar]