Our surprise findings contradict some previous studies that have suggested women are benefited from reduced cancer risk from gynecologic surgery. Rice et al found that simple hysterectomy is associated with a 38% decrease in OC risk. A recent meta-analysis concludes that women with BSO have near 50% reduced the risk of cancer. A multicenter study found that salpingo-oophorectomy was associated with an 85% reduction in gynecologic cancer for women who carried BRCA1/2 mutation when they were 40 years old or older. BSO is thought to decrease the estrogen level and its negative health impacts. A Memorial Sloan-Kettering Cancer Center study also found the BRCA-related gynecologic cancer risk is reduced for 75% in women with salpingo-oophorectomy.
Conversely, our study surprisingly reveals a reversed finding in Taiwanese women. This first population-based cohort study in the eastern Asian population demonstrated that women with hysterectomy are at an increased risk of subsequent OC with an adjusted HR of 3.88. The adjusted HR of subsequent OC could increase further to 10.5 for women with both hysterectomy and 1-side salpingectomy. Effective screening method for early detection for OC is currently unavailable, our findings may provide a new implication for public health for Taiwanese and eastern Asian women. The women received hysterectomies should be followed up regularly to early detection of OC.
Our data showed that the risk of OC increased further for women who underwent a gynecologic surgery with comorbidities of endometriosis, PID and/or ectopic pregnancy. It is important to note that this relationship is particularly strong for women with a salpingectomy or with both hysterectomy and salpingectomy. Among 11 OC cases in these 2 subcohorts, 10 cases were developed in unilateral salpingectomy, and 9 cases were found in those with 1 or 2 of the comorbidities. It indicates that the OC risk is reduced for women with bilateral salpingectomy, which is consistent with findings in Western ethnic groups.[12,13,15–18]
Finally, after we adjusted those comorbidities (endometriosis, PID, and ectopic pregnancy), hysterectomy and salpingectomy still associated with higher risk of OC (HR = 3.93, [95% CI = 2.53–6.09]; HR = 15.8 [95% CI = 2.18–114], respectively). However, the association between hysterectomy or salpingectomy with OC still needs further study to elucidate.
Another hypothesis is the influence of the hypothalamic-pituitary-ovarian (HPO) axis. Estrogen is the representative steroidal hormone regulating ovary activity in women, by luteinizing hormone (LH) with pulsatile release from the pituitary. The factor that increases ovarian activity may increase the risk of OC. We hypothesize that hysterectomy and salpingectomy might also disrupt the negative feedback regulation over the HPO axis besides oophorectomy; which then results in excessive gonadotropin secretion and hormonal over-activity in the ovary. The predominant action of estrogen is mediated by the biological effects of nuclear estrogen receptors (ERs), ERα and ERβ. There have been various studies on distributions of ERs for decades; but, the detail cellular mechanisms involved in the uterus and fallopian tube remain unclear.[31–33] Hysterectomy and/or salpingectomy may disrupt the estrogen signaling on the ER of the uterus and fallopian tube. Recent studies have demonstrated that patients with a hysterectomy are at an increased risk of subsequent depression, which probably occurs through the HPO system to change patients’ brain activity and behavior.[34–36] Therefore, disruptions in the LH and estrogen regulation with subtle hormonal over-activity after a hysterectomy or 1-side salpingectomy might relate to an increased risk of subsequent OC. However, more studies to get solid evidence would be necessary to confirm this hypothesis and evaluate whether it is globally applicable in the future. Further studies are needed to clarify whether our findings are consistent with other ethnic groups.
The other hypothesis is the similar pathophysiology shared by ovarian malignancy and the indication of gynecological surgery (the most common surgical indications in our study: uterine myoma, adenomyosis, uterine prolapse, endometrial, and cervical benign tumors). The previous study has been shown adenomyosis was associated with the risk of endometrial cancer (HR = 2.19 95% CI = 1.51–3.16). Another study also showed adenomyosis was associated with the risk of OC (HR = 5.50, 95% CI = 1.95–15.50). Pelvic floor disorders were also associated with gynecologic malignancy. Endometrial and endocervical polyps were reported associated with ovarian endometriosis, which was associated with OC. Genome-wide association study also showed leiomyoma shared some oncogene (eg, TP53 gene) and hormone-related gene variants (eg, ESR1 gene) with OC. Above all, the patients received hysterectomies due to benign indications that might predispose future ovarian malignancy development. Further study needs to be clarified about our findings.
However, there are limitations to this study. First, a maximum of 14-year follow-up time in the present study may not long enough to observe all OC cases to be developed, compared to the previous Western population studies. It took 35 years in the Sweden study and 29 years for the Denmark study to observe the outcomes.[16,17] Second, Information on pregnant frequency was not fully available in our cohorts due to a shorter period of the database. Pregnancy is a protective factor for OC, the shorter follow-up time could be confounding for assessing the risk. Third, we selected the reference cohort matched by age and with comorbidities adjusted for in the data analysis. But, it is possible that there were some potential confounders not considered in this study. Fourth, information on tubal ligation could not be retrieved in our database due to the insurance did not cover the expense of tubal ligation and enroll the subjects into the database. However, we did not note any OC event during the whole follow-up period in the bilateral salpingectomy group in our study. Fifth, we were unable to evaluate the OC risk associated with oral contraceptive use in the present study because of a few users in Taiwan. Oral contraceptive use is a well-known factor that can reduce OC development.[43,44] The surgical history before the database setup could not be obtained. There may be some detection bias that existed. Women who have surgery are more likely to see a doctor and be diagnosed with OC. The follow-up period is not very long in this study. However, our results indicated that the large study population size was sufficient to statistically demonstrate the subsequent risk of OC in patients who had undergone gynecological surgery.
. Jayson GC, Kohn EC, Kitchener HC, et al. Ovarian cancer
. Lancet 2014;384:1376–88.
. Chiang YC, Chen CA, Chiang CJ, et al. Trends in incidence and survival outcome of epithelial ovarian cancer
: 30-year national population
-based registry in Taiwan. J Gynecol Oncol 2013;24:342–51.
. Beral V, Doll R, Hermon C, et al. Collaborative Group on Epidemiological Studies of Ovarian Cancer
. Ovarian cancer
and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer
and 87,303 controls. Lancet 2008;371:303–14.
. Sun TH, Lee CH. Birth control experience in Taiwan. Contraception 1971;3:241–60.
. NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population
-based measurement studies with 19·2 million participants. Lancet 2016;387:1377–96.
. Chang HC, Yang HC, Chang HY, et al. Morbid obesity in Taiwan: Prevalence, trends, associated social demographics, and lifestyle factors. PLoS One 2017;12:e0169577.
. Kyrgiou M, Salanti G, Pavlidis N, et al. Survival benefits with diverse chemotherapy regimens for ovarian cancer
: meta-analysis of multiple treatments. J Natl Cancer Inst 2006;98:1655–63.
. Sopik V, Rosen B, Giannakeas V, et al. Why have ovarian cancer
mortality rates declined? Part III. Prospects for the future. Gynecol Oncol 2015;138:757–61.
. Eisenhauer EA. Real-world evidence in the treatment of ovarian cancer
. Ann Oncol 2017;28:viii61–5.
. Karst AM, Levanon K, Drapkin R. Modeling high-grade serous ovarian carcinogenesis from the fallopian tube. Proc Natl Acad Sci U S A 2011;108:7547–52.
. Kurman RJ, Shih IM. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer
—shifting the paradigm. Hum Pathol 2011;42:918–31.
. Cibula D, Widschwendter M, Májek O, et al. Tubal ligation and the risk of ovarian cancer
: review and meta-analysis. Hum Reprod Update 2011;17:55–67.
. Rice MS, Murphy MA, Tworoger SS. Tubal ligation, hysterectomy
and ovarian cancer
: a meta-analysis. J Ovarian Res 2012;5:13.
. Rice MS, Murphy MA, Vitonis AF, et al. Tubal ligation, hysterectomy
and epithelial ovarian cancer
in the New England Case-Control Study. Int J Cancer 2013;133:2415–21.
. Cibula D, Widschwendter M, Zikan M, et al. Underlying mechanisms of ovarian cancer
risk reduction after tubal ligation. Acta Obstet Gynecol Scand 2011;90:559–63.
. Falconer H, Yin L, Grönberg H, et al. Ovarian cancer
risk after salpingectomy
: a nationwide population
-based study. J Natl Cancer Inst 2015;107:dju410.
. Madsen C, Baandrup L, Dehlendorff C, et al. Tubal ligation and salpingectomy
and the risk of epithelial ovarian cancer
and borderline ovarian tumors: a nationwide case–control study. Acta Obstet Gynecol Scand 2015;94:86–94.
. Lessard-Anderson CR, Handlogten KS, Molitor RJ, et al. Effect of tubal sterilization technique on risk of serous epithelial ovarian and primary peritoneal carcinoma. Gynecol Oncol 2014;135:423–7.
. Hsieh CY, Su CC, Shao SC, et al. Taiwan's National Health Insurance Research Database: past and future. Clin Epidemiol 2019;11:349–58.
. Grimes DA, Hubacher D, Nanda K, et al. The good clinical practice guideline: a bronze standard for clinical research. Lancet 2005;366:172–4.
. Desai A, Xu J, Aysola K, et al. Epithelial ovarian cancer
: an overview. World J Transl Med 2014;3:1–8.
. Yang CY, Kuo HW, Chiu HF. Age at first birth, parity, and risk of death from ovarian cancer
in Taiwan: a country of low incidence of ovarian cancer
. Int J Gynecol Cancer 2007;17:32–6.
. Yoon SH, Kim SN, Shim SH, et al. Bilateral salpingectomy
can reduce the risk of ovarian cancer
in the general population
: a meta-analysis. Eur J Cancer 2016;55:38–46.
. Kauff ND, Domchek SM, Friebel TM, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol 2008;26:1331–7.
. Kauff ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2002;346:1609–15.
. Chen SC, Lo TC, Chang JH, et al. Variations in aging, gender, menopause, and obesity and their effects on hypertension in Taiwan. Int J Hypertens 2014;2014:515297.
. Chang WC, Wang JH, Ding DC. Hormone therapy in postmenopausal women associated with risk of stroke and venous thromboembolism: a population
study in Taiwan. Menopause 2019;26:197–202.
. Chiang AJ, Chang C, Huang CH, et al. Risk factors in progression from endometriosis to ovarian cancer
: a cohort
study based on medical insurance data. J Gynecol Oncol 2018;29:e28.
. Wang KC, Chang WH, Lee WL, et al. An increased risk of epithelial ovarian cancer
in Taiwanese women with a new surgico-pathological diagnosis of endometriosis. BMC Cancer 2014;14:831.
. Lee WL, Chang WH, Wang KC, et al. The risk of epithelial ovarian cancer
of women with endometriosis may be varied greatly if diagnostic criteria are different: a nationwide population
study. Medicine 2015;94:e1633.
. West NB, Verhage HG, Brenner RM. Suppression of the estradiol receptor system by progesterone in the oviduct and uterus of the cat. Endocrinology 1976;99:1010–6.
. Couse JF, Lindzey J, Grandien K, et al. Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse. Endocrinology 1997;138:4613–21.
. Li S, O’Neill SRS, Zhang Y, et al. Estrogen receptor α is required for oviductal transport of embryos. FASEB J 2017;31:1595–607.
. Harnod T, Chen W, Wang JH, et al. Hysterectomies are associated with an increased risk of depression: a population
study. J Clin Med Res 2018;7:E366.
. Bove R, Secor E, Chibnik LB, et al. Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology 2014;82:222–9.
. Wilson L, Pandeya N, Byles J, et al. Hysterectomy
and incidence of depressive symptoms in midlife women: the Australian Longitudinal Study on Women's Health. Epidemiol Psychiatr Sci 2017;27:1–2.
. Yeh CC, Su FH, Tzeng CR, et al. Women with adenomyosis are at higher risks of endometrial and thyroid cancers: a population
-based historical cohort
study. PLoS One 2018;13:e0194011.
. Kok VC, Tsai HJ, Su CF, et al. The risks for ovarian, endometrial, breast, colorectal, and other cancers in women with newly diagnosed endometriosis or adenomyosis: a population
-based study. Int J Gynecol Cancer 2015;25:968–76.
. Bretschneider CE, Doll KM, Bensen JT, et al. Prevalence of pelvic floor disorders in women with suspected gynecological malignancy: a survey-based study. Int Urogynecol J 2016;27:1409–14.
. Kontoravdis A, Augoulea A, Lambrinoudaki I, et al. Ovarian endometriosis associated with ovarian cancer
and endometrial-endocervical polyps. J Obstet Gynaecol Res 2007;33:294–8.
. Rafnar T, Gunnarsson B, Stefansson OA, et al. Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits. Nat Commun 2018;9:3636.
. Chie WC, Li CY, Huang CS, et al. Oral contraceptives and breast cancer risk in Taiwan, a country of low incidence of breast cancer and low use of oral contraceptives. Int J Cancer 1998;77:219–23.
. Rooth C. Ovarian cancer
: risk factors, treatment and management. Br J Nurs 2013;22:S23–30.
. Vecchia CL, La Vecchia C. Ovarian cancer
. Eur J Cancer Prevent 2017;26:55–62.