Ovarian cancer is a significant health concern, ranking as the second most common gynecological cancer in the United States and Western Europe and causing more deaths than all other gynecological cancers combined1 . Most ovarian cancers are epithelial ovarian cancers (EOC), accounting for about 90% of cases2 . Various factors influence the risk of developing ovarian cancer, including genetics, hormone exposure, reproductive history, and lifestyle factors3 4. Understanding these causes and risk factors is crucial for prevention and early detection.
Key Theories Behind Ovarian Cancer
Ovarian cancer is a complex disease with multiple contributing factors. While the exact cause of most ovarian cancers remains unknown, several theories explain how ovarian cancer may develop and what increases the risk.
Ovarian cancer is thought to arise from epithelial cells that cover the ovarian surface or, more frequently, line subserosal cysts5 . The transformation of these cells into cancerous ones likely involves a multi-step process with the accumulation of genetic lesions6 . Tumor cells and surrounding stromal cells stimulate the synthesis and activation of matrix metalloproteinases (MMPs), which aid in tumor growth, invasion, and metastasis7 . This disease is particularly insidious because it often goes undetected until late stages, contributing to its high mortality rate8 . It is mostly observed in postmenopausal women and is multifactorial in origin9 10.
Hormone Replacement Therapy (HRT)
Hormone replacement therapy, especially in postmenopausal women, has been linked to an increased risk of ovarian cancer. Studies show that three exposures of varying preparations and usage related to HRT increase the risk of developing ovarian cancer3 . Long-term use of estrogen alone or combined estrogen-progestin therapy may contribute to this elevated risk11 . This association highlights the importance of carefully weighing the benefits and risks of HRT in menopausal symptom management.
Late Onset Menopause
Starting menopause after the age of 52 is considered a risk factor for ovarian cancer. Prolonged exposure to estrogen due to late menopause may increase the likelihood of mutations in ovarian epithelial cells, contributing to carcinogenesis11 . This extended hormonal exposure is thought to promote cellular changes that predispose to cancer development.
Endometriosis
Endometriosis, a condition where tissue similar to the uterine lining grows outside the uterus, is associated with a higher risk of ovarian cancer12 . This abnormal tissue growth can cause chronic inflammation and cellular damage, potentially leading to malignant transformation in ovarian cells11 . Women with endometriosis should be aware of this increased risk and discuss it with their healthcare providers.
Reproductive History
Reproductive factors significantly influence ovarian cancer risk. Women who have never been pregnant or had their first full-term pregnancy after age 30 have a higher risk of developing ovarian cancer11 . Pregnancy and breastfeeding reduce the number of ovulatory cycles, which is thought to lower the risk by decreasing repetitive ovarian surface damage13 . Use of oral contraceptive pills also reduces risk by suppressing ovulation3 13. Early onset of menstruation (before age 12) and late menopause extend the duration of ovulatory cycles, further increasing risk11 .
Weight
Greater height and higher body mass index (BMI) are linked to increased ovarian cancer risk. Specifically, a BMI of 30 kg/m² or higher compared to normal weight is associated with a 27% increased risk3 . Obesity may influence hormone levels and inflammatory processes that promote cancer development, especially in postmenopausal women11 . Maintaining a healthy weight could be a modifiable factor to reduce ovarian cancer risk.
Individuals may have a higher chance of developing ovarian cancer if they inherited a faulty gene, such as BRCA1, BRCA2, or genes linked to Lynch syndrome, or if they had breast or bowel cancer20 .
Hereditary Ovarian Cancer Risks
Hereditary ovarian cancer syndromes account for a significant portion of ovarian cancer cases, with up to 25% linked to inherited gene mutations14 . The most well-known hereditary syndromes include hereditary breast–ovarian cancer syndrome (HBOC) and Lynch syndrome.
HBOC is caused by mutations in the BRCA1 and BRCA2 genes, which normally help control cell growth and prevent cancer. Women with BRCA1 mutations have a lifetime ovarian cancer risk ranging from 20% to 60%, while BRCA2 mutation carriers have a risk between 10% and 35% 815. These mutations are more common in certain populations, such as Ashkenazi Jewish women16 .
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, involves mutations in mismatch repair genes like MLH1 and MSH2. This syndrome increases the risk of colorectal, endometrial, and ovarian cancers, with ovarian cancer risk estimated around 12% 611. Other genes linked to hereditary ovarian cancer include RAD51C, RAD51D, BRIP1, PALB2, STK11, and ATM11 17.
Genetic testing is recommended for women with a family history suggestive of these syndromes or personal history of related cancers6 17. Identifying mutations can guide preventive strategies such as risk-reducing surgery or enhanced screening.
Inherited deleterious mutations in BRCA1 or BRCA2 and Lynch syndrome confer the highest risk of developing ovarian cancer but account for only approximately 10% of cases.
— Jelovac & Armstrong18
Ovarian Cancer Demographics and Statistics
Ovarian cancer primarily affects postmenopausal women, with most cases diagnosed after age 55 and a median diagnosis age of 639 11. It is the sixth most common cancer and the fifth leading cause of cancer death among women in developed countries9 . Incidence rates are higher in Western Europe and North America compared to Asia and Africa, with sub-Saharan Africa showing considerably lower prevalence9 .
Epithelial ovarian cancer (EOC) constitutes about 90% of ovarian malignancies2 . The disease is often diagnosed at advanced stages due to subtle early symptoms, contributing to poor survival rates8 9. The five-year survival rate varies by stage and population but averages around 49% overall19 .
Certain racial disparities exist in ovarian cancer outcomes. For example, five-year survival rates are higher in white women (approximately 50.6%) compared to Black women (about 43.2%) 11. These disparities reflect differences in access to care, early diagnosis, and treatment.
Primary Ovarian Cancer Risk Factors
Several established risk factors influence the likelihood of developing ovarian cancer. These factors can be grouped into genetic, hormonal, reproductive, lifestyle, and environmental categories.
- Genetic Mutations: BRCA1, BRCA2, Lynch syndrome, and other gene mutations increase risk significantly8 611.
- Age: Risk increases with age, especially after menopause9 12.
- Reproductive History: Never having been pregnant, late first pregnancy, and early menarche or late menopause increase risk11 13.
- Hormone Replacement Therapy (HRT): Use of HRT, particularly long-term, raises risk3 11.
- Obesity: Higher BMI (≥30 kg/m²) is associated with increased risk3 11.
- Endometriosis: Associated with increased risk due to chronic inflammation11 12.
- Family History: Having close relatives with ovarian, breast, uterine, or colorectal cancer increases risk12 17.
- Radiation Exposure: Pelvic radiation therapy may increase risk20 11.
- Lifestyle Factors: Smoking and possibly coffee intake have been linked to increased risk, though evidence varies21 22.
Preventive factors include:
- Oral Contraceptive Use: Reduces risk by about 26% to 50%, especially with use over five years3 134.
- Pregnancy and Breastfeeding: Both reduce risk by decreasing ovulatory cycles13 11.
- Surgical Procedures: Removal of fallopian tubes (salpingectomy), ovaries, or uterus can reduce risk, especially in high-risk women11 14.
Key ovarian cancer risk factors include BRCA1/BRCA2 mutations, Lynch syndrome, older age, hormone replacement therapy, and obesity (BMI ≥30). Protective factors include oral contraceptive use, pregnancy and breastfeeding, surgical removal of reproductive organs, and maintaining a healthy BMI11 133.
Summary of Ovarian Cancer Causes
Ovarian cancer arises from a combination of genetic, hormonal, reproductive, and lifestyle factors. The disease primarily originates from epithelial cells covering the ovary or lining cysts, with a multi-step process involving genetic mutations leading to malignancy5 6. Hereditary mutations in BRCA1, BRCA2, and mismatch repair genes significantly increase risk but account for only about 10% of cases18 .
Hormone replacement therapy, late menopause, and obesity are modifiable risk factors that elevate ovarian cancer risk, while pregnancy, breastfeeding, and oral contraceptive use reduce it3 1311. Understanding these factors can help women and healthcare providers identify those at higher risk and implement preventive strategies.
