The role of oestrogens and antibiotics on the development of cancer

Abstract: Despite advances in cancer treatment and surgery, cancer-related mortality remains the leading cause of death globally, harvesting over ten million lives annually. While the risk factors are both hormonal and non-hormonal, common prescription drugs’ long-term effects are understudied and likely even underestimated. Particularly drugs including oestrogens or those altering the metabolism of oestrogens may promote carcinogenesis of oestrogen receptor sensitive cancers and possibly even lower the risk of sex hormone-associated cancers. Two common examples of such prescription drugs are systemic menopausal hormone therapy (MHT) and oral antibiotic treatment. Historically, preventive measures have been the key factor in our unending battle against cancer’s burden. This doctoral thesis within clinical epidemiology was conducted to evaluate the association between exposure to contemporary MHT use and cancer risk (Studies I and II); and colorectal cancer mortality (Study IV). These associations were investigated on a population level, longitudinally, based on nationwide and population-based cohort studies, taking advantage of the unique Swedish prescription feature, including various MHT treatment options. Notably, these large-scale cohort studies are feasible to conduct only in a few other countries than Sweden, underscoring the importance of valid evidence from methodologically well-grounded studies with complete and reliable data sources. Furthermore, Study III aimed to clarify the posed association between exposure to oral antibiotic treatment and colorectal cancer risk based on a systematic review and dose-response meta-analysis. For Studies I, II, and IV, data were retrieved from the Swedish Prescribed Drug Registry, Swedish Cancer Registry, Causes of Death Registry, Patient Registry, and the Total Population Registry (Study I only). Study I evaluated the net effect of systemic MHT use on cancer risk; and 16 different cancer types. The findings suggested an association of menopausal hormones with a slightly (9%) elevated cancer risk compared with the background population of the same calendar period and age. The observed excess risk of cancer was mainly associated with female reproductive tract cancers, yet it was almost counterbalanced by the reduced risk of gastrointestinal tract cancers. However, the cancer risk varied between the different MHT treatment options and age at treatment initiation. Study II was a population-based matched cohort study evaluating the link between everuse of MHT and ovarian cancer risk. Whereas ovarian cancer is rare, it is the most lethal of gynaecological cancers, owing primarily to late detection, underscoring the need for preventive measures. The results suggested that the excess ovarian cancer risk was linked particularly with oestrogen combined progestin use, whilst no increased risk was shown among oestrogen-only users. Furthermore, cutaneous preparations indicated a possibly less prominent risk than oral MHT. Study IV was a nationwide cohort study investigating whether prediagnostic exposure to MHT treatment could influence colorectal cancer-specific or all-cause mortality risk among women diagnosed with colorectal cancer. The results suggested particularly past users of oestrogen-only therapy having a possibly better colorectal cancer survival than women diagnosed with colorectal cancer who did not receive menopausal hormones during the study period. Study III aimed to explore the posed link between oral antibiotic use with colorectal cancer risk. At the time being, the present study was the first systematic review and meta-analysis assessing the risk pattern’s shape, considering possible deviation from linearity. The results indicated modestly increased colorectal cancer risk, and the association appeared to be related particularly with the use of broad-spectrum antibiotics. However, the found dose-response relationship was weak, with similar risk patterns within the colorectal continuum. In conclusion, the risk of cancer associated with MHT treatment varies between the different treatment options and ages. The excess risk is seemingly related to female reproductive tract organ cancers, while the risk of gastrointestinal tract cancers appears to be lower, and prediagnostic use of MHT might even improve survival from colorectal cancer. Overall, MHT does not seem to increase cancer risk if the treatment is initiated near to menopausal onset among women without contraindications or high risk of breast, ovarian or endometrial cancer. The found association of oral antibiotic treatment with colorectal cancer raises further questions, and notably, the here shown association may not be causal.

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