The Effect of Androgen Deprivation Therapy on Gut and Urinary Microbiota in Patients With Prostate Cancer

Overview

The incidence of prostate cancer is increasing in Hong Kong, as well as that of recurrent or metastatic prostate cancer. Androgen deprivation therapy (ADT) is the standard treatment for recurrent or metastatic prostate cancer, with side effects such as obesity, type 2 diabetes mellitus, metabolic syndrome, osteoporosis and cognitive impairment. With the improvement of treatment, the 5-year survival rate of recurrent and metastatic prostate cancer is up to 20%, and therefore increases the chances of developing such side effects. Due to the introduction of next generation sequencing, investigators have more knowledge of the microbiota in our body, particularly the gut microbiota. Different studies have related gut dysbiosis with obesity, type 2 diabetes mellitus and metabolic syndrome. If investigators can show that ADT is leading to gut dysbiosis, this could be a way in preventing or treating the side effects of ADT. This study aims to identify whether ADT in patients with prostate cancer will have different composition in their gut and urine microbiota.

The prostate gland is a clinically important male accessory sex gland and vital for its production of semen. Prostate cancer (PCa) is now ranked 3th in annual incidence of male cancer and ranked 5th for cancer-related death in men in Hong Kong which accounts for about 10.9 deaths per 100,000 persons. (Hong Kong Cancer registry 2015) Its incidence is rising rapidly, almost tripled in the past 10 years. As the elderly population continues to increase, the impact of PCa on the men's health and also the burden on health care system will continue to rise. Despite the improvement in awareness of the disease and also increasing use of serum prostate specific antigen, many patients still presented at a late stage that beyond cure by local therapy. Together with those patients suffered recurrent disease after local therapy,1 many PCa patients required the use of androgen deprivation therapy (ADT) for the control of disease. However, unlike other malignancy, PCa is characterized by its slow progression nature and even for metastatic disease the 5-year survival is upto 20%. Therefore, while ADT can provide effective control of disease, there are increasing evidences suggesting that it can also result in many adverse effects in the patients, and these effects are particular important due to the long survival of these patients. From the western literature, the adverse effects can be quite diverse.2 Classical side effects after ADT include mood changes, hot flushes, change in cognitive function,3 loss of libido, erectile dysfunction, osteoporosis and pathological fracture.4 Also there are more and more evidences showed ADT will also altered the metabolic and cardiovascular status of the patients and resulted in increase in insulin resistance and increase in risk of cardiovascular related mortality.5-7 Similarly, from our local data, investigators also observed similar increase in adverse events also happened in Chinese patients treated with ADT.8 There are many possible mechanisms proposed for the occurrence of these adverse events in patients receiving ADT, including increase in obesity, dyslipidaemia, insulin resistance etc. All these factors will lead to increase in metabolic and cardiovascular risk. However, the exact link between of hypogonadism and the development of obesity, dyslipidaemia and insulin resistance was still unclear. Since the development of the next-generation sequencing, the knowledge of the microbiota in different sites made much progress. Of all other sites, the gut was the most frequently studied. It was found that a number of different conditions were associated with the composition of the gut microbiota, like age9, environmental factors (e.g. diet10-12), medications and diseases like obesity13, inflammatory bowel disease14 and colorectal cancer.15 Other than those mentioned, gender difference in gut microbiota was found in animal studies16 as well as human studies.17-20 On the other hand, urinary microbiota was also found to have gender differences21. The mechanism of this difference is proposed by animal studies to be related to sex hormone16,22, and it was proposed to be due to the hormone-microbe interaction, or due to the sex-specific immune response.23 Recent studies has suggested castration will affect the guts microflora and resulted in the development of obesity in mice.22 However, whether similar effect in human was unknown. Moreover, if the microflora in men was also changed by ADT, this might be one of the underlying mechanism for the increase in cardiovascular and metabolic risk observed in men receiving ADT. Therefore, investigators would like to perform a prospective study to examine the relationship between ADT and gut and urinary microbiota, and also the possible relationship with the development of metabolic and cardiovascular complications in our local population.