The prevalence of BPH increases with age: histologic prevalence reaches 60% at age 60 and 80% at age 80. The treatment of BPH is often multimodal and almost all guidelines reached a relatively uniform opinion considering as equal possible first treatment choices alpha 1-Blockers, muscarinic receptor antagonists or 5alpha-reductase (5AR) inhibitors (5ARis). 5ARis are widely prescribed for their antiandrogenic effects. However, 5AR are also involved in glucocorticoids metabolism and clearance: their inhibition reduces the clearance of cortisol by inhibiting its inactivation, thus leading to increased levels of active cortisol. This is particularly important considering that the circulating levels of GCs are locally regulated through a balance between synthesis in the adrenal cortex and clearance via metabolic pathways in the liver and other peripheral tissues, which accounts for the maintaining of physiological concentration of active GCs in the bloodstream and peripheral tissues. Inhibition of androgens and glucocorticoid transformation to their various metabolites may result in pathophysiological states, such as liver diseases, hyperglycemia, hyperlipidemia, IR, and type 2 diabetes mellitus (T2DM). So that, for 5ARis, it is reasonable to expect systemic effects which are not confined to the prostate gland. However, the ability of these drugs to regulate metabolic phenotype has only been examined in a very small number of studies. Most recently, analysis of data from primary care prescriptions suggested a significant association between 5alpha-RI prescriptions and the incidence of type 2 diabetes (T2D). Based on these premises, the present study will therefore aim to evaluate the effects of 5alpha-reductase inhibitors on glucose metabolism in patients with BPH and Type 2 diabetes mellitus over a 12-months period.
Other than androgen metabolism, 5AR are also involved in glucocorticoids metabolism and clearance, finally leading to increased levels of active cortisol. The latter results in: (1) accumulation of intra-abdominal fat; (2) impaired islet ß-cell function as well as increased gluconeogenesis in the liver, resulting in hyperglycemia and insulin resistance (IR); (3) impaired kidney function. Thus, increased cortisol levels may contribute to development of insulin resistance and T2DM, obesity, renal impairment. Considering the high worldwide prevalence of BPH, concerns regarding possible adverse metabolic consequences of 5ARis are particularly important, even for the long-term nature of treatment and the age of patients affected, in whom risk factors for metabolic syndrome are most prevalent. Endorsing these molecular mechanisms, the population-based cohort study from the UK Clinical Practice Research Datalink investigated the 5-years incidence of T2DM in almost 40-thousand men receiving steroid 5alpha-reductase inhibitors (dutasteride or finasteride) for long term treatment of BPH compared to 16-thousand men under tamsulosin treatment. The results demonstrated a higher risk (HR of 1.32) of developing new onset T2DM in men with BPH exposed to 5alpha-reductase inhibitors, with no differences between those men receiving dutasteride and those receiving finasteride. However this was a cross-sectional analysis, with heterogeneous cohort of patients with multiple treatments. Subgroup analysis for confounding factors and other variables that could affect the relationship between the 5ARi and the development of T2DM was not performed.
Recently, a randomized controlled trial on 46 healthy subjects demonstrated an impairment in insulin sensitivity in men treated with dutasteride after three months of treatment. However this was only modest due to the younger age of the patients enrolled compared to the general population affected by BPH, characterized by impaired ß-cell function and increased body fat. This limited to draw clinically relevant conclusions.
Through a high-quality approach, our study will evaluate the different impact of 5ARi on glucose metabolism in a well-selected cohort of patients with T2DM. This will give reliable data about the causality relationship between 5ARi treatment and glucose metabolism impairment gained from the observational studies conducted so far. The results will open a new promising research area aiming to identify possible predictor for the onset of the detrimental effects of this commonly prescribed drugs, with potential benefits on patients health and healthcare costs.
Our unit has consolidated experience in steroid hormones management in physiological environment and during adrenal disorders. Moreover, we have also experience in glucose metabolism impairment and related microvascular complications. In the latter, we have lead a considerable number of studies merging endocrinological and andrological licensed drug to successfully treat cardio-metabolic disorders. Indeed, the project has a multidisciplinary pioneering aim, embracing endocrinology, andrology, urology and immunology sciences. The Host Institute makes such approach feasible, facilitating networking and the sharing of research infrastructures, namely the Advanced Ultrasound diagnostic Unit, MOC/DEXA machine, LC/MS-MS and molecular and cellular endocrinology laboratory (all under my direct supervision); This will help limit costs relating to the customization of the available large equipment and save money.