Study evaluates pathophysiological changes in the prostate in animals
The increase in the elderly population is a worldwide phenomenon. Projections indicate that in 2020 Brazil will be the sixth country in the world in terms of the number of elderly people, which should exceed 30 million people. Recent clinical studies point to a strong correlation between aging and diseases of the genitourinary tract, with prostate diseases being highly prevalent in men, including benign prostatic hyperplasia (BPH). The disease is considered a public health problem in Brazil and around the world, negatively impacting patients' quality of life.
Symptoms of the lower urinary tract mainly include urinary urgency, urinary incontinence, nocturia - the need for multiple urinations at night - frequently reported in middle-aged men (40-50 years old) and elderly men (over 60 years old). In men, these symptoms are generally related to BPH, which becomes more frequent with aging and, when left untreated, can progress to complete retention of urine in the bladder, facilitating the emergence of inflammation and urinary infections, the formation of bladder stones and , in more serious cases, even kidney failure.
Despite the increase in the incidence of BPH already in middle age, most studies found in the literature, both in humans and in experimental animals, focus on evaluating prostate changes in the elderly, neglecting the middle age range, when the onset of the disease begins. Seeking to remedy this gap, Fabiano Beraldi Calmasini, a graduate in pharmacy with a specialization in pharmacology, set out to characterize the pathophysiological changes in the prostate of middle-aged rats which, like men, have the organ changing with aging. The work was supervised by professor Edson Antunes, from the Department of Pharmacology, from the Faculty of Medical Sciences (FCM) at Unicamp.
Little is known about the pathophysiology of BPH and why it progressively evolves with age. As a result, studies that aim to understand how hyperplasia is generated and establish its relationship with the aging process can contribute to preventive measures and treatments, thus improving the quality of life of individuals, reducing expenses with diagnosis and monitoring of patients.
BPH is associated with two distinct factors: the first arises from the physical growth of the prostate, called the static component of the disease. As the prostate is located around the urethra in humans, its excessive growth causes it to be compressed. The second factor results from the greater contraction force of the prostate muscles, known as the dynamic component of the disease. These two variables combined can restrict the flow of urine from the bladder by compression of the urethra, contributing to lower urinary tract symptoms.
The study developed at the Experimental Inflammation and Cardiovascular Laboratory of the Department of Pharmacology at Unicamp, by Calmasini and collaborators, showed for the first time that middle-aged rats, despite not yet being affected by BPH, already show structural and functional changes in the prostate, in addition to a reduction in systemic testosterone levels and impairment in insulin signaling (insulin resistance).
Development of work
To develop the work, the researcher used middle-aged rats (ten months old) and young rats (three and a half months old), used as a counterpoint. The initial idea was to work with animals in middle age, that is, at the beginning of aging, and verify what types of prostate changes may be present in this age group and whether they would be sufficient to generate hyperplasia when they are older.
In the first part of the study, functional, biochemical and molecular changes in the prostate of these rats were characterized. An increase in the contraction force of the prostate muscles was observed in these animals, that is, an increase in the prostatic dynamic component, in addition to a systemic reduction in testosterone levels and insulin resistance.
In the second part of the work, the researcher adopted chronic treatments, with medications that, for the most part, are already on the market, but not approved in the clinic to treat BPH, evaluating the effectiveness of each one on the increase in prostate contractions in the rats studied.
According to the characteristics found in the animals in the first part of the work, the researcher looked for drugs that could alter the found insulin resistance and reduced testosterone levels, factors that are known to lead to increased muscle contraction. prostate. To this end, in the first group, metformin (an oral antihyperglycemic agent) was used, an agent that improves insulin sensitivity, used mainly in cases of type 2 diabetes; and in a second group, hormone replacement therapy with testosterone. In both cases, the treatments were not able to reverse the changes in contraction in the animals' prostate, ruling out the direct participation of these pathways in the changes found.
Another pathway studied by the author was related to oxidative stress resulting from the accumulation of reactive species in the body and which is closely associated with the aging process. The accumulation of reactive species can lead to cellular damage, which would contribute, among other things, to an increase in prostate contractions in middle-aged animals. The animals were then treated for four weeks with the antioxidant apocynin and subsequently evaluated. The treatment also did not result in an improvement in prostate contractions, suggesting that oxidative stress is not directly associated with the development of prostate changes in middle age.
Having eliminated the previously suggested variables, Fabiano set out to test mirabegron, a drug approved in recent years by the FDA (Food and Drug Administration) – US health body of global reference – for the treatment of overactive bladder. The choice was based on conclusions from previous work published by the researcher and carried out in the same Department of Pharmacology at FCM, which showed the presence of the same receptor in which the drug acts in the bladder also in the human prostate. Furthermore, the study also showed that mirabegron is capable of reducing contraction vitro of prostate muscles in humans and rabbits. Therefore, the hypothesis raised was that chronic treatment with mirabegron could be beneficial in the prostate changes found in animals. In fact, after two weeks of treatment, the medication was able to completely reverse the increase in prostate contraction in middle-aged rats.
In general terms, the author concludes: “We showed that middle-aged rats already have prostate changes and that insulin resistance, testosterone deficiency and an increase in oxidative stress are not directly associated with an increase in prostate muscle contraction in this group. On the other hand, treatment with mirabegron, a medication approved for the treatment of overactive bladder, proved to be effective in reversing the increase in prostate muscle contraction in these animals. Likewise, drugs that have the same mechanism of action as mirabegron may constitute important pharmacological approaches for the treatment of increased prostate contraction in middle age. It is worth mentioning that the work was carried out with experimental animals and, therefore, more studies are needed to prove the real effectiveness of this class of medicines in the treatment of BPH”.
