Endocrine, prostatic vascular, and proapoptotic changes in dogs with benign prostatic hyperplasia treated medically or surgically

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Highlights

  • All finasteride doses were able to decrease prostate volume after 60 d.

  • Orchiectomy significantly decreased androgen concentration after 30 d onward.

  • Orchiectomy and 0.5-mg finasteride increased prostate artery resistance after therapy.

  • Orchiectomy has prostate proapoptotic effect, not different from 0.5-mg finasteride.

Abstract

Benign prostatic hyperplasia (BPH) is a disorder related to hormone imbalance, local angiogenesis, and prostate growth, which can be treated surgically (orchiectomy) or medically (most commonly with finasteride). However, finasteride therapy is not completely established in dogs regarding local action and posology. This study aimed to evaluate the effect of different doses of finasteride and orchiectomy on hormonal profile, prostate apoptosis, blood flow, and biometry in dogs with BPH. Dogs were assigned to the following groups: untreated, 0.1 mg, 0.2 mg, and 0.5 mg/kg/d of finasteride and orchiectomy. All dogs were assessed monthly: day 0 (before treatment), day 30, and day 60 and subjected to prostate B-mode and Doppler ultrasonography and hormonal analysis (testosterone and dihydrotestosterone). After 60 d, prostatic biopsy was performed for histology and immunohistochemical evaluation for apoptosis (caspase-3). On day 60, percentage reduction of prostatic volume was greater in orchiectomized dogs than that in finasteride groups, which, conversely, was greater than untreated dogs. On day 60, 0.2-mg finasteride, 0.5-mg finasteride, and orchiectomy groups had higher prostatic blood flow than 0.1-mg finasteride and untreated groups. In addition, both 0.5-mg finasteride and orchiectomy groups had an increase in prostate artery resistance. Orchiectomy significantly decreased androgen concentrations at 30 d onward, differing from the remaining groups. The orchiectomy group had lower caspase-3 immunostaining, however, not different from untreated and 0.5-mg finasteride. In conclusion, 0.5 mg/kg finasteride promoted more effective prostate apoptosis and hemodynamic effects among medical treatments, whereas orchiectomy caused prostate atrophy and sharp endocrine changes in dogs with BPH.

Introduction

Benign prostatic hyperplasia (BPH) affects equally men and dogs, mainly during senescence [1]. Over 90% of the men with more than 80 yr old develop BPH [2], whereas 95% of the dogs above 9 yr of age are affected by BPH [3]. Thus, age is considered an important risk factor for BPH, mostly due to reproductive hormonal imbalance caused by aging [2]. During youth, a hormonal equilibrium efficiently controls growth and apoptosis of prostatic cells. However, senescence triggers a disproportion between proliferation and cell death [1].

The main hormones responsible for prostate gland homeostasis are androgens (testosterone and dihydrotestosterone (DHT)) and estrogens (estradiol) [4]. Physiologically, testosterone is converted into DHT in the prostate through the enzymatic action of 5α-reductase [2]. Nonetheless, BPH is marked by an excessive androgen conversion, generating high concentrations of DHT, which in turn promote disequilibrium between prostate growth and apoptosis, ultimately causing glandular volume increase [1]. In fact, DHT stimulates the production of tissue growth factors such as epidermal growth factor (EGF), IGFs, and vascular endothelial growth factor [1]. On the other hand, DHT negatively affects the expression of transforming growth factor (TGF-β), which is a modulator of prostate apoptosis. Hence, prostate uncontrolled growth (BPH) is a hormonal disorder related to unbalanced expression of proliferative and cell death markers [5]. Thus, it is possible to suggest that prostate overgrowing in dogs is also a process by which prostate apoptosis is inhibited.

The main goal of BPH treatment is to block DHT synthesis and decrease DHT concentrations. For such purpose, both surgical and medical procedures can be preconized, in accordance with the breeding function of the dog [6]. The former mode of therapy includes bilateral orchiectomy as the treatment of choice, whereas medical therapy can be accomplished by the use of DHT blockers. The most wide known drug is finasteride, which is an inhibitor of the 5α-reductase enzyme [7] and can effectively diminish prostate volume [8]. Indeed, finasteride directly reduces prostatic vascularization and cell proliferation in men [9], in addition to activating apoptotic markers (such as caspase-3) after 6 to 8 wk of treatment in patients with BPH [10]. In dogs, recommended doses of finasteride may range from 0.1 to 0.5 mg/kg/d or 1 mg/kg/d [11,12]. However, there is no systematic evidence of the likely dose that can normalize hormonal profile and at the same time reduce prostate volume through apoptosis and, thus, mitigate BPH clinical signs. In spite of the wide use of finasteride as a therapeutic alternative for orchiectomy in stud dogs [13], the precise dosage and in-depth prostate effects are not fully understood.

Therefore, the aim of this study was to evaluate the effect of different doses of finasteride and orchiectomy treatment on hormonal profile, prostate apoptosis, blood flow, and biometry in dogs with BPH.

Section snippets

Material and methods

All procedures described in the present study were previously approved by the Bioethics Committee of the School of Veterinary Medicine and Animal Science–University of São Paulo (protocol number 7122171213).

Results

A significant interaction (P < 0.05) between groups and time was observed for the PV variation (PV%), RI of the prostate artery, prostate vascularization score, S/D of the prostate artery, testosterone and DHT concentrations (Table 1).

After a 30-d follow-up, all BPH clinical signs (tenesmus, hematuria, and dysuria) were reported by the dogs' owner to have ceased in the medically and surgically treated groups. At prostatic fluid evaluation, hematospermia was observed in only 3 medically treated

Discussion

In the present study, we aimed to evaluate the endocrine profile, prostate vascularization, and hemodynamic and proapoptotic effects of medical (finasteride on distinct therapeutic dosages) or surgical treatment (orchiectomy) in dogs with BPH.

As a synthetic inhibitor of 5-α reductase enzyme, finasteride acts directly reducing DHT concentrations, which in turn is considered the main consequence of the imbalance between testosterone and estrogen [1,23]. However, our data show that only the

CRediT authorship contribution statement

C.B. Lima: Carried out the study, Analyzed and interpreted the data, Writing - original draft, Conceptualization. D. de Souza Ramos Angrimani: Carried out the study, Analyzed and interpreted the data, Writing - original draft. R.B. Flores: Carried out the study, Analyzed and interpreted the data. C.I. Vannucchi: Supervised the experiments, Conceptualization.

Acknowledgments

The authors wish to thank Prof. Bruno Cogliati and Prof. Ricardo JG Pereira for the immunohistochemical evaluation, Prof. Claudio A Oliveira and Dr Priscila V Furtado for the hormonal evaluation, and Dr Gustavo Tiaen and Dr Gisele AL Veiga for the prostatic biopsy and orchiectomy surgery, respectively.

Declaration of interest: The authors declare no competing interests.

Funding: This work was supported by the São Paulo Research Foundation (Fundação de Amparo à Pesquisa do Estado de São Paulo

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