A comparison of prostatic development in xenografts of human fetal prostate and human female fetal proximal urethra grown in dihydrotestosterone-treated hosts

Abstract

The goal of this paper is to explore the ability of the human female urogenital sinus immediately below the bladder (proximal urethra) to undergo prostatic development in response to dihydrotestosterone (DHT). To establish this idea, xenografts of human fetal female proximal urethra were grown in castrated nude mouse hosts receiving a subcutaneous DHT pellet. To verify the prostatic nature of the resultant glands, DHT-treated human fetal female urethral xenografts were compared with human fetal prostatic xenografts (derived from male specimens) grown in untreated and DHT-treated castrated mouse hosts and human fetal female proximal urethral xenografts grown in untreated castrated hosts. The resultant glands observed in DHT-treated human fetal female proximal urethra expressed 3 prostate-specific markers, NKX3.1, prostate specific antigen and prostatic acid phosphatase as well as the androgen receptor. Glands induced by DHT exhibited a protein expression profile of additional immunohistochemical markers (seven keratins, RUNX1, ESR2, TP63 and FOXA1) consistent with the unique spatial pattern of these proteins in prostatic ducts. Xenografts of human fetal female proximal urethra grown in DHT-treated hosts expressed one of the salient features of prostatic development, namely androgen responsiveness. The experimental induction of prostatic differentiation from human fetal female proximal urethra makes possible future in-depth analysis of the molecular pathways directly involved in initiation of human prostatic development and subsequent epithelial differentiation, and more important whether the molecular pathways involved in human prostatic development are similar/identical versus different from that in murine prostatic development.

Ectopic Prostatic Tissue in Female Urethral Diverticulum

“…5,9 This mechanism has been linked to ectopic prostatic tissue in vaginal tissue of patients undergoing gender-affirming therapy with testosterone supplementation and in female proximal urethra in mice. 5,6…”

“…5,9 This mechanism has been linked to ectopic prostatic tissue in vaginal tissue of patients undergoing gender-affirming therapy with testosterone supplementation and in female proximal urethra in mice. 5,6 The management of testosterone therapy in the setting of ectopic prostatic tissue in female patients is not welldescribed. Prostatic ectopy has been reported as benign in most previously published cases.…”

“…Ninety-six full-text articles were assessed for eligibility. Of these, 72 were excluded for the following reasons: male population (44), non-English-language (18), wrong outcomes (6), wrong study design (3) and wrong intervention (1). Outcomes that were excluded included prospective animal studies.…”

A Review of Prostate Organogenesis and a Role for iPSC-Derived Prostate Organoids to Study Prostate Development and Disease

“…However, in the absence of androgen signalling, male embryos will develop female genitalia without prostates [ 52 , 56 ]. In contrast, exposure of the human or rodent female UGS to androgens, either in vivo or in vitro, leads to prostate development [ 44 , 57 , 58 ]. AR signalling is most important in the UGM during the early stages of prostate development, as revealed by testicular feminised (Tfm) mice, which are insensitive to androgens due to a frame-shift mutation in the AR gene [ 59 , 60 ].…”

Precision Targets for Intercepting the Lethal Progression of Prostate Cancer: Potential Avenues for Personalized Therapy

“…Androgens, synthesized predominantly in the testes, mediate biological effects via the androgen receptor (AR), which is a nuclear receptor and ligand-inducible transcription factor. Androgen-activated AR regulates normal prostate physiology and prostate cancer pathophysiology [ 3 , 4 , 5 , 6 ].…”