Changes in structure and functions of prostate by long-term administrationof an androgen, testosterone enanthate, in rhesus monkey (Macaca mulatta)

The increasing use of androgens in clinical trials for developing a safe, e ffective, and reversible male contraceptive has necessitated a critical eva luation of the effects of their long-term use on the structure and function s of the prostate gland, which is androgen dependent. Combination regimens using progestogens, gonadotropin-releasing hormone antagonists, or antiandr ogens along with androgens are undergoing clinical evaluation as antisperma togenic agents. The majority of these regimens have used testosterone enant hate (TE) as the androgen of choice, but very limited information is availa ble on the side effects of long-term androgen use. The present study is the first report that critically evaluates the effects of long-term use of TE on prostate structure and functions. Adult male rhesus monkeys received intramuscular injections of 50 mg of TE once in 14 days for 33 months. The cranial and caudal lobes of the prostate , which were removed under ketamine anesthesia, were processed for the prep aration of semithin sections to evaluate histological changes. The DNA dist ribution in the cells was studied in single cell suspensions of cranial and caudal lobes of the prostate by using flow cytometry. Changes in the level s of testosterone, estradiol, prostate-specific acid phosphatase (PAP), and prostate-specific antigen (PSA) in samples collected during the pretreatme nt period and at the time of removal of the prostate were estimated by usin g conventional procedures. Control samples were processed simultaneously. T he administration of TE for 33 months caused the following changes: 1) sign ificant increase in the weight of both lobes of the prostate, 2) cellular h ypertrophy and increase in secretory material in the cells and in the lumen of the acini in the central and peripheral zones of the two lobes of the p rostate, 3) cellular hyperplasia indicated by flow cytometric analysis of D NA content, 4) significant increase in the secretion of PAP and levels of e stradiol, and 5) a marked increase in fibromuscular stroma in the central a nd peripheral zones of both the lobes of the prostate. The present study is the first report to provide evidence that long-term an drogen treatment has caused hypertrophy of the prostatic epithelial cells, which showed increased secretory activity. The hyperplastic changes indicat e a need for the development of new androgens with a better pharmacokinetic profile for use in male contraceptive regimens. Anal. Rec. 252:637-645, 19 98. (C) 1998 Wiley-Liss, Inc.