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

Abstract

The increasing use of androgens in clinical trials for developing a safe, effective, and reversible male contraceptive has necessitated a critical evaluation of the effects of their long-term use on the structure and functions of the prostate gland, which is androgen dependent. Combination regimens using progestogens, gonadotropin-releasing hormone antagonists, or antiandrogens along with androgens are undergoing clinical evaluation as antispermatogenic agents. The majority of these regimens have used testosterone enanthate (TE) as the androgen of choice, but very limited information is available 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 preparation of semithin sections to evaluate histological changes. The DNA distribution in the cells was studied in single cell suspensions of cranial and caudal lobes of the prostate by using flow cytometry. Changes in the levels of testosterone, estradiol, prostate-specific acid phosphatase (PAP), and prostate-specific antigen (PSA) in samples collected during the pretreatment period and at the time of removal of the prostate were estimated by using conventional procedures. Control samples were processed simultaneously. The administration of TE for 33 months caused the following changes: 1) significant increase in the weight of both lobes of the prostate, 2) cellular hypertrophy 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 prostate, 3) cellular hyperplasia indicated by flow cytometric analysis of DNA content, 4) significant increase in the secretion of PAP and levels of estradiol, and 5) a marked increase in fibromuscular stroma in the central and peripheral zones of both the lobes of the prostate. The present study is the first report to provide evidence that long-term androgen treatment has caused hypertrophy of the prostatic epithelial cells, which showed increased secretory activity. The hyperplastic changes indicate a need for the development of new androgens with a better pharmacokinetic profile for use in male contraceptive regimens.

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Non-proliferative and Proliferative Lesions of the Non-human Primate (<i>M. fascicularis</i>)

“…Most reported prostate lesions were noted in the cranial lobe, represent a continuum of basal cell hyperplasia to adenoma and considered morphologically similar to benign basal cell lesions arising in the human prostate and thus macaque is considered a good animal model for studying prostatic diseases 412 , 432 , 433 , 442 . Functional or diffuse hyperplasia of prostate noted in rodents secondary to administration of exogenous androgens resulting in enlargement, weight increase, diffuse hyperplasia, and an increase in secretions 404 was also reported in rhesus macaques 441 . In addition, diffuse hyperplasia of prostate and seminal vesicles secondary to administration of recombinant human epidermal growth factor was noted in cynomolgus monkeys 429 ( Table 36…”

“…Comments: Squamous metaplasia of the prostate and atrophy with stromal fibrosis secondary to administration of estrogenic compounds has been observed in prostate and other accessory sex glands 432 , 441 , including seminal vesicles (personal observation, Eric Van Esch).…”