Effect of long-term treatment with aromatase inhibitor on testicular function of adult male bonnet monkeys (M. radiata)

Abstract

The role/need for estrogen in regulating testicular function of adult male bonnet monkeys (M. radiata) has been investigated by dosing orally a group of five normal males 2.5 mgs of CGP 47645, a long-acting nonsteroidal aromatase inhibitor (AI), once every 5 days for over 150 days. Such treatment resulted in a 10-fold increment in nocturnal serum testosterone (T) levels, which were sustained for 85 days of treatment, and a twofold increment in basal serum T levels was present throughout the 150 days of treatment. Analysis of ejaculated semen showed a marked reduction (approximately 90%) in sperm counts in four out of five monkeys between Days 55-85 of treatment. During this period, the motility score also was markedly reduced from a normal score of 3-5 to 0-2. Flow cytometric analysis of testicular germ cells obtained from biopsy tissue taken on Days 63 and 120 indicated a marked reduction only in elongating/elongated spermatid population (compared to Day 0 values), suggesting inhibition in spermiogenic process. Epididymal sperm maturation also seemed effected as sperm chromatin, on flow cytometric analysis for decondensability following exposure to 5 mM dithiotreitol, showed to be in a hypercondensed state. This study thus indicates that estrogen has an important role in providing normal testicular and sperm function in the primate.

Effect of chronic administration of an aromatase inhibitor to adult male rats on pituitary and testicular function and fertility

“…Nevertheless, several studies involving the inhibition of aromatisation have shown a consistent and rapid increase in testosterone concentrations (50%) in humans (Bhatnagar et al 1992, Trunet et al 1993, Hayes et al 1999, primates (Ellinwood et al 1984, Dukes et al 1996, Shetty et al 1998 and dogs (Juniewicz et al 1988). In the present study, an increase in plasma testosterone concentrations occurred within 1 week of anastrozole treatment and was maintained for approximately 5 months but not beyond this time.…”

“…This is in contrast to treatment of dogs with fadrozole for 6 months, which had no effect on sperm counts or gross testicular morphology ( Juniewicz et al 1988). Long-term treatment of adult bonnet monkeys with an analogue of letrozole resulted in a 90% reduction in sperm production after treatment for 55 days; flow cytometric analysis demonstrated a reduction in round and elongating spermatids, implying a defect in spermiogenesis (Shetty et al 1998). Administration to adult male rats of a protein purified from the ovary that had aromatase inhibitory activity also induced a reduction in the number of elongate spermatids (Tsutsumi et al 1987), and a similar late-onset lesion in ArKO mice has recently been described .…”

Estrogen Receptors α and β in Human Testis: Both Isoforms are Expressed

“…In human adult seminiferous tubules cultured in vitro, 17b-estradiol (E) acts as a germ cell survival factor [Pentikainen et al 2000]. This observation is supported by a study in male monkeys treated with an aromatase inhibitor which displayed a decrease in germ cell number [Shetty et al 1998]. Very recently it was demonstrated that E stimulates DNA synthesis in rat spermatogonia, an effect also maintained by the dihydrotestosterone metabolite, 5a-androstane-3b,17b-diol via interaction with ERb [Wahlgren et al 2008].…”

The association of aromatase (CYP19) gene variants with sperm concentration and motility

“…Oestrogen production and androgen bioavailability are regulated by cytochrome P450 aromatase activity. Although the role of the P450 aromatase in human spermatogenesis is still under investigation, the noteworthy decrease in round and elongated spermatids after the administration of an aromatase inhibitor in rat 23 and monkey, 24 and the P450 aromatase localisation in the germinal epithelium of the adult mouse testis, primarily in the Golgi region of round spermatids, throughout the cytoplasm of elongating spermatids and along the flagella of late spermatids, 25 support the idea that P450 aromatase is important for spermatogenesis in humans'.…”