Mechanism delineating differential effect of an antiestrogen, tamoxifen, on the serum LH and FSH in adult male rats

Abstract

Tamoxifen, a synthetic non-steroidal antiestrogen with residual estrogenic activity, administered to adult male rats reduces their fertility. A decrease in the circulating LH and testosterone levels with a transient rise or no change in circulating FSH levels was observed. The present study was carried out to delineate the mechanism causing the differential effect of tamoxifen on circulating gonadotropins by correlating it to changes in the hypothalamic LHRH, pituitary gonadotropins and testicular inhibin/activin. Hypothalamus, pituitary-hypothalamus complex (PHC) and intact pituitary (PI) from control and tamoxifen-treated male rats were superfused in vitro, and pulsatile release of LHRH by hypothalamus and that of LH and FSH by the PHC and PI were studied. Concomitantly, testicular immunoexpression of alpha and betaB subunits of inhibin/activin were studied by immunohistochemistry and enzyme-linked immunosorbent assays (ELISA). At 0.4 mg/kg/day dose of tamoxifen a decrease in mean hypothalamic LHRH and LH pulse frequency from PHC construct was observed. FSH pulse frequency was not affected under the same experimental conditions. At the same dose of tamoxifen, testicular expression of both alpha and betaB subunits of inhibin/activin was upregulated. The study demonstrated that reduced circulating LH levels were due to a decrease in hypothalamic LHRH concentration and in LH pulsatility following tamoxifen treatment. The lack of effect on circulating FSH under the same experimental conditions was likely due to its modulation by inhibin and activin.

Effects of tamoxifen on vaginal blood flow and epithelial morphology in the rat

“…It is possible that the effects of tamoxifen are partially dependent upon androgens. For example, in male rats, tamoxifen has been shown to decrease circulating levels of luteinizing hormone and testosterone and to increase liver enzymes that metabolize androgens [ 55 , 56 ]. In postmenopausal women with breast cancer, tamoxifen treatment resulted in increased sex hormone binding globulin and decreased levels of circulating androgens [ 57 ].…”

Oestrogens and spermatogenesis

“…(c) Direct effects of oestrogen on seminiferous epithelium Several studies have now presented data supporting the hypothesis that oestrogen does have a direct role in the regulation of spermatogenesis. An indirect role through the hypothalamus -pituitary -testicular feedback loop has been well established (O'Donnell et al 2001;Balasinor et al 2006;Ebling et al 2006) and direct effects on Leydig cell function are well known, as ERa is typically expressed in these cells with most fixation methods and antibodies (Hess et al 2002;Lucas et al 2008). The anti-oestrogen ICI 182,780 inhibits T production in WT Leydig cells but not in neo-ERKO cells (Akingbemi et al 2003).…”

Systemic hormonal modulation induces sperm nucleosomal imbalance in rat spermatozoa

“…Although the mechanism of differential nucleosome dynamics apparent in this study is not exactly clear, a possible hypothesis may be presented to explain this phenomenon (Figure ). Tamoxifen represents oestrogenic environmental pollutants that can either modulate the systemic hormonal balance (Balasinor, Parte, Gill‐Sharma, Kini, & Juneja, ) or affect the functioning of the hormone receptors (Pathak, D'Souza, Ankolkar, Gaonkar, & Balasinor, ). Nucleosome positioning is dependent on molecular determinants such as conserved DNA sequence, DNA methylation at CpG sites or certain chromatin structure modulators (Erkek et al., ; Lövkvist, Sneppen, & Haerter, ).…”