Comparative effects of testosterone propionate, oestradiol benzoate, ICI 182,780, tamoxifen and raloxifene on hypothalamic differentiation in the female rat

Abstract

Hypothalamic differentiation in the female rat during the neonatal period is critically dependent on the steroid milieu, as permanent changes in reproductive function are observed after administration of oestradiol and testosterone during such a critical stage. Selective oestrogen modulators (SERMs) constitute a family of drugs that, depending on the tissue, are able to exert oestrogenic or antioestrogenic actions. The present experiments were conducted to analyse whether the SERMs, tamoxifen and raloxifene, can cause oestrogenic actions during the hypothalamic differentiation period.Postnatal female rats were injected between days 1 and 5 with 100 µg/day tamoxifen, raloxifene or ICI 182,780 (a pure antioestrogen). Other groups of animals were injected on day 1 of age with 100 µg oestradiol benzoate (OeB) or 1·25 mg testosterone propionate (TP) alone or in combination with raloxifene (500 µg/day between days 1 and 5). In all experimental groups, the age, body weight and concentrations of serum gonadotrophins at vaginal opening were recorded, whereas vaginal cyclicity and the negative and positive feedback between oestradiol and LH were monitored in adulthood.The results obtained confirmed the ability of high doses of OeB or TP to alter the normal differentiation of the brain permanently. They also reinforced the hypothesis that oestrogens are also necessary for normal brain differentiation in female rats because administration of a pure antioestrogen, such as ICI 182,780 permanently altered the function of the reproductive axis. In addition, our data provided evidence for different actions of the two SERMs under analysis (raloxifene and tamoxifen) upon peripheral targets, as raloxifene advanced vaginal opening whereas tamoxifen did not. In contrast, their actions on brain differentiation appeared similar and analogous to those obtained after neonatal administration of oestradiol, as evidenced by vaginal acyclicity, ovarian atrophy, sterility and abolition of negative and positive feedback between oestradiol and LH, thus suggesting an oestrogenic action of these SERMs on hypothalamic differentiation. Moreover, the oestrogenic activity of raloxifene was supported by its inability to block the effects of OeB and TP administered neonatally.In conclusion, the present results indicated that the SERMs, tamoxifen and raloxifene, exert an oestrogen-like effect upon hypothalamic differentiation of the neonatal female rat.

Early postnatal oestradiol exposure causes insulin resistance and signs of inflammation in circulation and skeletal muscle

“…35 mg oestradiol benzoate used in this study is based on our previous study (Alexanderson et al 2007) since this dose is known to affect insulin sensitivity and metabolism in adult female rats. There is no standardised dose or administration procedure when studying the postnatal effects of oestrogenisation, several different doses and administration regimes have been used (Arai 1964, Pinilla et al 2002, Sotomayor-Zarate et al 2008. However, the injected dose used in our study concurs with other studies where 0 .…”

“…However, the injected dose used in our study concurs with other studies where 0 . 1 mg oestradiol benzoate (Pinilla et al 2002) or 0 . 1 mg oestradiol valerate (Sotomayor-Zarate et al 2008) has been injected into 1-day-old female rats.…”

Neonatal exposure to single doses of estradiol or testosterone programs ovarian follicular development–modified hypothalamic neurotransmitters and causes polycystic ovary during adulthood in the rat

“…Such effects might underlie the changes in reproductive function previously identified in adult animals neonatally exposed to EV or TP (8,14,22).…”

“…The doses of EV and TP were chosen based on previous studies of adult and prepubertal rats (7,13). In choosing the dose of TP, we considered the report of Pinilla et al (14), which used 0.1 mg estradiol benzoate and 1.25 mg TP for 1-day postpartum (P1) rats. DHT dose was chosen based on the report of Arai et al (15).…”

Mechanisms for altered reproductive function in female rats following neonatal administration of raloxifene

“…In fact, conflicting results on the presence or absence of any estrogenic activity of raloxifene on hypothalamicpituitary function have been presented (14)(15)(16). In this context, data from our laboratory indicated that administration of raloxifene during the neonatal period of hypothalamic sex differentiation induced an estrogen-like effect on the functional organization of the hypothalamic -pituitary unit (17,18); however, raloxifene did not act in the same way as estrogen on the neuronal systems controlling sexual receptivity in the female rat (18). In adult animals, raloxifene increased serum prolactin concentrations and decreased luteinizing hormone (LH) levels in ovariectomized rats, thus indicating an activational estrogenic action of this SERM in the regulation of hypothalamic -pituitary function (19).…”