The Influence of the Route of Administration of 17β-estradiol, Intravenous (Pulsed) Versus Oral, Upon DMBA-Induced Mammary Tumour Development in Ovariectomised Rats

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Abstract
A wide variety of routes of administration and formulations are employed in estrogen replacement therapy. These exhibit differences in the pharmacokinetics and metabolism of estradiol and in the resulting biological effects. This study set out to investigate the effects of pulsed estrogen administration (via the nasal route) compared to oral therapy, as a reference, with regard to breast cancer risk. This was assessed in an experimental model whereby mammary tumours were induced by 7,12-dimetbylbenz(a)anthracene in ovariectomised rats. To mimic a pulsed treatment given via the nasal route doses of estrogen were administered by I.V. route (0.4, 10 and 250 μg/kg). These dosages were predicted to have similar estrogenic activity to doses administered by the oral route (100, 300 and 900 μg/kg). Controls were groups of ovariectomised and SHAM-operated rats and ovarectomised rats administered with either vehicle alone. Two studies were carried out on separate populations of rats and ran in parallel. Tumour appearance (study 1) and tumour growth (study 2) were evaluated. In study 1 (n = 20/group), treatments with estradiol were conducted for 20 weeks after carcinogen administration; in study 2 (n = 10/group), an 8-week treatment with estradiol was initiated once 7,12-dimethylbenz(a)anthracene-induced tumours appeared. Intravenous dose levels achieved equivalent estrogenicity to corresponding oral dose levels, as assessed by measuring uterus weight. Estrogen deficit was made up by both routes but only the higher doses restored physiological uterus weight. Nevertheless administration via the I.V. route resulted in a lower rate of tumour incidence (p ≤ 0.05) than the rate recorded for the oral route. In addition, tumour development was lower with the I.V. route. In conclusion, in this experimental model, pulsed estrogen therapy with 17 β-estradiol administered via the I.V. route resulted in a reduced effect on mammary carcinogenesis when compared to oral administration.