Oestrogen uptake and metabolism in vivo

Abstract

SynopsisUptake of oestrogens into breast tissue and their subsequent metabolism can be studied by infusing radio-labelled steroids into volunteer patients. Such studies show that oestradiol is preferentially accumulated in breast tumours, oestradiol concentrations exceeding those of oestrone. This contrasts with plasma, in which oestrone concentrations in postmenopausal women are greater than those of the oestradiol. This observation suggests that tissue factors can modulate local oestrogen metabolism, and thus local steroid concentrations.We have studied the local production of oestrogens from androgen, and also the interconversion of the major oestrogens, oestrone and oestradiol. Using isotopic techniques, it is possible to calculate the proportion of endogenous oestrogen produced from androgen, as opposed to uptake from the circulation. These studies suggest that a very variable proportion of tissue oestrogen derives from endogenous synthesis. After administration of aromatase inhibitors, aromatase activity is substantially inhibited, both in vivo and in vitro.Relative oestrogen concentrations are determined in part by the activity of oestradiol dehydrogenase. In breast tissue, dehydrogenase activity is present and this is modified by various factors, including androgens. In addition, we have demonstrated that normal, benign and malignant breast tissues produce factors which can modulate both growth and dehydrogenase activity of cancer cells in vitro.We conclude that breast tissue is a site of synthesis of oestrogens, and that a number of factors can affect their local concentration. Tumour cells produce growth factors which can influence steroid metabolism, and may thus be able to enhance favourably their own endocrine environment.

Tissue estradiol is selectively elevated in receptor positive breast cancers while tumour estrone is reduced independent of receptor status

“…Yet, results so far with respect to local versus systemic contribution have been restricted to a limited number of individuals, providing conflicting results [31,32].…”

Aromatase inhibitors: Assessment of biochemical efficacy measured by total body aromatase inhibition and tissue estrogen suppression

“…The potential role of spliced transcripts [30] remains undefined. While these factors, together with evidence suggesting mechanisms for active uptake of steroids [31,32], as well as findings from tracer studies revealing a substantial interindividual variation in contribution from local estrogen production versus uptake from the circulation in tumors [26,33] have generated doubt whether evaluation of changes in circulating estrogens is a valid parameter for aromatase inhibition efficacy, notably there is one aromatase protein only. So far, there is no evidence suggesting a different drug effect upon the aromatase protein in different compartments.…”

Aromatase regulation and breast cancer

“…In an attempt to determine whether oestrogen formed in situ as a result of aromatase activity exerted a biological effect, the activity of this enzyme was related to DNA polymerase α activity, which is a marker of cellular proliferation. Overall, a weak but significant correlation ( r = 0·57, P < 0·05) was found suggesting that sufficient oestrogen could be synthesized in situ to exert a biological effect (James et al ., 1989). Reinvestigation of subjects after treatment with the aromatase inhibitor, 4‐hydroxy androstenedione revealed a marked reduction in 3 H‐oestrone formation in situ .…”