Review
The Role of Local Estrogen Biosynthesis in Males and Females

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Abstract

Natural (human) and experimental (mouse) models of estrogen insufficiency have revealed hitherto unexpected roles for estrogens in both males and females. In postmenopausal women, and in men, estrogen no longer has a major role as a circulating hormone, but rather it functions locally as a paracrine or even ‘intracrine’ factor in tissue sites where it is formed. As a consequence, the tissue-specific nature of aromatase production assumes physiological and pathophysiological significance. The availability of circulating precursors is also important in sites where there is no local supply of C19 precursors, particularly in elderly women. The potential clinical significance of these findings in terms of the development of new therapeutic modalities is discussed.

Section snippets

The Concept of Local Estrogen Biosynthesis

Although the ovaries are the principal source of systemic estrogen in the premenopausal non-pregnant woman, other sites of estrogen biosynthesis are present throughout the body, and these become the major sources of estrogen after the menopause. These sites include the mesenchymal cells of the adipose tissue and skin (reviewed in Ref. 1) osteoblasts18 and perhaps chondrocytes19 in bone, vascular endothelial and aortic smooth muscle cells20, as well as several sites in the brain, including the

Precursor Availability

A key factor in the gender difference in the incidence of these diseases appears to be the availability of precursor C19 steroids for aromatization to estrogens in extragonadal sites, a concept also advanced by Labrie and colleagues31. In postmenopausal women, the principal source of C19 steroid production is the adrenal cortex, which elaborates androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). However, the secretion of these steroids and their plasma concentrations

Regulation of Aromatase Production in Adipose Tissue

We have suggested previously1 that aromatase is a marker of the undifferentiated adipose mesenchymal cell phenotype. In support of this, the factors that stimulate its production in adipose tissue of cancer-free individuals are factors that either inhibit or reverse the differentiated phenotype of adipocytes, namely class I cytokines, such as IL-6, oncostatin M and IL-11, or TNF-α (Fig. 1). Moreover, all of these factors act via the mesenchymal promoter I.4 of CYP19 and require glucocorticoids

Testicular Estrogen and Spermatogenesis

Following our recent observations that male ArKO mice develop a progressive infertility such that by the age of one year most are infertile, we have examined the phenotype of these animals17. We observed that the seminiferous tubules are grossly dysmorphic, with an absence of mature spermatids and developmental arrest at the level of early round spermatid differentiation. In some cases, multinucleate and apoptotic cells can be seen sloughing into the lumen. There is also marked Leydig cell

Clinical Considerations

An important issue pertaining to the role of estrogen in the development of breast cancer in postmenopausal women is the relationship between HRT and breast cancer risk. A collaborative analysis of a large body of the available epidemiological data found that systemic administration of estrogen with/without progestin to postmenopausal women is associated with an overall 1.35-fold increase in breast cancer risk46. The increase in risk was reported to be greater in women of very low body mass

Acknowledgements

This work was supported by the Victorian Breast Cancer Research Consortium Inc, by Project Grant Number 981126 from the NH and MRC (Australia) and by Grant Number AGO8174 from the NIA (USA). The authors thank Sue Elger for skilled editorial assistance.

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