Estrogen production and action,☆☆,,★★

https://doi.org/10.1067/mjd.2001.117432Get rights and content

Abstract

Estradiol production is most commonly thought of as an endocrine product of the ovary; however, there are many tissues that have the capacity to synthesize estrogens from androgen and to use estrogen in a paracrine or intracrine fashion. In addition, other organs such as the adipose tissue can contribute significantly to the circulating pool of estrogens. There is increasing evidence that in both men and women extraglandular production of C18 steroids from C19 precursors is important in normal physiology as well as in pathophysiologic states. The enzyme aromatase is found in a number of human tissues and cells, including ovarian granulosa cells, the placental syncytiotrophoblast, adipose and skin fibroblasts, bone, and the brain, and it locally catalyzes the conversion of C19 steroids to estrogens. Aromatase expression in adipose tissue and possibly the skin primarily accounts for the extraglandular (peripheral) formation of estrogen and increases as a function of body weight and advancing age. Sufficient circulating levels of the biologically active estrogen estradiol can be produced as a result of extraglandular aromatization of androstenedione to estrone that is subsequently reduced to estradiol in peripheral tissues to cause uterine bleeding and endometrial hyperplasia and cancer in obese anovulatory or postmenopausal women. Extraglandular aromatase expression in adipose tissue and skin (via increasing circulating levels of estradiol) and bone (via increasing local estrogen concentrations) is of paramount importance in slowing the rate of postmenopausal bone loss. Moreover, excessive or inappropriate aromatase expression was demonstrated in adipose fibroblasts surrounding a breast carcinoma, endometriosis-derived stromal cells, and stromal cells in endometrial cancer, giving rise to increased local estrogen concentrations in these tissues. Whether systemically delivered or locally produced, elevated estrogen levels will promote the growth of these steroid-responsive tissues. Finally, local estrogen biosynthesis by aromatase activity in the brain may be important in the regulation of various cognitive and hypothalamic functions. The regulation of aromatase expression in human cells via alternatively used promoters, which can be activated or inhibited by various hormones, increases the complexity of estrogen biosynthesis in the human body. Aromatase expression is under the control of the classically located proximal promoter II in the ovary and a far distal promoter I.1 (40 kilobases upstream of the translation initiation site) in the placenta. In skin, the promoter is I.4. In adipose tissue, 2 other promoters (I.4 and I.3) located between I.1 and II are used in addition to the ovarian-type promoter II. In addition, promoter use in adipose fibroblasts switches between promoters II/I.3 and I.4 upon treatments of these cells with PGE2 versus glucocorticoids plus cytokines. Moreover, the presence of a carcinoma in breast adipose tissue also causes a switch of promoter use from I.4 to II/I.3. Thus there can be complex mechanisms that regulate the extraglandular production of estrogen in a tissue-specific and state-specific fashion. (J Am Acad Dermatol 2001;45:S116-24.)

Section snippets

Aromatase expression in adipose tissue

Hemsell et al8 first addressed the significance of human adipose tissue as a major source of estrogen production and demonstrated that in both women and men with advancing age, there is a progressive increase in the efficiency with which circulating androstenedione is converted to estrone. The authors and others27, 28 have subsequently shown that this age-related elevation of peripheral estrogen formation is associated with increases in both aromatase activity and mRNA levels in the adipose

Aromatase expression in skin

Aromatase expression in skin fibroblasts might account for a significant portion of peripheral estrogen formation in postmenopausal women. The relationship between peripheral aromatization and body weight is highly suggestive of a significant role of adipose tissue in this process. However, an increase in weight results in an increase of body surface area; thus it is very difficult to accurately estimate the relative contributions of skin and adipose tissue on extraglandular estrogen formation.

Aromatase expression in bone

It is tempting to speculate that postmenopausal bone loss may be modified by levels of local aromatase activity in bone. In fact, aromatase expression has been demonstrated in osteoblasts and chondrocytes from both fetal and adult bone tissues.15, 16 Conversely, another group of investigators45 failed to demonstrate aromatase mRNA in normal bone tissue from the femoral neck. Aromatase expression in cultured osteoblastic cells seems to be regulated by glucocorticoids and cytokines primarily via

Aromatase expression in brain

Several recent studies12 suggest estrogen replacement in postmenopausal women improves cognition, reduces the risk of developing dementia, and reduces the severity of existing dementia. This raises a question as to the significance of local estrogen formation because aromatase is expressed in many regions of the brain.9, 11, 48 Aromatase expression in brain tissue of birds and rodents regulates the activation of sexual behavior.9, 13, 14 Although aromatase is expressed in many sites and cell

Aromatase deficiency states

Until the 1990s, aromatase deficiency was considered incompatible with life; this belief may have inhibited the investigation of this diagnosis in suspected cases. After the first description in 1991 of a Japanese newborn girl with an aromatase P450 (P450arom) gene defect,50, 51 there have been several recent reports in world literature describing aromatase deficiency.3, 50, 52, 53, 54 Convincingly, estrogen biosynthesis in all these patients was virtually absent, giving rise to a number of

Estrogen receptors

Estrogen action in most tissues is mediated through the estrogen receptor (ER), a member of a large superfamily of nuclear receptors that function as ligand-activated transcription factors.60 These receptor proteins share a common structural and functional organization, with distinct domains that are responsible for ligand binding, DNA binding, and transcriptional activation. There are 2 forms of the ER that have been identified: the initially cloned ERα and the more recently cloned ERβ.61 In

Summary

Aromatase is a key enzyme for estrogen formation in human tissues. In women of reproductive age, the ovarian granulosa cells are important sites of estrogen formation for local use within the ovary as well as for endocrine signaling to a host of tissues, including the uterus, skin appendages, brain, bone, vascular system, and breast. However, there is an increasing awareness of the importance of local production of estrogens from precursor androgens within these target tissues themselves. This

Acknowledgements

We thank Margarita Guerrero for her expert editorial assistance.

References (63)

  • Y Zhao et al.

    Aromatase P450 gene expression in human adipose tissue: role of a Jak/STAT pathway in regulation of the adipose-specific promoter

    J Biol Chem

    (1995)
  • J Wei et al.

    Increase of plasma IL-6 concentration with age in healthy subjects

    Life Sci

    (1992)
  • N Harada

    A unique aromatase (P-450AROM) mRNA formed by alternative use of tissue-specific exons 1 in human skin fibroblasts

    Biochem Biophys Res Commun

    (1992)
  • CK Lea et al.

    Aromatase cytochrome P450 transcripts are detected in fractured human bone but not in normal skeletal tissue

    Bone

    (1997)
  • N Harada et al.

    Biochemical and molecular genetic analyses on placental aromatase (P450arom) deficiency

    J Biol Chem

    (1992)
  • A Cagnacci et al.

    Effects of low doses of transdermal 17β-estradiol on carbohydrate metabolism in postmenopausal women

    J Clin Endocrinol Metab

    (1992)
  • C Caranci et al.

    Effect of testosterone and estradiol in a man with aromatase deficiency

    N Engl J Med

    (1997)
  • A Morishima et al.

    Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens

    J Clin Endocrinol Metab

    (1995)
  • EP Smith et al.

    Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man

    N Engl J Med

    (1994)
  • ER Simpson et al.

    Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis

    Endocrinol Rev

    (1994)
  • JM Grodin et al.

    Source of estrogen production in postmenopausal women

    J Clin Endocrinol Metab

    (1973)
  • PC MacDonald et al.

    Origin of estrogen in normal men and in women with testicular feminization

    J Clin Endocrinol Metab

    (1979)
  • DL Hemsell et al.

    Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age

    J Clin Endocrinol Metab

    (1974)
  • J Balthazart et al.

    Identification of catecholaminergic inputs to and outputs from aromatase-containing brain areas of the Japanese quail by tract tracing combined with tyrosine hydroxylase immunocytochemistry. European Graduate School for Neurosciences, University of Liege, Laboratory of Biochemistry, Belgium

    J Comp Neurol

    (1997)
  • K Yaffe et al.

    Estrogen in postmenopausal women: effects on cognitive function and dementia

    JAMA

    (1998)
  • CR Fisher et al.

    Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the CYP19 gene

    Proc Natl Acad Sci U S A

    (1998)
  • H Sasano et al.

    Aromatase in human bone tissue

    J Bone Miner Res

    (1997)
  • LS Noble et al.

    Aromatase expression in endometriosis

    J Clin Endocrinol Metab

    (1996)
  • SE Bulun et al.

    CYP19 (aromatase cytochrome P450) gene expression in human malignant endometrial tumors

    J Clin Endocrinol Metab

    (1994)
  • SE Bulun et al.

    A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription

    J Clin Endocrinol Metab

    (1993)
  • VHT James et al.

    Regulation of estrogen concentrations in human breast tissues

    Ann NY Acad Sci

    (1990)
  • Cited by (593)

    View all citing articles on Scopus

    This article is part of a supplement whose publication was supported by an unrestricted educational grant from Pharmacia Consumer Healthcare.

    ☆☆

    Supported in part by National Institutes of Health grants CA67167 and HD37108 and USAMRMC grant DAMD17-97-1-7025 (to S. E. B.).

    Disclosure: The authors attest that they have no conflicts of interest to disclose.

    ★★

    Reprint requests: Linda R. Nelson, MD, PhD, Department of Obstetrics-Gynecology, University of Illinois at Chicago, 820 S Wood St, M/C 808, Chicago, IL 60612. E-mail: [email protected].

    View full text