Relationship of Obesity to Blood Estrogens1

It has become conventional wisdom that estrogenic stimula tion of breast tissue has something to do with the causation of breast cancer and that the reason obesity is a risk factor for breast cancer is that obese women are hyperestrogenized. However, it has been very difficult to demonstrate that exces sive exogenous estrogen increases the incidence of breast cancer, that endogenous estrogen excess is present in breast cancer, or that obese women are hyperestrogenized. We have examined the last question by measuring 24-hr mean plasma estrone and estradiol levels in the midfollicular phase in 18 healthy, regularly cycling, very obese (53 to 218% above ideal weight) women and 16 regularly cycling, age matched, nonobese control women. Unlike obese men, the obese women showed no significant elevation of either estrone or estradiol. Their average estrone level was 72 compared with 64 pg/ml in controls; their average estradiol level was 65 compared with 57 pg/ml in controls. In the combined group (obese plus nonobese), there was a significant correlation of percentage of deviation from ideal weight with plasma estrone (y = 63 + 0.12x; p < 0.05) but not with estradiol. This correlation sup ports the current hypothesis that there is increased androstenedione —¿ » estrone conversion (i.e., increased aromatase activity) in obesity. The reason plasma estrone levels are not significantly elevated in obese women is that the small amount derived from androstenedione is swamped by the much larger amount derived from ovarian secretion, which is apparently unaffected by obesity. Unless there is increased local formation of estrogens in the breast tissue of obese women, the absence of elevated plasma estrogens in them means that their breasts are not "seeing" increased estrogen levels. Thus, endogenous hyperestrogenization is unlikely to be a causative factor of breast cancer in obese women. The facts that the normal female breast is responsive to estrogenic stimulation, that the growth of breast cancer may be accelerated by increased endogenous estrogen (as in preg nancy) or by administration of exogenous estrogen, and that breast cancer may regress when endogenous estrogen is decreased (by oophorectomy) or antagonized (by antiestrogens) have led to the concept that an increased level of endogenous estrogenic stimulation may be a major factor in the development of breast cancer (the "estrogen hypothesis"). It should be emphasized, however, that the background facts relate to already existing cancer; thus, the notion of a relation ship of increased estrogen levels to the development of breast cancer represents a conceptual leap of considerable magni' Presented at the Conference "Aromatase: New Perspectives for Breast Cancer," December 6 to 9, 1981, Key Biscayne, Fla. This work was supported by Grants RR-53, HL-14734, CA-07304, and CA-22795 from the NIH and Contract F-496270-79-C-0136 from the United States Air Force Office of Sci entific Research. tude. To be sure, breast cancer can be produced in susceptible animals by the administration of estrogens, but there is no clear-cut evidence of increased estrogenicity in human female breast cancer (47), and the evidence that estrogen administra tion increases the incidence of human breast cancer is uncon vincing (25, 44). Some workers (20) have reported increased estrogenicity in women at risk for familial breast cancer, but others (5, 15, 35) have not confirmed this finding. What I will discuss is the evidence for increased estrogenicity in obese women, who some workers (6,11, 34) believe are at increased risk for breast cancer, although others (1, 46) disagree. The simplest version of the "estrogen hypothesis" invokes an increase in the level of the primary estrogen, estradiol, but several more complex variants of the hypothesis have been proposed: 1. Excess of a particular estrogen metabolite may be the culprit. One version of this is the "estrone hypothesis" pro mulgated by Siiteri ef al. (41), which was initially developed with respect to endometrial cancer and was later extended to breast cancer. This hypothesis was based on the notion that estrone is carcinogenic, while other estrogens are not. Since estrone formation is said to be increased in obese women (13, 18), the estrone hypothesis would account for an increase of breast cancer in these women. However, recent pharmacolog ical studies (3, 16) have demonstrated clearly that both the estrogenic and carcinogenic effects of estrone are quantita tively and qualitatively essentially indistinguishable from those of estradiol or estriol; therefore the estrone hypothesis appears to be untenable at this time, regardless of whether estrone formation is indeed increased in obesity, a point to which I will return. A second version of this variant is the "abnormal metabolite hypothesis" proposed by Oilman ef al. (12), based on findings of increased urinary excretion of uncharacterized "estrogen metabolites" in women with breast cancer. Nothing further has been published in this area. 2. An imbalance between harmful estrogen metabolites (es trone and estradiol) and a protective estrogen metabolite (es triol) may be the culprit. This is the "estriol hypothesis," which is associated with Lemon ef al. (31) and Cole and MacMahon (8). This variant too has been rendered untenable by the recent comparative pharmacological studies of estrone, estradiol, and estriol mentioned above, and Cole has abandoned it (7). 3. An imbalance between the harmful effects of estrogen and the protective effects of progesterone may be the culprit. The initial version of this variant was the "anovulation-luteal inade quacy hypothesis" proposed by Sherman and Korenman (40), which is based on evidence that women with a variety of risk factors for cancer have in common a high incidence of frequent or chronic anovulation and/or luteal inadequacy and therefore a subnormal progesterone/estrogen ratio. The existence of an increased incidence of anovulation and/or luteal inadequacy in women with breast cancer has been supported by the