Abnormal production of androgens in women with breast cancer

G Secreto; Zumoff B

General Gynecology · Breast Health

Abnormal production of androgens in women with breast cancer

Secreto G, Zumoff B

Published September 1994 Anticancer Research, 14(5B), 2113-2117

PMID 7840509

Abstract

Two long and broad streams of medical literature, from the 1950's to date, have established the existence of two unrelated abnormalities of androgen production in women with breast cancer. One is the genetically determined presence of subnormal production of adrenal androgens (i.e. DHEA and DHEAS) in women with premenopausal breast cancer and their sisters, who are at increased risk for breast cancer. The other is excessive production of testosterone, of ovarian origin, in subsets of women with either premenopausal or postmenopausal breast cancer and women with atypical breast-duct hyperplasia, who are at increased risk for breast cancer; along with the hypertestosteronism, there is frequently chronic anovulation in the premenopausal patients. The combination of ovarian hypertestosteronism and chronic anovulation is characteristic of the polycystic ovary syndrome and is also frequently seen in women with abdominal ("android") obesity; both PCOS and abdominal obesity are known to be characterized by high risk for postmenopausal cancer. The elevated testosterone levels and the increased levels of insulin, IGF-I, and IGF-II that are seen in PCOS and abdominal obesity could favor the development of breast cancer in several ways, all of which have been demonstrated experimentally: binding of testosterone to cancer cells bearing testosterone receptors, with direct stimulation; intratissular aromatization of testosterone to estradiol, with stimulation of estrogen-sensitive cells; stimulation of the production of epithelial growth factor (EGF) by testosterone, with direct mitogenic effect of EGF on cancer cells; stimulation of aromatase by insulin and IGF-I; direct mitogenic stimulation of cancer cells by insulin, IGF-I, and IGF-II; and stimulation by IGF-I and IGF-II of the intratissular reduction of estrone to estradiol. Since PCOS is probably largely genetically determined, and abdominal obesity may also be, the hypertestosteronism of these conditions may represent a second genetically determined hormonal risk factor for breast cancer.

Topics

By this author

Breast Health · Breast Cancer Risk

Increased androgenic activity and breast cancer risk in premenopausal women

Secreto G et al., 1984 Cancer Res

Blood and urine specimens from 27 premenopausal breast cancer patients and 62 healthy controls have been compared with respect to concentration of testosterone and progesterone in blood and of testosterone and androstanediol in urine, measured in the luteal phase of the menstrual cycle. There was a strong positive association between the concentration of the two androgens, either in blood or urine, and breast cancer risk. A strong association was also observed with decreasing levels of progesterone. The association was statistically significant (p for trend less than 0.01) for each hormone; the rate ratios were 10.2 for serum testosterone (highest category), 5.6 for serum progesterone (lowest category), 8.4 for urinary testosterone (highest category), and 5.2 for androstanediol (highest category). The rate ratio for women presenting both high serum testosterone and low progesterone was 21.8 (4.1 to 116.1). Considering the exposure to at least one of three androgens at the highest level and low progesterone, the rate ratio was as high as 90.2 (8.2 to 989.7). This study provides evidence for the hypothesis that increased androgenic activity is an important risk indicator for breast cancer, particularly when associated with anovulation, as indicated by low serum progesterone level.

Breast Health · Breast Cancer Risk

High testosterone and low progesterone circulating levels in premenopausal patients with hyperplasia and cancer of the breast

Secreto G et al., 1984 Cancer Res

Serum testosterone, progesterone, luteinizing hormone, prolactin, and sex hormone-binding globulin levels were measured in 55 normal controls, in 31 patients with hyperplastic alterations of breast epithelium, and in 23 patients with breast cancer. All patients and controls were premenopausal, and they were comparable for age, weight, and body surface. In the controls, the mean level of testosterone [0.47 +/- 0.16 (S.D.) ng/ml] was lower and the mean level of progesterone (17.63 +/- 8.11 ng/ml) was higher than in breast cancer patients [testosterone level, 0.62 +/- 0.22 ng/ml (p less than 0.005); progesterone level, 11.4 +/- 8.0 ng/ml (p less than 0.005)] and in patients with breast epithelial hyperplasia [testosterone level, 0.55 +/- 0.2 ng/ml (p less than or equal to 0.05); progesterone level, 13.9 +/- 8.6 ng/ml (p less than 0.05)]. No difference was found in the mean circulating levels of luteinizing hormone, prolactin, or sex hormone-binding globulin between controls and patients. These results confirm previous findings of increased urinary testosterone excretion in women with anovulatory menstrual cycles and epithelial hyperplasia or cancer of the breast and strongly support the hypothesis that androgens play an important role in both induction and development of breast cancer.

Breast Health · Breast Cancer Risk

Androgen excretion in women with a family history of breast cancer or with epithelial hyperplasia or cancer of the breast

Secreto G et al., 1983 Eur J Cancer Clin Oncol

Urinary testosterone and androstanediol were measured by gas chromatography in four groups of premenopausal 22 healthy women (control group), 21 healthy women with a family history of breast cancer (familiality group), 39 patients with breast lumps which consisted of ductal or lobular hyperplasia (hyperplasia group) and 18 patients with infiltrating breast carcinoma (carcinoma group). On the basis of normal values found in our laboratory, steroid levels were above normal in 4.5% of the controls, 4.7% of the familiality group, 38.5% of the hyperplasia group (P less than 0.01 vs controls) and 61.1% of the carcinoma group (P less than 0.001 vs control group). The mean testosterone level in the carcinoma group (11.3 +/- 6.78 S.D.) and the mean androstanediol level in the hyperplasia group (47.25 +/- 31.0 S.D.) were significantly higher than those of the control group (testosterone 6.25 +/- 3.48 S.D., androstanediol 32.55 +/- 20.0 S.D.). No significant difference was found in mean testosterone or androstanediol levels between the control group and the familiality group (testerone 5.41 +/- 3.6 S.D., androstanediol 29.38 +/- 15.89 S.D.). We conclude that increased excretion of androgenic steroids is a hormonal abnormality common to breast cancer patients and to patients with breast epithelial hyperplasia, but not to subjects with a family history of carcinoma of the breast.

Related research

Breast Health · Breast Cancer Risk

Nutrition, hormones, and breast cancer: is insulin the missing link?

Kaaks R, 1996 Cancer Causes Control

Breast cancer incidence rates are high in societies with a Western lifestyle characterized by low levels of physical activity, and by an energy-dense diet rich in total and saturated fat and refined carbohydrates. Epidemiologic studies, so far mostly on postmenopausal women, have shown that breast cancer risk is increased in hyperandrogenic women, with decreased levels of plasma sex-hormone binding globulin, and with increased levels of testosterone and of free estrogens. This paper describes the role of hyperinsulinemia as a physiologic link between nutritional lifestyle factors, obesity, and the development of a hyperandrogenic endocrine profile, and reviews evidence that may or may not support the theory that chronic hyperinsulinemia is an underlying cause of breast cancer. An hypothesis is presented, stipulating that breast cancer risk is increased not only in hyperandrogenic postmenopausal women, but also in premenopausal women with mild hyperandrogenism and normal (ovulatory) menstrual cycles. The author suggests further investigation as to whether there is a positive association between risk of breast cancer before menopause and subclinical forms of the polycystic ovary syndrome (PCOS), and to what extent diet and physical activity during childhood, by modulating the degree of insulin resistance during adolescence, may or may not be determinants of a PCO-like hyperandrogenic endocrine profile persisting into adulthood.

Gynecologic Oncology · Endometrial Cancer

Hyperinsulinemia and stromal luteinization of the ovaries in postmenopausal women with endometrial cancer

Nagamani M et al., 1988 J Clin Endocrinol Metab

Ovarian secretion of testosterone and androstenedione is increased in postmenopausal women with endometrial cancer, and insulin stimulates ovarian stromal androgen synthesis in vitro. We undertook this study to investigate whether women with endometrial cancer have increased serum immunoreactive insulin levels. Ten postmenopausal women with endometrial carcinoma and 10 postmenopausal women without cancer who matched the cancer patients in age, years since menopause, and percentage of ideal body weight were studied. The women with endometrial cancer had significantly higher fasting serum insulin levels than the normal women [mean, 187 +/- 26 (+/- SE) vs. 55 +/- 11 pmol/L; P less than 0.01]. The cancer patients had significantly higher insulin responses after glucose administration than normal women (sum of 1, 2, and 3 h postglucose values, 5545 +/- 1526 vs. 1444 +/- 156 pmol/L; P less than 0.02), even though their glucose responses were similar. Nests of luteinized cells, which were positive for testosterone by immunoperoxidase staining, were found in the ovarian stroma of 8 of the women with endometrial cancer, but in only 1 of those without cancer (P less than 0.01). Specific high affinity insulin receptors were demonstrable in the stroma of the postmenopausal ovaries. These results suggest that the frequency of stromal luteinization is increased in women with endometrial cancer and that insulin may play a role in the pathogenesis of this luteinization.

Breast Health · Breast Cancer Risk

Re: "Polycystic ovaries and the risk of breast cancer"

Toniolo P et al., 1992 Am J Epidemiol

Gammon and Thompson (1) recently reported in the Journal the results of an analysis of data from the Center for Disease Control's Cancer and Steroid Hormones Study to examine the association between a history of physician-diagnosed polycystic ovaries and the risk of breast cancer. Despite the small number of exposed cases (n =23) and controls (nm 44), their data strongly support the conclusion that a history of polycystic ovaries protects against premenopausal and carly postmenopausal breast cancer. These results are in apparent conflict with those reported in a previous cohort study by Coulam et al. (2), who found a threefold increase in postmenopausal breast cancer in women with polycystic ovaries. Such discrepancy may reflect real, albeit unexplained differences between premenopausal and postmenopausal women in the influence of endogenous hormones on breast cancer.

Breast Health · Breast Cancer Risk

Polycystic ovaries and the risk of breast cancer

Gammon MD et al., 1991 Am J Epidemiol

Data from a case-control study that was conducted between 1980 and 1982 were analyzed to investigate the possible association between polycystic ovaries and the risk of breast cancer. The multicenter, population-based study included in-home interviews with 4,730 women with breast cancer and 4,688 control women aged 20-54 years. The age-adjusted odds ratio for breast cancer among women with a self-reported history of physician-diagnosed polycystic ovaries was 0.52 (95% confidence interval 0.32-0.87). The inverse association was not an artifact of infertility, age at first birth, or surgical menopause. Because women with this syndrome have abnormal levels of certain endogenous hormones, the observation of a low risk of breast cancer in this group may provide new insights into hormonal influences on breast cancer.

General Gynecology › Breast Health › Breast Cancer Risk · Reproductive Endocrinology › Ovarian Hormones › Androgens · PMOS / PCOS › Pathophysiology › Hyperandrogenism

PMID 7840509 7840509 Secreto et al. 1994, Secreto 1994

Cite this article

Secreto, G., & Zumoff, B. (1994). Abnormal production of androgens in women with breast cancer. Anticancer research, 14(5B), 2113-2117.

Keywords

Adrenal Glands/metabolism, Androgens/biosynthesis, Breast Neoplasms/metabolism, Female, Humans, Ovary/metabolism, Polycystic Ovary Syndrome/metabolism, Testosterone/biosynthesis, Androgens, Testosterone