[CANCER RESEARCH 38, 4029-4035, November 1978] 0008-5472/78/0038-0000$02.00 Androgen-Estrogen Production Rates in Postmenopausal Women with Breast Cancer1

Marvin A. Kirschner,2 Frederick B. Cohen, and Catherine Ryan

Newark Beth Israel Medical Center, New Jersey Medical School, Newark, New Jersey 07112

Abstract as playing a promoting role in the genesis of human breast cancer, previous studies of estrogen excretion and endog In an attempt to define the hormonal environment of enous estrogen production rates in women with breast women with breast cancer, we examined the blood pro cancer have not shown consistent abnormalities (1, 2, 9, duction rates of androstenedione and its contributory role 11, 13, 15-18, 22, 24, 29, 32). In the current study we have as a prehormone of estrone in a group of 46 postmeno- explored both estrone production rates and the contribu pausal women with advanced metastatic breast cancer. tory role of its major prehormone, androstenedione, in a Androstenedione blood production rates averaged 1.85 group of 46 postmenopausal women with advanced breast mg/day and were not significantly different from 9 age- cancer. Whereas estrone production rates were not abnor matched women with other neoplasms or from 4 noncan- mal in women with breast cancer, a significant proportion cer controls. Similarly, blood production rates of estrone of estrone produced in these patients arose from sources were not significantly different, averaging 56.9 /¿g/dayin other than androstenedione. women with breast cancer compared with 43.9 and 41.8 pig/day in the control groups. The blood transfer con stants (/>íj¡)wereagain similar in the breast cancer Patients women versus the 2 control groups (2.13% versus 2.35 and Forty-six postmenopausal women with advanced meta 2.74%, respectively). Despite the similar magnitude of androstenedione, es static breast cancer were studied before or between trone production rates, and transfer constants, andros courses of systemic chemotherapy. All women had under tenedione conversion to estrone accounted for only 72% gone natural menopause (no menses for 2 years) or had of the total estrone production rate in women with breast experienced surgically induced menopause prior to the cancer versus 92 and 95% in the 2 control groups. These discovery of their breast cancer. None of the patients had differences were significant at P < 0.05. undergone endocrine-ablative surgery (except oophorec- As part of these studies, we noted that 14 of 46 women tomy in the distant past for unrelated reasons), and no with breast cancer exhibited unusually high metabolic systemic endocrine therapy was used for at least 6 months clearance rates of estrone ranging from 2600 to 5400 prior to these studies. Nine age-matched women with metastatic carcinomas liters/day. These women could not be differentiated from other breast cancer patients on clinical grounds. Five originating from sites other than the breast served as patients had elevated clearance rates of androstenedi cancer controls, and 4 postmenopausal women recuperat ing from non-cancer-related illnesses, excluding hepatic one, but testosterone and estradici clearance rates were not abnormal. Patients with the high metabolic clearance and cardiac disorders, served as noncancerous controls. rates of estrone had lower plasma estrone concentrations Informed consent was obtained from each patient prior so that blood production rates were similar to those noted to her entry into the study. The studies were performed in breast cancer patients with normal clearances. The between 8 and 10 a.m., in the fasting state, and before the differences in metabolic clearance rates were not associ patient arose from her overnight supine position. ated with changes in the binding protein, sex hormone- binding globulin. Methods We concluded that androstenedione production rates MCR's.3 During the initial phase of this study, MCR's of and conversion to estrone are normal in postmenopausal women with breast cancer and that estrone production androstenedione and estrone were determined sequen tially. [3H]Androstenedione was infused at a rate of approx rates are normal in these women, yet that approximately 30% of estrone produced in postmenopausal women with imately 50 /nCi/hr following a 10% loading dose given 30 breast cancer comes from source(s) other than prehor- min prior to the onset of the infusion. A Bowman constant monal androstenedione. infusion pump was calibrated to deliver approximately 1.5 to 1.8 ml of infusion solution per min. Blood samples were Introduction drawn distant to the infusing site at 60, 75, and 90 min. Immediately following the androstenedione infusion, a 10% Although estrogenic hormones have long been suggested loading dose of [3H]estrone was given and the second infusion of [3H]estrone (15 /¿Ci/hr)wasbegun, with samples 1 Presented at the John E. Fogarty International Center Conference on Hormones and Cancer, March 29 to 31, 1978, Bethesda, Md. Supported by USPHS Grant CA-14296. 3The abbreviations used are: MRC, metabolic clearance rate; superscript 2 To whom requests for reprints should be addressed at: Newark Beth or subscript E,, E2, A, and T, estrone, estradiol, androstenedione, and Israel Medical School, 201 Lyons Ave.. Newark, N. J. 07112. testosterone, respectively; SHBG, sex hormone-binding globulin.

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Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1978 American Association for Cancer Research. M. A. Kirschner et al. taken at 60, 75, and 90 min. These sequential infusion estrone and estradiol fractions were then methylated, and studies took approximately 4 hr. the methyl ethers were purified on thin-layer chromatogra Because of patient discomfort associated with the pro phy with benzene:ethyl acetate (80:20). Appropriate ali- longed infusion times, subsequent studies were performed quots following each purification step were again taken for as a single infusion with a combination of 80 /uCi counting. [3H]androstenedione and 4 /¿ciof [14C]estrone. This latter Radioactivity was determined in each sample with a procedure, taking approximately 120 min, was better toler Packard Model 3380 liquid scintillation counter. Samples ated by the patients. The blood samples obtained in lightly were counted to accumulate approximately 10,000 3H and heparinized syringes were immediately centrifuged, and the 14Ccounts. In general, each sample was counted for 50 to plasma was stored at -15°for work-up at a later time. 100min. Sample Purification. For the sequential studies, 10-ml For the simultaneous infusion studies, approximately portions of plasma taken at the various infusion times were 1500 cpm of [14C]testosterone and [14C]androstenedione used. Approximately 1500 cpm of ['"CJandrostenedione, were added to each plasma sample prior to extraction. [14C]testosterone, [14C]estrone, and [14C]estradiol were Since the estrogen fractions contained both 3H and 14Cla added to each plasma sample to monitor procedural losses bels, approximately 500 /¿gofunlabeled estrone were used and to serve as markers to determine the purity of the as a mass marker to monitor recovery. Samples were ex plasma extracts. For work-up of the [3H]estrone infusions, tracted and subsequently worked up as described above; only [14C]estrone and [14C]estradiol were added to the however, for determination of estrone and estradiol recov plasma samples. To each tube were added 50 to 100 /xg of ery, samples were estimated for their mass with a Beck- unlabeled androstenedione, testosterone, estrone, and es- mann spectrophotometer, after the method of Longcope tradiol to simplify the recovery procedure. (C. Longcope, personal communication). Plasma samples were extracted 3 times with equal vol Plasma concentrations of androstenedione, testosterone, umes of ether. The combined extracts were washed twice estrone, and estradiol were estimated from blood samples with 0.1 volume of water and dried. Separation of neutral taken overa 10-min period prior to the onset of the infusion. from phenolic fractions was accomplished by toluene: 1 N Androstenedione and testosterone were measured by ra- NaOH partition, with the use of countercurrent procedure dioimmunoassay, as previously reported (12). Estrone was involving 3 sequential separatory funnels. The toluene lay measured by radioimmunoassay according to the method ers following these partitions were combined, washed twice of Longcope ef a/. (21). Estradiol was measured by a with 0.1 volume of water, dried over sodium sulfate, and specific estradiol antibody provided by Dr. D. L. Loriaux. filtered, and the extracts were dried. Preliminary purifica Preliminary purification of the estrogens was accomplished tion of the samples was achieved by means of thin-layer by using Sephadex LH-20 chromatography of the ether chromatography with benzene:ethyl acetate (65:35). Tes extract in each case. tosterone fractions were separated from androstenedione Equilibrium dialysis of plasma samples was performed fractions in this system. The testosterone and androstene after the method of Chopra ef al. (6) with a 1:5 dilution of dione fractions were separately eluted with ethyl acetate, plasma. and the dried eluates were acetylated with 10 drops of acetic acid and 5 drops of pyridine left overnight at room temperature. The acetates formed were further separated Results on the thin-layer system with benzene:ethyl acetate (90:10). Metabolic Clearance Rates The testosterone acetate and androstenedione fractions were purified further by forming methoxime derivatives by Estrone. The mean MCRKl was 2420 liters/day in our adding a few crystals of methoxyamime hydrochloride and breast cancer patients, as noted in Chart 1. This value was 3 drops of pyridine. The methoxime derivatives were chro- somewhat higher than the 1955 liters/day and 1820 liters/ matographed in the thin-layer system benzene:ethyl acetate day noted in our non-breast cancer and noncancerous (80:20). Aliquots (20%) of the eluates following each of the control patients, although the differences were not signifi 3 thin-layer chromatography steps were taken for counting. cant. On closer inspection of the MCRK] values, we were Samples were considered "pure" when constancy of 3H:14C struck with several extraordinarily high values observed in ratios were obtained (usually after the second thin-layer some of our breast cancer patients. Indeed, 14 of the 46 chromatography). women with breast cancer exhibited MCRKl in excess of The phenolic fraction following the toluene:NaOH parti 2600 liters/day ranging up to 5400 liters/day. This group of tion was neutralized to pH 5.5 with glacial acetic acid. The women with extraordinarily high clearance rates of estrone estrogens were extracted twice with equal volumes of ether, was separately analyzed as Subgroup 2 (Table 1). They had and the ether extracts were washed with 0.1 volume of a mean MCRKl of 3550 liters/day, which was significantly water and dried. These fractions were further purified by higher than the mean MCRKl of 1760 liters/day observed in formation of acetates as above, and separation of the the remaining 24 breast cancer women. Unfortunately, we acetates in the thin-layer system benzene:ethyl acetate could identify no unusual clinical features of the women (90:10). The dried thin-layer eluates were then saponified with high MCREl versus those with normal MCREl. The ages with 0.5 ml of 0.15 N NaOH in 80% methanol overnight, and of the women, duration and extent of metastatic disease, the saponified estrogens were then chromatographed in and drug history were similar for breast cancer patients the thin-layer system benzene:ethyl acetate (65:35). The with both high and low clearance rates. There was more

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6000 r values of 88 and 94 ng/100 ml in the 2 groups of control patients. As noted above, the women with higher clearance rates of estrone had slightly lower values of plasma andros tenedione averaging 81 ng/100 ml versus 92 ng/100 ml in the breast cancer patients with normal clearance rates.

4000 Blood Production Rates Estrone. The mean blood production rate of estrone 3000 S -i (P,,E.)was 56.9 ng/day in women with breast cancer com pared with mean values of 43.9 and 41.8 /¿g/dayin the

BREAST Co NON-BREAST HW-Ca the both groups were of similar magnitude. Ça Androstenedione. The mean blood production rate for Chan 1. Metabolic clearance rates of estrone in 46 women with breast androstenedione in the women with breast cancer was 1.85 cancer (Ca), in 9 women with non-breast cancer, and in 4 control patients mg/day, with no significant difference in production rates without cancer. L, liter. observed in Subgroups 1 versus 2. The values for P,,Awere obesity in the women with high MCRK|, with 13 of 14 women not different from those noted in women with other cancers having body weights of 160 to 200 pounds. By contrast the or without cancer. women with normal estrone clearance rates had a lesser frequency of obesity; however, none of the women in our Steroid Interconversions study was grossly obese (over 220 pounds). Androstenedione. The mean MCR¿inour 46 women with Conversion of Androstenedione to Testosterone. The breast cancer was 2220 liters/day, not significantly different blood conversion rate of androstenedione to testosterone from the 2 control groups. Five women had had MCR¿in averaged 7.81% in breast cancer women versus 7.93 and excess of 2800 liters/day, 3 of whom also had high MCRKl. 8.05 in the 2 groups of control women. These differences The mean MCR¿ofthe breast cancer Groups 1 and 2 were were not significant. 2130 versus 2500 liters/day and were not statistically signif Conversion of Estrone to Estradiol. The conversion of icant from each other or from the control patients. estrone to estradiol wa 7.51% in women with breast cancer Estradici. In a separate group of 8 women with postmen- versus 6.88% in the women with cancers at other sites. Only opausal breast cancer of similar degree, metabolic clear 2 values were available in the noncancerous controls, 10.3 ance rates of estradici and testosterone were determined to and 4.2%. see whether any elevations of clearance existed for these Conversion of Androstenedione to Estrone. The blood hormones. The mean MCRK, was 1620 ±300 (S.D.) liters/ transfer constant (p) of androstenedione to estrone was day. The highest clearance rate for estradiol was 2215 determined from the expression: liters/day, comparing favorably with values reported by Longcopeef al. (21). Testosterone. In the 8 women with metastatic breast cancer, the mean MCR, was 724 liters/day. Two women where C-iKl is the conversion rate of infused tracers. In had clearance rates of 930 and 1050 liters/day, respectively, women with breast cancer the pAKl was 2.13% compared whereas the remainder of the group had values in the range with mean values of 2.35 and 2.74% in the control groups. of 500 to 700 liters/day. The mean value for the group was Within the group of breast cancer women, those with high not statistically different from previous values reported in metabolic clearance rates of estrone had somewhat higher young premenopausal women (14). pAElvalues (2.34%) compared with 1.96% in those women with normal MCRKl. The differences between groups and Plasma Steroid Concentrations within the breast cancer women were not statistically signif icant. Estrone. Plasma estrone averaged 2.5 ng/100 ml, not significantly different versus the 2 groups of control women. Of interest, the subgroup of breast cancer women Origin of Estrone with high MCRK] exhibited somewhat lower plasma estrone values averaging 1.8-ng values versus 2.9 ng/100 ml in the The contributory role of androstenedione (A) to the blood production rate of estrone (E,) was determined in each women with normal MCREl. women from the expression: Androstenedione. Plasma androstenedione averaged 89 ng/100 ml in the women with breast cancer versus mean Contribution A to E, = P„AxpAl:'/P/'

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4032 CANCER RESEARCH VOL. 38

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1978 American Association for Cancer Research. Androgen-Estrogen Production Rates where P,,A is the blood production rate of androstenedione, with normal estrone clearance rates. These values were not P/1 is the blood production rate of estrone and pAK>isthe statistically significant from each other. As for estrone blood transfer constant. The values are displayed in Chart binding affinity, breast cancer women exhibited slightly 2. In both groups of women with breast cancer (high higher dialyzable fractions compared with the control MCREl and normal MCREl), 68 and 76% of their blood groups, but again there was no difference in dialyzable estrone production rate arose from peripheral metabolism fractions in those breast cancer patients with high clear of androstenedione. By contrast, in both control groups ance rates versus normal clearance rates for estrone. No virtually all their estrone production rate arose from periph significant differences in dialyzable fractions existed for eral transformation of androstenedione. These differences estradiol or for androstenedione in the varying groups. It were statistically significant at p < 0.05. was thus apparent that the differences noted in metabolic clearance rates could not be explained by alterations in the Dialyzable Fractions of Plasma Androgens and Estrogens sex hormone-binding protein.

In view of the subgroup of breast cancer patients with Discussion unusually high clearance rates of estrone, we wished to examine the binding of various androgens and estrogens to A large body of circumstantial evidence from the areas of their carrier protein, SHBG. We thus set up dialysis cells epidemiology, experimental biology, and clinical medicine after the method of Chopra to determine the dialyzable suggests that estrogens are important in the genesis of fraction of testosterone, estrone, and estradici as well as human breast cancer (13,15-18, 22, 32). Indeed, if estrogen that of androstenedione (a control C,9 androgen with no production and/or metabolism were found to be abnormal appreciable binding affinity for SHBG). These values are in women with breast cancer, these findings might be of shown in Table 1. The dialyzable testosterone fraction was great potential significance as a possible attack point for 2.80% in the breast cancer women versus 1.87 to 2.18 in the prevention of the disease. Unfortunately, previous stud the control groups, respectively. Within the breast cancer ies of estrogen production and urinary estrogen metabolites patients, those women with high MCREl exhibited slightly in women with breast cancer have been equivocal and higher values, with a mean of 3.08% versus 2.68% in women conflicting. The epidemiological data of MacMahon et al. (23) and Dickinson ef al. (7) showing differing ratios of ANDROSTENEDIONE PRODUCTION urinary estriol versus estrone and estradiol in women at differing risks for breast cancer probably reflect differing pathways of estrogen metabolism, since estriol production 2000 r rates were shown to be similar in women with high estriol ratios and low estriol ratios (20). Over the past 2 decades Bulbrook ef al. (3-5) reported 1500 - that women with established breast cancer who responded poorly to endocrine therapy as well as women destined to develop breast cancer excreted lesser amounts of urinary 1000 - 17-ketosteroid metabolites, androsterone, and etiocholan- olone. Subsequently, Poortman (25, 26) and Thijssen ef al. (30), reported lower production and excretion of dehydro- 500 --^1 epiandrosterone and its sulfate in women with breast can cer. These data suggesting a possible link between andro gen production and metabolism versus breast cancer were BREAST Co NON-CO unexpected since androgens were not thought to play an important role in the growth of breast tissue. It is now well appreciated that androgens serve as prehormones of estro gens (Chart 2). Indeed studies of Grodin et al. (8) and 75i- Longcope (19) and in our control patients have shown that virtually all estrogens made in postmenopausal women arise from prehormone metabolism to estrogens. We thus set out to test the hypothesis that women with breast cancer might metabolize androgens to estrogens to a greater degree than do normal women. This could result in greater production rates of estrogens, at levels still undetected by the less sensitive urinary estrogen excretion measurements. If women with breast cancer excrete less 17-keto-steroid metabolites because they convert more C,„prehormonesto ESTRONE PRODUCTION estrogens, these findings would relate Bulbrook's observa Chart 2. Androstenedione production rates, conversion to estrone, and estrone production rates in women with breast cancer (Ca), women with tions to abnormal estrogen production rates. non-breast cancer, and noncancerous controls. In women with breast This exciting hypothesis was, unfortunately, not con cancer, only 72% of the total estrone production arises from androstenedi one metabolism. By contrast, virtually all estrone produced in the control firmed by the data in this study. We found that androstene patients comes from androstenedione. See text for details. Bars, S.D. dione and estrone production rates were no different in

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Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1978 American Association for Cancer Research. M. A. Kirschner et al. women with breast cancer compared with 2 groups of occurred at a much earlier age and that with increasing age control patients; also, the conversion of androstenedione and debility, etc., these differences in estrogen production to estrone was not abnormal in women with breast cancer. may have become blunted so that they are no longer These data thus confirm earlier studies of Poortman ef al. discernible. It would seem that studies of prehormone (25, 26) in this respect. Our studies showed, however, that metabolism in high-risk groups must be done before this conversion of androstenedione to estrone accounts for only attractive hypothesis is entirely abandoned. 65 to 75% of the total blood production rate of estrone in women with breast cancer versus 92 and 95%, respectively, in the control groups. Thus, women with breast cancer References appear to have an extra source of estrone production not 1. Arguelles. Hoffman, C., and Poggi, U. L. Endocrine Profiles and Breast noted in other postmenopausal women. Our studies do not Cancer. Lancet, 1: 165-168. 1973. shed light on whether a different prehormone is metabo 2. Bulbrook, R. D., Greenwood. F. C., and Hadfield. G. Oophorectomy in lized directly to estrone without mixing with the blood Breast Cancer; an Attempt to Correlate Clinical Results with Estrogen Production. Brit. Med. J.,2: 7-11, 1958. androstenedione pool or whether the estrone is secreted 3. Bulbrook, R. D., Greenwood. F. C., and Hayward. J. L. Selection of directly by the ovary or adrenals, or perhaps even produced Breast Cancer Patients for Adrenalectomy or Hypophysectomy by Deter mination of 17-Hydroxycorticosteroids and Aetiocholanolone. Lancet 2 within the malignant breast tissue. 1154-1157, 1960. Unexpectedly, we found a subgroup of 14 of 46 women 4. Bulbrook. R. D., and Hayward. J. L. Abnormal Urinary Steroid Excretion with breast cancer who exhibited markedly elevated clear and Subsequent Breast Cancer. A Prospective Study in the Island of Guernsey. Lancet, 2: 519-521. 1967. ance rates of estrone and 5 women with increased clear 5. Bulbrook, R. D.. Hayward, J. L.. and Spicer, C. C., ef al. Abnormal ance rates of androstenedione. This group of women had Excretion of Urinary Steroids by Women with Early Breast Cancer. no specific clinically differentiating characteristics. Al Lancet, 2. 1238-1240, 1962. 6. Chopra, I. J.. Abraham. G. E., Chopra, U.. Solomon. D. H.. and Odell. though there was more obesity in the women with high W. D. Alterations in Circulating Estradiol-17/3 in Male Patients with clearance rates, the magnitude of the obesity was not of the Graves' Disease. New Engl. J. Med.. 286: 124-127, 1972. proportion reported by Schneider ef al. (28) to be associ 7. Dickinson. L. E., MacMahon, B., Cole, P., and Brown. J. B. Estrogen ated with high MCR's. Poortman (25) observed similar Profiles of Oriental and Caucasian Women in Hawaii, New Engl. J. Med., 297: 1211-1213, 1974. unusual MCR's in some of his breast cancer patients but 8. Grodin, J. M., Siiteri, P. K., and MacDonald, P. C. Source of Estrogen Production in Post-menopausal Women. J. Clin. Endocrinol. Metab 36- made no further comment. In our studies, the higher MCRK, 207-214, 1973. was associated with lower plasma levels of estrone so that 9. Hellman. L.. Zumoff. B., Fishman. J., and Gallagher, T. F. Peripheral estrone production rates were not appreciably changed. Metabolism of 3H-Estradiol and the Excretion of Endogenous Estrone and Estriol Glucosiduronate in Women with Breast Cancer. J. Clin. Similarly, the women with high clearance rates of estrone Endocrinol. Metab.,33: 138-144, 1971. also exhibited slightly lower plasma concentrations of an 10. Henderson, B. E., Gerkins, V., Rosario, I., ef a/. Elevated Serum Levels of Estrogen and Prolactin in Daughters of Patients with Breast Cancer. drostenedione and testosterone, as well as slightly different New Engl. J. Med., 293: 790-795. 1975. metabolic conversion rates of androstenedione to testoster 11. Irving, W. T., Aitken, E. H.. Rendelman. D. F., and Folca. P. J. Urinary one and estrone to estradiol. Thus plasma hormone con Oestrogen Measurements after Oophorectomy and Adrenalectomy for Advanced Breast Cancer. Lancet, 2: 791-796, 1961. centrations and hormone metabolism seemed different in a 12. Kirschner, M. A. Determination of Androgens in Biological Fluids. In: B. subgroup of women with breast cancer. Rothfeld (ed.), Nuclear Medicine in Vitro, pp. 164-178. New York: J. B. Biologically active androgens and estrogens are bound Lippincott. 1974. 13. Kirschner. M. A. The Role of Hormones in the Etiology of Human Breast in plasma to a carrier protein, SHBG. Since clearance rates Cancer. Cancer, 39: 2716-2726, 1977. of sex hormones are inversely related to protein binding 14. Kirschner, M. A., and Bardin. C. W. Androgen Production and Metabo lism in Normal and Virilized Women. Metabolism. 27: 667-788, 1972. (31), we examined the binding proteins in our patients with 15. Leis, H. P. Hormone in the Epidemiology of Breast Cancer. Diseases high versus normal clearance rates. No significant differ Breast, 2: 7-13, 1976. ences in binding characteristics for estrone, estradiol. or 16. Lemon, H. M. Endocrine Influences on Human Mammary Formation: A Critique. Cancer, 23: 781-790, 1969. testosterone could be found between the breast cancer 17. Lemon, H. M., Wotiz, H. H.. Parson, L., and Mozden, P. L. Reduced women with high versus normal clearance rates. Thus, the Estriol Excretion in Patients with Breast Cancer prior to Endocrine cause(s) of elevated estrone clearance rates in women with Therapy. J. Am. Med. Assoc.. 796: 112-120, 1966. 18. Lipsett. M. B. Hormonal Induction of Breast Cancer. In: M. L. Girem ef breast cancer remains unclear. In view of the high clearance al. (eds.). Breast Cancer: A Challenging Problem, pp. 28-30. New York: rates noted in approximately 25% of breast cancer women, Springer-Verlag, 1973. 19. Longcope, C. Metabolic Clearance and Blood Production Rates of the significance of plasma hormone concentrations in Estrogens in Post-menopausal Women. Am. J. Obstet. Gynecol., 777: women with this disease must be carefully considered. 778-781. 1971. The data presented in the current study do not support 20. Longcope. C., and Pratt, H. J. Blood Production Rates of Estrogens in Women with Differing Ratios of Urinary Estrogen Conjugates. Steroids. the hypothesis that women with established breast cancer 29:483-492,1977. make excessive amounts of estrogens from a prehormone 21. Longcope, C.. Watson, D.. and Williams, K.I. H. The Effects of Synthetic pathway. Is it possible that our patient population, with Estrogens in the Metabolic Clearance and Production Rates of Estrone and Estradiol. Steroids, 24: 15, 1974. established metastatic disease was not the optimal group 22. MacMahon, B., Cole, P., and Brown. J. B. Etiology of Human Breast to study? Henderson ef al. (10) have shown that daughters Cancer: A Review. J. Nati. Cancer Inst., 50: 21-42, 1973. 23. MacMahon. B., Cole, P., Brown, J. B.,ef a/. Urine Oestrogen Profiles of of women with breast cancer (high risk) have higher plasma Asian and North American Women. Intern. J. Cancer, 14: 161-167, 1974. estradiol and prolactin levels (at comparable times of the 24. McAllister, R. A., Sim, A. W., Hobkirk, R., Stewart, H., Blair, D. W., and menstrual cycle) than do other young women. It thus seems Forest, A. P. M. Urinary Oestrogens after Endocrine Ablation. Lancet, 7: 1102-1105, 1960. entirely possible that endogenous overproduction of estro 25. Poortman, J. Geslachtshormonen en Mamma-carcinoom. Production of gens via direct secretion or from prehormones might have Androgens and Oestrogens in Normal Postmenopausal Women and in

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Marvin A. Kirschner, Frederick B. Cohen and Catherine Ryan

Cancer Res 1978;38:4029-4035.

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