[CANCER RESEARCH 38, 4029-4035, November 1978]0008-5472/78/0038-0000$02.00

Androgen-Estrogen Production Rates in Postmenopausal Women withBreast 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

In an attempt to define the hormonal environment ofwomen with breast cancer, we examined the blood production rates of androstenedione and its contributory roleas a prehormone of estrone in a group of 46 postmeno-pausal women with advanced metastatic breast cancer.

Androstenedione blood production rates averaged 1.85mg/day and were not significantly different from 9 age-matched women with other neoplasms or from 4 noncan-cer controls. Similarly, blood production rates of estronewere not significantly different, averaging 56.9 /¿g/dayinwomen with breast cancer compared with 43.9 and 41.8pig/day in the control groups. The blood transfer constants (/>íj¡)were again similar in the breast cancerwomen versus the 2 control groups (2.13% versus 2.35 and2.74%, respectively).

Despite the similar magnitude of androstenedione, estrone production rates, and transfer constants, androstenedione conversion to estrone accounted for only 72%of the total estrone production rate in women with breastcancer versus 92 and 95% in the 2 control groups. Thesedifferences were significant at P < 0.05.

As part of these studies, we noted that 14 of 46 womenwith breast cancer exhibited unusually high metabolicclearance rates of estrone ranging from 2600 to 5400liters/day. These women could not be differentiated fromother breast cancer patients on clinical grounds. Fivepatients had elevated clearance rates of androstenedione, but testosterone and estradici clearance rates werenot abnormal. Patients with the high metabolic clearancerates of estrone had lower plasma estrone concentrationsso that blood production rates were similar to those notedin breast cancer patients with normal clearances. Thedifferences in metabolic clearance rates were not associated with changes in the binding protein, sex hormone-binding globulin.

We concluded that androstenedione production ratesand conversion to estrone are normal in postmenopausalwomen with breast cancer and that estrone productionrates are normal in these women, yet that approximately30% of estrone produced in postmenopausal women withbreast cancer comes from source(s) other than prehor-monal androstenedione.

Introduction

Although estrogenic hormones have long been suggested

1 Presented at the John E. Fogarty International Center Conference on

Hormones and Cancer, March 29 to 31, 1978, Bethesda, Md. Supported byUSPHS Grant CA-14296.

2 To whom requests for reprints should be addressed at: Newark Beth

Israel Medical School, 201 Lyons Ave.. Newark, N. J. 07112.

as playing a promoting role in the genesis of human breastcancer, previous studies of estrogen excretion and endogenous estrogen production rates in women with breastcancer have not shown consistent abnormalities (1, 2, 9,11, 13, 15-18, 22, 24, 29, 32). In the current study we haveexplored both estrone production rates and the contributory role of its major prehormone, androstenedione, in agroup of 46 postmenopausal women with advanced breastcancer. Whereas estrone production rates were not abnormal in women with breast cancer, a significant proportionof estrone produced in these patients arose from sourcesother than androstenedione.

Patients

Forty-six postmenopausal women with advanced metastatic breast cancer were studied before or betweencourses of systemic chemotherapy. All women had undergone natural menopause (no menses for 2 years) or hadexperienced surgically induced menopause prior to thediscovery of their breast cancer. None of the patients hadundergone endocrine-ablative surgery (except oophorec-tomy in the distant past for unrelated reasons), and nosystemic endocrine therapy was used for at least 6 monthsprior to these studies.

Nine age-matched women with metastatic carcinomasoriginating from sites other than the breast served ascancer controls, and 4 postmenopausal women recuperating from non-cancer-related illnesses, excluding hepaticand cardiac disorders, served as noncancerous controls.

Informed consent was obtained from each patient priorto her entry into the study. The studies were performedbetween 8 and 10 a.m., in the fasting state, and before thepatient arose from her overnight supine position.

Methods

MCR's.3 During the initial phase of this study, MCR's of

androstenedione and estrone were determined sequentially. [3H]Androstenedione was infused at a rate of approx

imately 50 /nCi/hr following a 10% loading dose given 30min prior to the onset of the infusion. A Bowman constantinfusion pump was calibrated to deliver approximately 1.5to 1.8 ml of infusion solution per min. Blood samples weredrawn distant to the infusing site at 60, 75, and 90 min.Immediately following the androstenedione infusion, a 10%loading dose of [3H]estrone was given and the secondinfusion of [3H]estrone (15 /¿Ci/hr)was begun, with samples

3The abbreviations used are: MRC, metabolic clearance rate; superscriptor subscript E,, E2, A, and T, estrone, estradiol, androstenedione, andtestosterone, respectively; SHBG, sex hormone-binding globulin.

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M. A. Kirschner et al.

taken at 60, 75, and 90 min. These sequential infusionstudies took approximately 4 hr.

Because of patient discomfort associated with the prolonged infusion times, subsequent studies were performedas a single infusion with a combination of 80 /uCi[3H]androstenedione and 4 /¿ciof [14C]estrone. This latter

procedure, taking approximately 120 min, was better tolerated by the patients. The blood samples obtained in lightlyheparinized syringes were immediately centrifuged, and theplasma was stored at -15°for work-up at a later time.

Sample Purification. For the sequential studies, 10-mlportions of plasma taken at the various infusion times wereused. Approximately 1500 cpm of ['"CJandrostenedione,[14C]testosterone, [14C]estrone, and [14C]estradiol were

added to each plasma sample to monitor procedural lossesand to serve as markers to determine the purity of theplasma extracts. For work-up of the [3H]estrone infusions,only [14C]estrone and [14C]estradiol were added to the

plasma samples. To each tube were added 50 to 100 /xg ofunlabeled androstenedione, testosterone, estrone, and es-tradiol to simplify the recovery procedure.

Plasma samples were extracted 3 times with equal volumes of ether. The combined extracts were washed twicewith 0.1 volume of water and dried. Separation of neutralfrom phenolic fractions was accomplished by toluene: 1 NNaOH partition, with the use of countercurrent procedureinvolving 3 sequential separatory funnels. The toluene layers following these partitions were combined, washed twicewith 0.1 volume of water, dried over sodium sulfate, andfiltered, and the extracts were dried. Preliminary purification of the samples was achieved by means of thin-layerchromatography with benzene:ethyl acetate (65:35). Testosterone fractions were separated from androstenedionefractions in this system. The testosterone and androstenedione fractions were separately eluted with ethyl acetate,and the dried eluates were acetylated with 10 drops ofacetic acid and 5 drops of pyridine left overnight at roomtemperature. The acetates formed were further separatedon the thin-layer system with benzene:ethyl acetate (90:10).The testosterone acetate and androstenedione fractionswere purified further by forming methoxime derivatives byadding a few crystals of methoxyamime hydrochloride and3 drops of pyridine. The methoxime derivatives were chro-matographed in the thin-layer system benzene:ethyl acetate(80:20). Aliquots (20%) of the eluates following each of the3 thin-layer chromatography steps were taken for counting.Samples were considered "pure" when constancy of 3H:14C

ratios were obtained (usually after the second thin-layerchromatography).

The phenolic fraction following the toluene:NaOH partition was neutralized to pH 5.5 with glacial acetic acid. Theestrogens were extracted twice with equal volumes of ether,and the ether extracts were washed with 0.1 volume ofwater and dried. These fractions were further purified byformation of acetates as above, and separation of theacetates in the thin-layer system benzene:ethyl acetate(90:10). The dried thin-layer eluates were then saponifiedwith 0.5 ml of 0.15 N NaOH in 80% methanol overnight, andthe saponified estrogens were then chromatographed inthe thin-layer system benzene:ethyl acetate (65:35). The

estrone and estradiol fractions were then methylated, andthe methyl ethers were purified on thin-layer chromatography with benzene:ethyl acetate (80:20). Appropriate ali-quots following each purification step were again taken forcounting.

Radioactivity was determined in each sample with aPackard Model 3380 liquid scintillation counter. Sampleswere counted to accumulate approximately 10,000 3H and14Ccounts. In general, each sample was counted for 50 to

100min.For the simultaneous infusion studies, approximately

1500 cpm of [14C]testosterone and [14C]androstenedione

were added to each plasma sample prior to extraction.Since the estrogen fractions contained both 3H and 14Cla

bels, approximately 500 /¿gof unlabeled estrone were usedas a mass marker to monitor recovery. Samples were extracted and subsequently worked up as described above;however, for determination of estrone and estradiol recovery, samples were estimated for their mass with a Beck-mann spectrophotometer, after the method of Longcope(C. Longcope, personal communication).

Plasma concentrations of androstenedione, testosterone,estrone, and estradiol were estimated from blood samplestaken overa 10-min period prior to the onset of the infusion.Androstenedione and testosterone were measured by ra-dioimmunoassay, as previously reported (12). Estrone wasmeasured by radioimmunoassay according to the methodof Longcope ef a/. (21). Estradiol was measured by aspecific estradiol antibody provided by Dr. D. L. Loriaux.Preliminary purification of the estrogens was accomplishedby using Sephadex LH-20 chromatography of the etherextract in each case.

Equilibrium dialysis of plasma samples was performedafter the method of Chopra ef al. (6) with a 1:5 dilution ofplasma.

Results

Metabolic Clearance Rates

Estrone. The mean MCRKl was 2420 liters/day in ourbreast cancer patients, as noted in Chart 1. This value wassomewhat higher than the 1955 liters/day and 1820 liters/day noted in our non-breast cancer and noncancerouscontrol patients, although the differences were not significant. On closer inspection of the MCRK] values, we werestruck with several extraordinarily high values observed insome of our breast cancer patients. Indeed, 14 of the 46women with breast cancer exhibited MCRKl in excess of2600 liters/day ranging up to 5400 liters/day. This group ofwomen with extraordinarily high clearance rates of estronewas separately analyzed as Subgroup 2 (Table 1). They hada mean MCRKl of 3550 liters/day, which was significantlyhigher than the mean MCRKl of 1760 liters/day observed inthe remaining 24 breast cancer women. Unfortunately, wecould identify no unusual clinical features of the womenwith high MCREl versus those with normal MCREl. The agesof the women, duration and extent of metastatic disease,and drug history were similar for breast cancer patientswith both high and low clearance rates. There was more

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Androgen-Estrogen Production Rates

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Chan 1. Metabolic clearance rates of estrone in 46 women with breastcancer (Ca), in 9 women with non-breast cancer, and in 4 control patientswithout cancer. L, liter.

obesity in the women with high MCRK|, with 13 of 14 womenhaving body weights of 160 to 200 pounds. By contrast thewomen with normal estrone clearance rates had a lesserfrequency of obesity; however, none of the women in ourstudy was grossly obese (over 220 pounds).

Androstenedione. The mean MCR¿in our 46 women withbreast cancer was 2220 liters/day, not significantly differentfrom the 2 control groups. Five women had had MCR¿inexcess of 2800 liters/day, 3 of whom also had high MCRKl.The mean MCR¿of the breast cancer Groups 1 and 2 were2130 versus 2500 liters/day and were not statistically significant from each other or from the control patients.

Estradici. In a separate group of 8 women with postmen-opausal breast cancer of similar degree, metabolic clearance rates of estradici and testosterone were determined tosee whether any elevations of clearance existed for thesehormones. The mean MCRK, was 1620 ±300 (S.D.) liters/day. The highest clearance rate for estradiol was 2215liters/day, comparing favorably with values reported byLongcopeef al. (21).

Testosterone. In the 8 women with metastatic breastcancer, the mean MCR, was 724 liters/day. Two womenhad clearance rates of 930 and 1050 liters/day, respectively,whereas the remainder of the group had values in the rangeof 500 to 700 liters/day. The mean value for the group wasnot statistically different from previous values reported inyoung premenopausal women (14).

Plasma Steroid Concentrations

Estrone. Plasma estrone averaged 2.5 ng/100 ml, notsignificantly different versus the 2 groups of controlwomen. Of interest, the subgroup of breast cancer womenwith high MCRK] exhibited somewhat lower plasma estronevalues averaging 1.8-ng values versus 2.9 ng/100 ml in thewomen with normal MCREl.

Androstenedione. Plasma androstenedione averaged 89ng/100 ml in the women with breast cancer versus mean

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

Blood Production Rates

Estrone. The mean blood production rate of estrone(P,,E.)was 56.9 ng/day in women with breast cancer compared with mean values of 43.9 and 41.8 /¿g/dayin thecontrol women. These differences were of borderline significance. The breast cancer women with high MCRKl had amean P/. of 68 ¿¿g/day,but this value was not significantlydifferent from the mean of the remaining women with breastcancer. The group of women with high MCRKl had lowerplasma estrone concentrations; thus production rates ofthe both groups were of similar magnitude.

Androstenedione. The mean blood production rate forandrostenedione in the women with breast cancer was 1.85mg/day, with no significant difference in production ratesobserved in Subgroups 1 versus 2. The values for P,,Awere

not different from those noted in women with other cancersor without cancer.

Steroid Interconversions

Conversion of Androstenedione to Testosterone. Theblood conversion rate of androstenedione to testosteroneaveraged 7.81% in breast cancer women versus 7.93 and8.05 in the 2 groups of control women. These differenceswere not significant.

Conversion of Estrone to Estradiol. The conversion ofestrone to estradiol wa 7.51% in women with breast cancerversus 6.88% in the women with cancers at other sites. Only2 values were available in the noncancerous controls, 10.3and 4.2%.

Conversion of Androstenedione to Estrone. The bloodtransfer constant (p) of androstenedione to estrone wasdetermined from the expression:

where C-iKl is the conversion rate of infused tracers. Inwomen with breast cancer the pAKl was 2.13% compared

with mean values of 2.35 and 2.74% in the control groups.Within the group of breast cancer women, those with highmetabolic clearance rates of estrone had somewhat higherpAElvalues (2.34%) compared with 1.96% in those womenwith normal MCRKl. The differences between groups andwithin the breast cancer women were not statistically significant.

Origin of Estrone

The contributory role of androstenedione (A) to the bloodproduction rate of estrone (E,) was determined in eachwomen from the expression:

Contribution A to E, = P„Ax pAl:'/P/'

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where P,,A is the blood production rate of androstenedione,P/1 is the blood production rate of estrone and pAK>is the

blood transfer constant. The values are displayed in Chart2. In both groups of women with breast cancer (highMCREl and normal MCREl), 68 and 76% of their bloodestrone production rate arose from peripheral metabolismof androstenedione. By contrast, in both control groupsvirtually all their estrone production rate arose from peripheral transformation of androstenedione. These differenceswere statistically significant at p < 0.05.

Dialyzable Fractions of Plasma Androgens and Estrogens

In view of the subgroup of breast cancer patients withunusually high clearance rates of estrone, we wished toexamine the binding of various androgens and estrogens totheir carrier protein, SHBG. We thus set up dialysis cellsafter the method of Chopra to determine the dialyzablefraction of testosterone, estrone, and estradici as well asthat of androstenedione (a control C,9 androgen with noappreciable binding affinity for SHBG). These values areshown in Table 1. The dialyzable testosterone fraction was2.80% in the breast cancer women versus 1.87 to 2.18 inthe control groups, respectively. Within the breast cancerpatients, those women with high MCREl exhibited slightlyhigher values, with a mean of 3.08% versus 2.68% in women

ANDROSTENEDIONE PRODUCTION

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estrone production rates in women with breast cancer (Ca), women withnon-breast cancer, and noncancerous controls. In women with breastcancer, only 72% of the total estrone production arises from androstenedione metabolism. By contrast, virtually all estrone produced in the controlpatients comes from androstenedione. See text for details. Bars, S.D.

Androgen-Estrogen Production Rates

with normal estrone clearance rates. These values were notstatistically significant from each other. As for estronebinding affinity, breast cancer women exhibited slightlyhigher dialyzable fractions compared with the controlgroups, but again there was no difference in dialyzablefractions in those breast cancer patients with high clearance rates versus normal clearance rates for estrone. Nosignificant differences in dialyzable fractions existed forestradiol or for androstenedione in the varying groups. Itwas thus apparent that the differences noted in metabolicclearance rates could not be explained by alterations in thesex hormone-binding protein.

Discussion

A large body of circumstantial evidence from the areas ofepidemiology, experimental biology, and clinical medicinesuggests that estrogens are important in the genesis ofhuman breast cancer (13,15-18, 22, 32). Indeed, if estrogenproduction and/or metabolism were found to be abnormalin women with breast cancer, these findings might be ofgreat potential significance as a possible attack point forthe prevention of the disease. Unfortunately, previous studies of estrogen production and urinary estrogen metabolitesin women with breast cancer have been equivocal andconflicting. The epidemiological data of MacMahon et al.(23) and Dickinson ef al. (7) showing differing ratios ofurinary estriol versus estrone and estradiol in women atdiffering risks for breast cancer probably reflect differingpathways of estrogen metabolism, since estriol productionrates were shown to be similar in women with high estriolratios and low estriol ratios (20).

Over the past 2 decades Bulbrook ef al. (3-5) reportedthat women with established breast cancer who respondedpoorly to endocrine therapy as well as women destined todevelop breast cancer excreted lesser amounts of urinary17-ketosteroid metabolites, androsterone, and etiocholan-olone. Subsequently, Poortman (25, 26) and Thijssen ef al.(30), reported lower production and excretion of dehydro-epiandrosterone and its sulfate in women with breast cancer. These data suggesting a possible link between androgen production and metabolism versus breast cancer wereunexpected since androgens were not thought to play animportant role in the growth of breast tissue. It is now wellappreciated that androgens serve as prehormones of estrogens (Chart 2). Indeed studies of Grodin et al. (8) andLongcope (19) and in our control patients have shown thatvirtually all estrogens made in postmenopausal womenarise from prehormone metabolism to estrogens. We thusset out to test the hypothesis that women with breast cancermight metabolize androgens to estrogens to a greaterdegree than do normal women. This could result in greaterproduction rates of estrogens, at levels still undetected bythe less sensitive urinary estrogen excretion measurements.If women with breast cancer excrete less 17-keto-steroidmetabolites because they convert more C,„prehormones toestrogens, these findings would relate Bulbrook's observa

tions to abnormal estrogen production rates.This exciting hypothesis was, unfortunately, not con

firmed by the data in this study. We found that androstenedione and estrone production rates were no different in

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M. A. Kirschner et al.

women with breast cancer compared with 2 groups ofcontrol patients; also, the conversion of androstenedioneto estrone was not abnormal in women with breast cancer.These data thus confirm earlier studies of Poortman ef al.(25, 26) in this respect. Our studies showed, however, thatconversion of androstenedione to estrone accounts for only65 to 75% of the total blood production rate of estrone inwomen with breast cancer versus 92 and 95%, respectively,in the control groups. Thus, women with breast cancerappear to have an extra source of estrone production notnoted in other postmenopausal women. Our studies do notshed light on whether a different prehormone is metabolized directly to estrone without mixing with the bloodandrostenedione pool or whether the estrone is secreteddirectly by the ovary or adrenals, or perhaps even producedwithin the malignant breast tissue.

Unexpectedly, we found a subgroup of 14 of 46 womenwith breast cancer who exhibited markedly elevated clearance rates of estrone and 5 women with increased clearance rates of androstenedione. This group of women hadno specific clinically differentiating characteristics. Although there was more obesity in the women with highclearance rates, the magnitude of the obesity was not of theproportion reported by Schneider ef al. (28) to be associated with high MCR's. Poortman (25) observed similarunusual MCR's in some of his breast cancer patients but

made no further comment. In our studies, the higher MCRK,was associated with lower plasma levels of estrone so thatestrone production rates were not appreciably changed.Similarly, the women with high clearance rates of estronealso exhibited slightly lower plasma concentrations of androstenedione and testosterone, as well as slightly differentmetabolic conversion rates of androstenedione to testosterone and estrone to estradiol. Thus plasma hormone concentrations and hormone metabolism seemed different in asubgroup of women with breast cancer.

Biologically active androgens and estrogens are boundin plasma to a carrier protein, SHBG. Since clearance ratesof sex hormones are inversely related to protein binding(31), we examined the binding proteins in our patients withhigh versus normal clearance rates. No significant differences in binding characteristics for estrone, estradiol. ortestosterone could be found between the breast cancerwomen with high versus normal clearance rates. Thus, thecause(s) of elevated estrone clearance rates in women withbreast cancer remains unclear. In view of the high clearancerates noted in approximately 25% of breast cancer women,the significance of plasma hormone concentrations inwomen with this disease must be carefully considered.

The data presented in the current study do not supportthe hypothesis that women with established breast cancermake excessive amounts of estrogens from a prehormonepathway. Is it possible that our patient population, withestablished metastatic disease was not the optimal groupto study? Henderson ef al. (10) have shown that daughtersof women with breast cancer (high risk) have higher plasmaestradiol and prolactin levels (at comparable times of themenstrual cycle) than do other young women. It thus seemsentirely possible that endogenous overproduction of estrogens via direct secretion or from prehormones might have

occurred at a much earlier age and that with increasing ageand debility, etc., these differences in estrogen productionmay have become blunted so that they are no longerdiscernible. It would seem that studies of prehormonemetabolism in high-risk groups must be done before thisattractive hypothesis is entirely abandoned.

References

1. Arguelles. Hoffman, C., and Poggi, U. L. Endocrine Profiles and BreastCancer. Lancet, 1: 165-168. 1973.

2. Bulbrook, R. D., Greenwood. F. C., and Hadfield. G. Oophorectomy inBreast Cancer; an Attempt to Correlate Clinical Results with EstrogenProduction. Brit. Med. J.,2: 7-11, 1958.

3. Bulbrook, R. D., Greenwood. F. C., and Hayward. J. L. Selection ofBreast Cancer Patients for Adrenalectomy or Hypophysectomy by Determination of 17-Hydroxycorticosteroids and Aetiocholanolone. Lancet 21154-1157, 1960.

4. Bulbrook. R. D., and Hayward. J. L. Abnormal Urinary Steroid Excretionand Subsequent Breast Cancer. A Prospective Study in the Island ofGuernsey. Lancet, 2: 519-521. 1967.

5. Bulbrook, R. D.. Hayward, J. L.. and Spicer, C. C., ef al. AbnormalExcretion of Urinary Steroids by Women with Early Breast Cancer.Lancet, 2. 1238-1240, 1962.

6. Chopra, I. J.. Abraham. G. E., Chopra, U.. Solomon. D. H.. and Odell.W. D. Alterations in Circulating Estradiol-17/3 in Male Patients withGraves' Disease. New Engl. J. Med.. 286: 124-127, 1972.

7. Dickinson. L. E., MacMahon, B., Cole, P., and Brown. J. B. EstrogenProfiles of Oriental and Caucasian Women in Hawaii, New Engl. J. Med.,297: 1211-1213, 1974.

8. Grodin, J. M., Siiteri, P. K., and MacDonald, P. C. Source of EstrogenProduction in Post-menopausal Women. J. Clin. Endocrinol. Metab 36-207-214, 1973.

9. Hellman. L.. Zumoff. B., Fishman. J., and Gallagher, T. F. PeripheralMetabolism of 3H-Estradiol and the Excretion of Endogenous Estroneand Estriol Glucosiduronate in Women with Breast Cancer. J. Clin.Endocrinol. Metab.,33: 138-144, 1971.

10. Henderson, B. E., Gerkins, V., Rosario, I., ef a/. Elevated Serum Levelsof Estrogen and Prolactin in Daughters of Patients with Breast Cancer.New Engl. J. Med., 293: 790-795. 1975.

11. Irving, W. T., Aitken, E. H.. Rendelman. D. F., and Folca. P. J. UrinaryOestrogen Measurements after Oophorectomy and Adrenalectomy forAdvanced Breast Cancer. Lancet, 2: 791-796, 1961.

12. Kirschner, M. A. Determination of Androgens in Biological Fluids. In: B.Rothfeld (ed.), Nuclear Medicine in Vitro, pp. 164-178. New York: J. B.Lippincott. 1974.

13. Kirschner. M. A. The Role of Hormones in the Etiology of Human BreastCancer. Cancer, 39: 2716-2726, 1977.

14. Kirschner, M. A., and Bardin. C. W. Androgen Production and Metabolism in Normal and Virilized Women. Metabolism. 27: 667-788, 1972.

15. Leis, H. P. Hormone in the Epidemiology of Breast Cancer. DiseasesBreast, 2: 7-13, 1976.

16. Lemon, H. M. Endocrine Influences on Human Mammary Formation: ACritique. Cancer, 23: 781-790, 1969.

17. Lemon, H. M., Wotiz, H. H.. Parson, L., and Mozden, P. L. ReducedEstriol Excretion in Patients with Breast Cancer prior to EndocrineTherapy. J. Am. Med. Assoc.. 796: 112-120, 1966.

18. Lipsett. M. B. Hormonal Induction of Breast Cancer. In: M. L. Girem efal. (eds.). Breast Cancer: A Challenging Problem, pp. 28-30. New York:Springer-Verlag, 1973.

19. Longcope, C. Metabolic Clearance and Blood Production Rates ofEstrogens in Post-menopausal Women. Am. J. Obstet. Gynecol., 777:778-781. 1971.

20. Longcope. C., and Pratt, H. J. Blood Production Rates of Estrogens inWomen with Differing Ratios of Urinary Estrogen Conjugates. Steroids.29:483-492,1977.

21. Longcope, C.. Watson, D.. and Williams, K.I. H. The Effects of SyntheticEstrogens in the Metabolic Clearance and Production Rates of Estroneand Estradiol. Steroids, 24: 15, 1974.

22. MacMahon, B., Cole, P., and Brown. J. B. Etiology of Human BreastCancer: A Review. J. Nati. Cancer Inst., 50: 21-42, 1973.

23. MacMahon. B., Cole, P., Brown, J. B.,ef a/. Urine Oestrogen Profiles ofAsian and North American Women. Intern. J. Cancer, 14: 161-167, 1974.

24. McAllister, R. A., Sim, A. W., Hobkirk, R., Stewart, H., Blair, D. W., andForest, A. P. M. Urinary Oestrogens after Endocrine Ablation. Lancet, 7:1102-1105, 1960.

25. Poortman, J. Geslachtshormonen en Mamma-carcinoom. Production ofAndrogens and Oestrogens in Normal Postmenopausal Women and in

4034 CANCER RESEARCH VOL. 38

on March 19, 2020. © 1978 American Association for Cancer Research.cancerres.aacrjournals.org Downloaded from

Androgen-Estrogen Production Rates

Selected Patients with Mammary Cancer. Utrecht, The Netherlands:Drukkerij Elinkwijk BV, 1974.

26. Poortman, J., Thijssen, J. H. H., and Schwartz. F. Androgen Productionand Conversion to Estrogens in Normal Post-menopausal Women and inSelected Breast Cancer Patients. J. Clin. Endocrinol. Metab.. 37: 101-109.1973.

27. Pratt, J. H., and Longcope, C. Estriol Production Rates and BreastCancer. J. Clin. Endocrinol. Metab.,46. 44-47, 1978.

28. Schneider. G., Kirschner, M. A., and Ertel, N H. Increased SerumEstradici in Morbidly Obese Males. Program of the 59th EndocrineSociety. Chicago, 1976, no. 310.

29. Swyer. G. l. M., Lee, A. E., and Masterton, M. B. Oestrogen Excretion ofPatients with Breast Cancer. Brit. Med. J., 1: 617-619, 1961.

30. Thijssen, J. H. H.. Poortman. J., and Schwarz, F. Androgens in Post-menopausal Breast Cancer: Excretion, Production and Interaction withEstrogens. J. Steroid Biochem.. 6: 729-734, 1975.

31. Vermeiden, A.. Verdonec. M., Van der Straeton, M.. and Orie, N.Capacity of Testosterone Binding Globulin in Human Plasma and Influence of Specific Binding of Testosterone on Its Metabolic ClearanceRate. J. Clin. Endocrinol., 29: 1470-1477, 1969.

32. Wynder. E. L., Bross, I. J.. and Hirayama. T. A Study of the Epidemiologyof Cancer of the Breast. Cancer, 13: 559-601. 1960.

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1978;38:4029-4035. Cancer Res   Marvin A. Kirschner, Frederick B. Cohen and Catherine Ryan  Women with Breast CancerAndrogen-Estrogen Production Rates in Postmenopausal

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