[CANCER RESEARCH 43,1884-1890, April 1983] 0008-5472/83/0043-0000$02.00 Abnormal Estrogen Conjugation in Women at Risk for Familial Breast Cancer at the Periovulatory Stage of the Menstrual Cycle1 Jack Fishman,2 H. Leon Bradlow, David K. Fukushima, John O'Connor, Robert S. Rosenfeld, G. Jay Graepel, Robert Elston,3 and Henry Lynch The Rocketeller University. New York. New York 10021 ¡J.F.. H. L. B.¡;Montefiore Hospital and Medical Center, Bronx. New York 10467 [D. K. F., J. 0., R. S. R.]; E. I. du Pont de Nemours, Wilmington, Delaware 19898 [G. J. G.]; Louisiana State University Medical Center, New Orleans, Louisiana 70112 [R. E.J; and Creighton University, Omaha, Nebraska 68178 [H. L] ABSTRACT A number of such studies have been carried out on the population of the Isle of Guernsey, and the results to date have The present study was designed to establish whether women suggested the existence of endocrine differences residing prin with a family history of breast cancer exhibit endocrine abnor cipally in the androgenic hormones which appear to correlate malities which could be responsible for their increased risk for with increased risk for breast cancer (4, 5). Because these the disease. Plasma hormone levels were measured every sec studies were carried out on a very large heterogeneous popula ond day throughout the menstrual cycle in 30 women at risk for tion, an extensive library of hormones and their daily changing familial breast cancer and in an equal number of matched con levels during the menstrual cycle could not be assessed. Even trols. Thirteen of the 14 substances measured exhibited no now, detailed studies on a population large enough to yield a differences between the two populations, but plasma androster- meaningful number of positive cases would be prohibitive in one sulfate was significantly lower in the high-risk subjects. terms of time and effort. Therefore, a more realistic prospective Thirteen urinary hormones were measured every day throughout in-depth study would require a small select population of individ the cycle with only the mean estrone and estradiol glucuronide uals known to be at high risk for breast cancer which could be but not estriol glucuronide content being significantly lower in compared to a matched group of normal-risk women. Studies of the high-risk subjects. A compensatory increase in the urinary this type which have used racial or ethnic high- and low-risk estrogen sulfates was observed. Daily analysis of these differ populations can be faulted because the risks may incorporate ences showed that they were most pronounced in the periovu- environmental factors which may not be reflected in any endo latory period of the cycle. These results suggest that the genetic crine disturbances. Also, the environmental influences may alter risk for breast cancer is associated with an abnormality in the endocrine milieu in directions unrelated to breast cancer risk. estrogen conjugation at a specific time of the ovulatory cycle. Indeed, several such studies of endocrine differences between high- and low-risk racial groups have produced contradictory INTRODUCTION results (10, 32). One of the most secure epidemiological observations in breast The participation of endocrine factors in the etiology of human cancer is that a family history of the disease very significantly breast cancer is supported by several lines of evidence. These increases the risk for it (1, 23, 26). This makes a population at include a series of epidemiological studies and the well-charac genetic risk for breast cancer a particularly suitable group in terized impact of endocrine manipulation on the onset and prog which to attempt to identify hormonal factors which could be ress of the disease in animals and humans. Intensive efforts involved in the increased risk for the disease. Comparative have been devoted to identifying specific endocrine differences studies of such high-risk and low-risk women eliminate the between women with the disease and unaffected controls which question of environmental impact when these groups are could be involved in the disease process (2, 11, 15-17, 21, 25, matched also for geographic location, as well as dietary and 28, 29). Few, if any, clear-cut differences have been securely behavioral patterns. It is clear that any endocrine differences identified to date, and even these are subject to uncertainty as noted in such studies may represent factors which are associ to whether they were present prior to the disease or were a ated only with the risk for familial breast cancer and need not consequence of the illness. Furthermore, available epidemiolog necessarily apply to the population at large. Moreover, it is ical evidence suggests that it is the endocrine milieu in the early reproductive years of a woman's life which determines the risk certainly possible that endocrine abnormalities observed in our high-risk population may be overridden by other environmental of the development of breast cancer many years later (18), so factors in the population at large. It is, however, possible that that endocrine studies carried out after the diagnosis of the the individuals at genetic risk for breast cancer could constitute cancer could be irrelevant or even misleading insofar as the an enriched pool of endocrine abnormalities which could be endocrine role in the onset of the disease is concerned. These factors in nonfamilial disease as well. Therefore, disturbances in considerations have directed attention to prospective studies in endocrine profiles in a population at risk for familial breast cancer which endocrine profiles, obtained a considerable time prior to which are not present in a matched group free of genetic risk for the emergence of the disease, can be related to its subsequent the disease could provide leads to specific endocrine features incidence. linked to the incidence of breast cancer in all individuals. Such 1Supported by Grant CA 22795 from the National Cancer Institute. differences could provide a way of identifying women at risk for 2 To whom requests for reprints should be addressed, at The Rockefeller the disease and, more importantly, offer insight into the mecha University, 1230 York Avenue, New York. N. Y. 10021. 3 Recipient of Grant CA 28198 from the National Cancer Institute nisms of hormonal participation in the oncogenic process. Received August 19,1982; accepted December 10, 1982. Preliminary results of such an in-depth study in which hormonal 1884 CANCER RESEARCH VOL. 43 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1983 American Association for Cancer Research. Estrogen Metabolism in Women at Risk for Breast Cancer Table 1 Matching of high- and low-risk population statistics Ofpairs3030302130303030Case case-controldifference0.23 mean1943.9712.331.7721.6727.3313.73137.5765.60Controlmean1943.7312.732.3721.6726.7313.20128.9764.70Mean Birth date(yr)Menarche ±0.44"-0.36 (yr)ParityAge ±0.36-0.60 ±0.320.00 atfirstpregnancy(yr)Cycle ±0.290.60 length(days)UH ±0.850.53 peak(days)Wt ±0.968.60 (Ib)HI ±3.490.83 (inches)" ±0.53t0.55-1.01-1.870.000.700.552.461.57PNS"NSNSNSNSNS<0.05NS S.E."Mean ± NS. not significant.NO. levels throughout the menstrual cycle in 30 young women at an area as close as possible to the matching subject to avoid any high risk for familial breast cancer were compared with 30 possible microenvironmental effects. To avoid any possibility of seasonal matched controls have already been reported (13, 14). No sig changes, each subject and control pair was studied at the same time. nificant differences between these populations were observed in As shown in Table 1, the matching of the 2 populations for all of these the plasma levels of either prolactin, LH," FSH, estrone, estradiol, parameters was extremely close except for body weight where a small difference existed. Although the high-risk subjects were on average 3.97 or estriol at any stage of the menstrual cycle, although a con kg heavier than the controls, this is too small an amount to result in sistent trend toward lower values in all of these, except estriol, significant endocrine changes (12), particularly since it has been sug was noted in the high-risk populations (14). Analysis of urinary gested that height rather than weight is the more critical risk factor (9). metabolites, on the other hand, revealed highly significant differ Furthermore, our data show no correlation between body weight and ences in estrone and estradiol glucuronides, with the high-risk any of the significant hormonal differences observed, indicating that this individuals excreting lower amounts of these metabolites than matching factor had no influence on the results. Blood samples (15 ml) the controls (13). We now present further results from this study were obtained at the same time on alternate mornings from the start of which include differences in urinary estrone sulfate and in plasma one menstrual cycle to the start of the next cycle by a visiting nurse. Blood samples were promptly centrifuged, and the plasma samples were androsterone sulfate content. The temporal relationship of the kept at -20° until the analyses were carried out. Following careful various hormonal differences to the stages of the menstrual instructions, all subjects collected 12-hr urine samples (7 p.m. to 7 a.m.) cycle is also analyzed and discussed. These results provide every day starting from the cessation of one menstrual cycle to the compelling evidence that women at risk for familial breast cancer beginning of the next. On one day in the follicular phase and one day in display an abnormality in their metabolism of estradiol which is the luteal phase, a complete 24-hr urine collection was obtained to serve centered at the periovulatory period.