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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 11 3914-3918
Copyright © 1999 by The Endocrine Society

From the Clinical Research Centers

Menstrual Cycle Effects on Urinary Estrogen Metabolites1

Xia Xu, Alison M. Duncan, Barbara E. Merz-Demlow, William R. Phipps and Mindy S. Kurzer

Department of Food Science and Nutrition, University of Minnesota (X.X., A.M.D., B.E.M., M.S.K.), St. Paul, Minnesota 55108; and the Department of Obstetrics and Gynecology, University of Rochester Medical Center (W.R.P.), Rochester, New York 14642

Address all correspondence and requests for reprints to: Mindy S. Kurzer, Ph.D., Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, Minnesota 55108. E-mail: mkurzer{at}tc.umn.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Endogenous estrogen metabolism may play an important role in the pathogenesis of hormone-related cancers, most notably breast cancer. Despite the importance of estrogen metabolism, little is known about estrogen metabolite profiles during different phases of the menstrual cycle. This study was performed to evaluate the effects of the menstrual cycle on endogenous estrogen metabolism. Twenty-four-hour urine samples were collected daily during 4 precisely defined phases of the menstrual cycle (early follicular, midfollicular, periovulatory, and midluteal phases) from 6 healthy premenopausal women. Urine samples were analyzed for 15 endogenous estrogens and their metabolites by an ion exchange chromatography and the capillary gas chromatography-mass spectrometry method. The patterns of urinary estrogen metabolites (including potentially genotoxic 16{alpha}-hydroxyestrone, 4-hydroxyestradiol, and 4-hydroxyestrone) followed those of plasma estradiol and estrone, showing significant increases in the periovulatory and midluteal phases. Compared to the early and midfollicular phases, the ratios of 2-hydroxyestrogens/16{alpha}-hydroxyestrogens and 2-hydroxyestrogens/4-hydroxyestrogens were significantly increased during the periovulatory and midluteal phases (by 28% and 72%, respectively; P < 0.05), suggesting that estrogen metabolism is significantly affected by menstrual cycle phase. These data indicate that menstrual cycle phase must be considered in studies of estrogen metabolism in premenopausal women.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SUBSTANTIAL evidence supports a causal relationship between the risk of human breast cancer and levels of endogenous estrogens (1). Increased risk has been reported in women with high serum and urinary estrogen levels (2, 3) as well as those exposed to increased estrogen concentrations over time as a result of postmenopausal obesity, early onset of menstruation, and late menopause (4). Substantial evidence indicates that the key mechanisms probably involve 1) mitogenic properties of the parent estrogens and their metabolites through classical estrogen receptor-mediated processes, and 2) metabolic activation of estradiol (E2) and estrone (E1) to potentially genotoxic metabolites such as 16{alpha}-hydroxyestrone [16{alpha}-(OH)E1)], 4-hydroxyestradiol [4-(OH)E2], and 4-hydroxyestrone [4-(OH)E1] (5, 6, 7, 8). Excessive estrogen exposure, particularly unopposed by progesterone, is also, of course, strongly linked to endometrial cancer risk (9).

The main estrogen metabolite that has been proposed to be a risk factor for breast cancer is 16{alpha}-(OH)E1. 16{alpha}-(OH)E1 shows properties consistent with initiation of mammary cell transformation, including induction of unscheduled DNA synthesis and stimulation of anchorage-independent growth of mammary epithelial cells (10). This estrogen metabolite exhibits estrogenicity comparable to that of E2, low binding affinity to sex hormone-binding globulin (11), and irreversible binding to the estrogen receptor, causing long-lasting effects, such as persistent hyperproliferation and up-regulated expression of the c-myc oncogene even after its withdrawal (12). Human studies show that the relative extent of estrogen metabolism via the 16{alpha}-hydroxylation pathway is significantly increased in patients with breast cancer (13, 14, 15, 16, 17) and in healthy women who later develop breast cancer (18), although a recent case-control study of healthy breast cancer survivors found no differences between cases and controls (19).

Recent studies suggest that 4-hydroxylated catechol estrogens may be as harmful as 16{alpha}-(OH)E1 because their electrophilic quinone products react with DNA to form depurinating adducts known to generate mutations that initiate cancer both in vitro and in vivo (8). 4-(OH)E2 is a potent long acting estrogen (20, 21, 22) that has been shown to induce DNA single strand breaks and other mutagenic products of oxidative damage in Syrian hamster liver and kidney (23, 24). Human studies support the significance of 4-hydroxylation of estrogens. Microsomes prepared from human mammary adenocarcinoma and fibroadenoma predominantly catalyze the 4-hydroxylation of E2, unlike microsomes prepared from normal mammary tissue (25). Aldercreutz et al. (26) reported that urinary 4-(OH)E1 excretion in Asian women at low risk of breast cancer was significantly lower than that in Finnish women at high risk of breast cancer. Finally, Xu et al. (27) reported that urinary 16{alpha}-(OH)E1, 4-(OH)E1, and 4-(OH)E2 were all significantly reduced by soy phytoestrogen consumption, suggesting that effects on estrogen metabolism may contribute to the observed cancer-preventive effects of soy.

Despite the potential importance of estrogen metabolism in breast and endometrial carcinogenesis, there is little information regarding the effect of the normal menstrual cycle on the profile of urinary estrogen metabolites. Berg and Kuss (28) reported that urinary excretion of E2, E1, estriol (E3), 2-hydroxyestrogens, 4-hydroxyestrogens, and 2-methoxyestrogens followed the patterns of parent estrogens during the menstrual cycle, and Chen et al. (29) reported that the ratio of 2-(OH)E1/16{alpha}-(OH)E1 was increased by about 50% from the follicular to the luteal portions of the menstrual cycle. These two studies were limited, however, by the low specificity of the analytical methods, RIA and enzyme-linked immunoassay, respectively, as well as imprecise definition of menstrual cycle phases. In this study we analyzed 15 endogenous estrogens and their metabolites by state of the art ion exchange chromatography and gas chromatography-mass spectrometry methods in daily 24-h urine samples collected during precisely defined early follicular, midfollicular, periovulatory, and midluteal phases of the normal menstrual cycle in six healthy premenopausal women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

This study was a substudy of a larger project performed to evaluate the effects of soy isoflavone consumption on reproductive hormones in women (27, 30). Fourteen subjects participated in the larger study. Exclusionary criteria included athleticism; vegetarian diet; regular consumption of a high fiber, high soy, or low fat diet; cigarette smoking; regular consumption of vitamin and mineral supplementation greater than the Recommended Dietary Allowances; current pregnancy or lactation; regular use of medication including aspirin; use of hormones or antibiotics within 6 months of the start of the study; history of chronic disorders, including endocrine or gynecological diseases; benign breast disease; irregular menstrual cycles; less than 90% or more than 120% ideal body weight; weight change of more than 10 lb within the previous year or weight change of more than 5 lb within the previous 2 months; consumption of more than two alcoholic beverages per day; and a history of food allergies. Health status of each subject was verified by health history, physical exam, and routine blood and urine screening.

Samples from 6 of the 14 subjects recruited into the larger study were analyzed for this substudy. Subjects were selected after evaluation of reproductive hormone data and the quality of 24-h urine collections as reflected by urinary creatinine variability. All subjects showed normal ovulatory cycles. Prestudy averages (±SD) for age, body weight, body mass index, percent body fat, and menstrual cycle length were 27.8 ± 6.4 yr, 62.2 ± 4.9 kg, 22.7 ± 1.6 kg/m2, 28.2 ± 4.1%, and 28.9 days, respectively.

Study design and diet

Before the study, the protocol was approved by the University of Minnesota institutional review board, human subjects committee. Detailed descriptions of the larger study design and diet have been published previously (27, 30). Subjects for this substudy were studied during the third menstrual cycle of three cycles, during which they lived at home and consumed their habitual diets supplemented with a soy protein powder (Protein Technologies International, St. Louis, MO), providing a daily dose of 0.99 ± 0.03 mg total isoflavones/kg BW (63 ± 5 mg total isoflavones/day). The composition of the soy protein powder has been described previously (30).

Subjects were free living during the entire study. They performed serial urinary LH testing (OvuQUICK Self-Test, Quidel, San Diego, CA) at home, beginning on day 9 of the menstrual cycle until detection of the LH surge. In most cases, the day of ovulation was assumed to be the day after the LH surge, as determined by a positive OvuQUICK result. If the OvuQUICK results were ambiguous, plasma hormones, urinary LH, and basal body temperature charts were used as adjuncts, allowing for precise identification of the day of ovulation by a reproductive endocrinologist (W.R.P.).

Food intake was monitored by two 3-day diet records, one kept during the follicular phase (days 7–9) and one kept during the luteal phase (7–9 days after ovulation). Energy, macronutrient, and dietary fiber intakes were analyzed by a computerized nutrient analysis program (Nutritionist IV, version 4.0, The Hearst Corp., San Bruno, CA). Body density was calculated from the sum of four skinfold thicknesses, and a predictive equation was used to determine percent body fat (31).

Sample collection and analysis

Twenty-four-hour urines were collected daily during the entire menstrual cycle in 3-l bottles containing 3 g ascorbic acid. After recording the 24-h urine volume, sodium azide was added to achieve a 0.1% (w/v) concentration. Urinary creatinine was measured to evaluate the completeness of urine collection using an enzymatic assay kit (Johnson & Johnson Clinical Diagnostics, Inc., Rochester, NY). Urine samples were stored at -20 C until analysis.

Aliquots of each 24-h urine sample collected during the early follicular phase (days 2–4), midfollicular phase (days 7–9), periovulatory phase (ovulation-3 to ovulation+1), and midluteal phase (5–9 days after ovulation) were extracted and analyzed for 15 endogenous estrogens and their metabolites [Fig. 1Go; E1, E2, E3, 16{alpha}-(OH)E1, 2-hydroxyE1 (2-(OH)E1), 2-hydroxyE2 (2-(OH)E2), 4-(OH)E1, 4-(OH)E2, 2-methoxyestrone (2-MeOE1), 2-methoxyestradiol (2-MeOE2), 4-methoxyestrone (4-MeOE1), 4-methoxyestradiol (4-MeOE2), 16-ketoestradiol (16-ketoE2), 16-epiestriol (16-epiE3), and 17-epiestriol (17-epiE3)] by an ion exchange chromatography and capillary gas chromatography-mass spectrometry method originally developed by Adlercreutz and colleagues (32, 33, 34). The method used in this laboratory has been described previously (27).



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  		Figure 1. Main pathways of estrogen metabolism in women (modified from Ref. 35).

 
All samples from each subject were analyzed in duplicate in the same batch. Duplicate quality control urine samples from the midfollicular and midluteal phases were also analyzed with each batch. The intraassay coefficients of variation ranged from 0.6–6.9%; interassay coefficients of variation ranged from 0.8–16.1%, except for 2-MeOE2 and 17-epiE3, which had coefficients of variation of 27.8% and 23.1%, respectively.

Statistics

The effects of menstrual cycle phase on urinary estrogen metabolites were determined by repeated measures ANOVA using the Statistical Analysis System (version 6.12, SAS Institute, Inc., Cary, NC), blocking on subject and phase. Data were examined for homogeneity of variance and normality before ANOVA. If necessary, log transformation of data was performed before analysis, and these data are presented as the geometric mean (95% confidence interval). In the event of unbalanced data, least squares means are presented. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Diet and body weight

Dietary and body weight and composition data for the entire group of 14 subjects have been reported separately (30). The mean consumption of energy, macronutrients, and dietary fiber for the 6 subjects in this substudy are shown in Table 1Go. There were no significant differences in daily consumption of energy, macronutrients, or dietary fiber between the midfollicular and midluteal phases of the menstrual cycle (Table 1Go). There were also no significant differences in body weight, body mass index, or percent body fat between the midfollicular and midluteal phases.


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  		Table 1. Dietary intake

 
Urinary estrogens and estrogen metabolites

In general, urinary excretion of estrogen metabolites followed the patterns of plasma E2 and E1, being highest in the periovulatory phase, followed by the midluteal, midfollicular and early follicular phases (Table 2Go). The most predominant estrogen metabolite was 2-(OH)E1, which made up 25%, 28%, 34%, and 35% of total estrogens during the early follicular, midfollicular, periovulatory, and midluteal phases, respectively.


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  		Table 2. Urinary estrogens and estrogen metabolites (nanomoles per 24 h)

 
The ratio of genotoxic estrogen metabolites [16{alpha}-(OH)E1, 4-(OH)E2, and 4-(OH)E1] to total estrogens was significantly lower during the periovulatory phase than during the early and midfollicular phases and was significantly lower in the midluteal phase than in the midfollicular phase (Table 3Go). The ratios of 2-(OH)E1 to 16{alpha}-(OH)E1, 2E-total to 16{alpha}-total (which reflects the ratio of 2-hydroxylation to 16{alpha}-hydroxylation) (35), and 2E-total to 4E-total (which reflects the ratio of 2-hydroxylation to 4-hydroxylation) were significantly greater during the periovulatory and midluteal phases than during the early and midfollicular phases (Table 3Go).


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  		Table 3. Urinary estrogen metabolite ratios

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
These data are the first to characterize 15 endogenous estrogens and their metabolites by gas chromatography-mass spectrometry in 24-h urine samples collected during four precisely defined menstrual cycle phases in healthy premenopausal women. Although the subjects consumed a soy protein isolate during the study, we have no reason to believe that this influenced the pattern of estrogen metabolite excretion across the menstrual cycle. Consistent with data reported by Berg and Kuss (28), urinary excretion of almost all estrogen metabolites was significantly increased during the periovulatory and midluteal phases, following the patterns of plasma E2 and E1. Of substantial interest is our observation that 2-hydroxylation of estrogens was increased to a greater extent than 16{alpha}-hydroxylation and 4-hydroxylation, a seemingly beneficial menstrual cycle event from a genotoxicity standpoint. The ratios of estrogen 2-hydroxylation to 16{alpha}-hydroxylation and 2-hydroxylation to 4-hydroxylation were 28% and 72% greater, respectively, during the periovulatory and midluteal phases than during the early follicular and midfollicular phases. These data are consistent with those of Chen et al. (29), who found that the ratio of 2-(OH)E1 to 16{alpha}-(OH)E1 was greater in the luteal than the follicular phase of the menstrual cycle. However, in that study the day of ovulation was not determined, and menstrual cycle phases were not precisely defined.

Variations in hormone concentrations across the menstrual cycle are known to have a potentially clinically significant impact on the metabolism of exogenous chemicals such as drugs (36) in addition to that of endogenous substances such as the estrogens described in this report. Wilson et al. (37) reported a doubling of methaqualone metabolism at midcycle, and Bruguerolle et al. (38) and Nagata et al. (39) reported increased theophyline metabolism in the follicular phase. Although the exact mechanism responsible for the menstrual cycle effects on estrogen metabolism is unknown, it is likely that menstrual cycle hormone fluctuations modulate hepatic enzyme activities such as CYP1A2 [the enzyme catalyzing the 2-hydroxylation of E1 (40) and E2 (41)], and CYP3A4 [the enzyme catalyzing estrogen 16{alpha}- and 4-hydroxylation (40)]. This idea is supported by data showing that progesterone activates 2-hydroxylation of endogenous estrogen in human liver microsomes (42) and in MCF-7 human breast cancer cells (43). The lack of such seemingly beneficial menstrual cycle effects in some anovulatory women, for example, those with polycystic ovarian syndrome, might in part account for their increased endometrial cancer risk above and beyond that simply due to diminished progesterone action on the endometrium. In any event, regardless of the underlying mechanism, our data strongly suggest the need to control for menstrual cycle phase in studies of estrogen metabolism involving normally cycling premenopausal women.


   Acknowledgments
 
We are grateful to Prof. Herman Adlercreutz, Department of Clinical Chemistry, University of Helsinki (Helsinki, Finland), for his advice on our analytic work, and to Dr. Will Thomas, Division of Biostatistics, School of Public Health, University of Minnesota, for his advice on our statistical analysis. We also thank the subjects and staff at the General Clinical Research Center, University of Minnesota. The soy powder was kindly donated by Protein Technologies International (St. Louis, MO).


   Footnotes
 
1 This work was supported by NIH Grant CA-66016 and General Clinical Research Center Grant MO1-RR-00400 from the National Center for Research Resources. Back

Received March 11, 1999.

Revised June 30, 1999.

Accepted July 8, 1999.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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