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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 2 410-414
Copyright © 1998 by The Endocrine Society

Original Studies

Comparison of the Impact of Transdermal Versus Oral Estrogens on Biliary Markers of Gallstone Formation in Postmenopausal Women1

Meike L. Uhler2, Jay W. Marks, Barbara J. Voigt and Howard L. Judd

Department of Obstetrics and Gynecology (M.L.U., B.J.V., H.L.J.) and Internal Medicine (J.W.M.), Cedars-Sinai Medical Center and the University of California School of Medicine, Los Angeles, California 90095

Address all correspondence and requests for reprints to: Howard L. Judd, M.D., Department of Obstetrics and Gynecology, Olive View-University of California-Los Angeles Medical Center, 14445 Olive View Drive, Room 2B163, Sylmar, California 91342-1495.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
This prospective, randomized, double blind, parallel study was undertaken to elucidate further the potential mechanisms through which estrogens could promote the formation of cholesterol gallstones and to compare the impact of nonoral (transdermal) and oral estrogens on serum, hepatic, and biliary markers of estrogen action. Ninety-seven postmenopausal women were randomized to receive either transdermal estradiol (E2; 0.1 mg every 3.5 days; n = 48) or oral conjugated equine estrogens (1.25 mg every day; n = 49) for 8 weeks. Blood samples were drawn, and bile samples were obtained by cholecystokinin-stimulated duodenal drainage before and after 8 weeks of estrogen administration. The main outcome measures included serum FSH, LH, E2, estrone, estrone sulfate, sex hormone-binding globulin, lipid profiles, biliary cholesterol saturation index, cholesterol nucleation time, presence of cholesterol crystals in bile, as well as biliary arachidonate, PGE2, and mucous glycoproteins. Estrogens administered by both routes increased circulating estrogens and resulted in similar suppression of both gonadotropins. Sex hormone-binding globulin was clearly increased, and the changes in serum lipids were more pronounced with oral conjugated equine estrogens than with transdermal E2. The biliary cholesterol saturation index was significantly increased compared to the baseline values with both transdermal E2 (1.08 ± 0.04 vs. 1.00 ± 0.03; mean change, 8%) and oral conjugated equine estrogens (1.04 ± 0.03 vs. 0.99 ± 0.03; mean change, 6%); however, there was no difference between the treatments. The number of patients with cholesterol crystals detected in bile was similar after both estrogen regimens. Transdermal and oral estrogens decreased nucleation time in vitro, increased arachidonate and PGE2 levels, and minimally raised total glycoprotein concentrations. In conclusion, transdermal and oral estrogens exerted comparable nonhepatic effects, as evidenced by similar reductions of gonadotropin levels, but oral therapy exhibited substantially greater actions on hepatic markers of estrogen action. Both transdermal E2 and oral conjugated equine estrogens significantly elevated the biliary cholesterol saturation index and reduced the nucleation time. These results suggest that estrogens at the doses studied could promote gallstone formation by alteration of biliary lipids and cholesterol nucleation time that have been incriminated in this process.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE FORMATION of cholesterol gallstones is thought to require alteration of three physiological processes: enhanced saturation of bile with cholesterol, more rapid precipitation (nucleation) of solid crystals of cholesterol in bile, and growth of individual crystals into microscopic and then macroscopic gallstones (1, 2). Recently, it has been theorized that nucleation is the critical step in the formation of cholesterol gallstones (2), and several pro- and antinucleating factors have been identified in bile. Mucous glycoprotein appears to be a pronucleating factor (3, 4) and may also be important in the growth of gallstones (5). Studies in animal models have revealed that the synthesis and secretion of mucous glycoproteins in the gallbladder may be controlled by the levels of biliary arachidonate via its conversion to PGs (6). In obese women during rapid weight loss, a situation known to increase gallstone formation (7), enhanced saturation of bile with cholesterol, decreased nucleation time, and increased levels of arachidonate, PGE2, and total glycoproteins have all been found, thereby revealing the potential pathophysiology of stone formation (8, 9, 10, 11).

Estrogen is also thought to promote the formation of gallstones. Epidemiologically, women have more gallstones than men. Gallstone formation is increased in pregnancy, with oral contraceptive usage (12, 13), in men treated with estrogen (14, 15), and in some studies of postmenopausal women on estrogen therapy (16, 17, 18). Mechanistically, estrogens have been shown to increase cholesterol saturation of bile, alter bile acid composition, and decrease bile flow (19, 20). Each or all of these effects could contribute to enhanced stone formation. The oral administration of estrogen elicits enhanced hepatic actions on lipid and protein synthesis compared to nonoral administration. Thus, it has been hypothesized that the nonoral administration of estrogen may reduce the impact this hormone has on the composition of bile and the formation of cholesterol gallstones.

The objectives of the present investigation were 1) to elucidate further the potential mechanisms through which estrogens could promote cholesterol gallstone formation, and 2) to compare the impact of nonoral (transdermal) and oral estrogen administration on a variety of serum, hepatic, and biliary end points of estrogen action.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
A total of 97 postmenopausal women participated in this randomized 8-week study. Inclusion criteria included women who were between 40–70 yr of age and had undergone spontaneous menopause more than 1 yr or surgical menopause more than 3 months before the start of the study. Menopausal status was confirmed by serum levels of FSH greater than 40 mIU/mL and levels of estradiol (E2) less than 30 pg/mL. The subjects had not received injectable hormone therapy within 1 yr or oral estrogens within 2 months before entry into the study. All subjects were within 30% of their ideal body weight. Exclusion criteria included a history of gallbladder disease in the past or present, gallstones documented by ultrasound in the past or present, prior cholecystectomy, liver disease (defined as aspartate aminotransferase and/or alanine aminotransferase >2 times the upper limits of normal), renal disease (defined as blood urea nitrogen >30 mg/dL or creatinine >2.0 mg/dL), hypercholesterolemia (defined as low density lipoprotein cholesterol >190 mg/dL), use of lipid-lowering drugs or drugs that would alter biliary lipids, dieting or major weight loss greater than 20 lb, cancer, alcohol or drug abuse, current vaginal bleeding, uncontrolled hypertension, and diabetes mellitus.

Using a double blind and parallel study design, all subjects were randomized to receive either E2 (0.1 mg administered by a transdermal patch that was applied every 3.5 days; Estraderm, Ciba-Geigy Pharmaceuticals, Summit, NJ) or oral conjugated equine estrogens (1.25 mg daily; Premarin, Wyeth-Ayerst Laboratories, Philadelphia, PA). Each was administered for 8 weeks. These doses were chosen because these have been shown to have comparable effects on nonhepatic markers of estrogen action and to increase the likelihood that any biliary effects elicited would be observed (21). A placebo tablet identical to conjugated equine estrogens was given to those subjects receiving an active patch, and a placebo patch identical to the active one was applied to those subjects taking active conjugated equine estrogen tablets. All study medications and placebo patches and tablets were supplied by Ciba-Geigy Pharmaceuticals. The study was approved by the institutional review board at Cedars-Sinai Medical Center (Los Angeles, CA), and each woman gave written informed consent.

All participants underwent a complete history and physical, pelvic examination, complete blood count, serum chemistry and lipid panels, Papanicolaou smear, vaginal cytology, endometrial biopsy, mammogram, and ultrasound of the gallbladder. For entry of a subject into the study, the results of all of these tests had to be normal.

Blood samples were drawn at baseline and after 8 weeks of estrogen administration. The end of treatment blood samples were obtained at 0800–0900 h on the second day of the application of the last patch and 24 h after the ingestion of the last tablet. Bile was also collected after venipuncture at baseline and again after 8 weeks of estrogen therapy in women who fasted overnight. A nasoduodenal tube was passed, and its position in the duodenum near the opening of the common bile duct was verified by fluoroscopy. Contraction of the gallbladder was stimulated with an iv infusion of the octapeptide of cholecystokinin at a rate of 0.5 ng/kg/min for 20 min. The darkest bile obtained during continuous aspiration was used for analysis (7). After the study was completed, all subjects with an intact uterus received medroxyprogesterone acetate (10 mg, orally; Provera, Upjohn Co., Kalamazoo, MI) for 30 days to avoid the development of endometrial hyperplasia.

Serum FSH, LH, E2, estrone (E1), estrone sulfate (E1S), and sex hormone-binding globulin (SHBG) were measured in both serum samples by methods that have been described previously (21, 22). Serum total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol, and triglycerides were assessed in both samples by the Physicians Clinical Laboratories (Burbank, CA). Lipoprotein cholesterol fractions were precipitated by dextran sulfate and magnesium, and measured with an Olympus AU5200 (Lake Success, NY) along with total cholesterol and triglycerides (23).

An aliquot of bile obtained from the duodenum was centrifuged at 100,000 x g for 2 h. The supernatant was used for biochemical analyses. Cholesterol crystals were identified in the sediment by light microscopy at x400. The concentration of cholesterol in bile was measured by gas-liquid chromatography (24), total bile acids by the steroid dehydrogenase enzymatic method of Talalay (25), and total phospholipids according to the method of Fiske and Subbarow (as lipid phosphorus; recovery, 97.6%) (26). The cholesterol saturation index was determined using Carey’s critical tables (27). Total glycoproteins (which include mucous glycoproteins) were determined by the method of Yamazaki and LaRusso (28) and Perdigoto et al. (29). PGE2 levels in bile were measured by RIA as previously described (30). Nucleation time was determined as previously described (11). The use of duodenal bile for biochemical determinations and nucleation time has been validated previously (7, 10, 11, 31).

Sample size calculations were based on the biliary cholesterol saturation index data from Van Erpecum et al. (32) where the SE of the cholesterol saturation index for each of the two treatment groups was approximately 0.33 (based on an overall approximate SE of 0.08 and a sample size of 17). In this parallel group trial, to achieve an {alpha} level of 0.05, a ß level of 0.20 (study power of 0.80), and a {delta} of 0.20 would require a minimum of 43 participants in each treatment group to be studied. All values are expressed as the mean ± SD unless otherwise noted. Comparison of baseline values between groups was performed by a two-sample t test. A paired t test was used to determine whether the percent change or the change from baseline of each treatment was significantly different from zero. Between-treatment comparisons were carried out by examining the differences between treatments in percent change and change from baseline. Two sample t tests or McNemar tests were used for these comparisons. Significance was accepted at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The demographic characteristics for the subjects in the two study groups demonstrated no statistically significant differences with respect to race, gravidity, parity, age of onset of menopause, weight, or number of participants with a prior history of hormone therapy. The ages of the subjects ranged from 40–68 yr, with a mean of 56 yr for transdermal E2 and 53 yr for the oral conjugated equine estrogens group.

The baseline laboratory values by treatment groups were not significantly different for serum hormones, lipid profiles, and biliary measurements. The levels of both gonadotropins were elevated, whereas the concentrations of the three estrogens were within the ranges observed in hypogonadal women, reflecting the postmenopausal status of the participants. Mean total cholesterol levels (219.3 ± 29.2 mg/dL for transdermal E2 and 222.9 ± 31.1 mg/dL for oral conjugated equine estrogens) were in the borderline elevated range, whereas the cholesterol fractions and triglyceride levels were in the normal ranges for women in this age group. For the biliary end points, the cholesterol saturation indexes for transdermal E2 and oral conjugated equine estrogens were 1.0 ± 0.2 and 0.99 ± 0.2, respectively, and the nucleation times for transdermal E2 and oral conjugated equine estrogens were 17.8 ± 5.8 and 18.1 ± 5.6 days, respectively. These values were similar to those observed in healthy perimenopausal women and obese women without gallstones (7, 33). Eight women in each group had cholesterol crystals at baseline. Levels of archidonate (4.5 ± 2.3% for transdermal E2 and 4.5 ± 2.4% for oral conjugated equine estrogens), PGE2 (262.6 ± 141.4 pg/mL for transdermal E2 and 256.6 ± 179.1 pg/mL for oral conjugated equine estrogens), and total glycoproteins (2.5 ± 3.2 mg/mL for transdermal E2 and 1.8 ± 1.4 mg/mL for oral conjugated equine estrogens) in these postmenopausal women were also comparable to values in obese patients without gallstones (10). The values of all of these end points were not significantly different between groups, again indicating that randomization of the participants was successful in separating two similar groups.

The percent change with each treatment from baseline as well as a comparison of the percent change for each parameter between groups are listed in Table 1Go. Both treatments elicited significant and similar decreases from baseline in the values of serum FSH and LH. Both also showed significant increases from baseline in the values of serum E2, E1, and E1S. The mean increase in E2 was significantly greater with transdermal E2, whereas the increases in E1 and E1S were significantly greater with oral conjugated equine estrogens. For SHBG, no significant change from baseline was observed with transdermal E2, whereas a significant increase was seen with oral conjugated equine estrogens. This between-treatment difference was statistically significant (P < 0.05) for SHBG.


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  		Table 1. Percent change from baseline for FSH, LH, E2, E1, E1S, and SHBG and percent change comparison between groups

 
For circulating lipids, transdermal E2 elicited significant decreases in total cholesterol and low density lipoprotein cholesterol only (Table 2Go). For conjugated equine estrogens, significant increases in high density lipoprotein cholesterol, very low density lipoprotein cholesterol, and triglycerides and significant decreases in total cholesterol and low density lipoprotein cholesterol were observed. In comparisons between groups, the percent changes with oral conjugated equine estrogens were always greater than those elicited with transdermal E2, with the exception of total cholesterol.


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  		Table 2. Percent change from baseline for lipid profile and percent change comparison between groups

 
For the biliary parameters, the percent changes from baseline showed significant increases (P < 0.05) in the cholesterol saturation index, arachidonate, PGE2, and total cholesterol and a significant decrease in nucleation time for both treatment groups (Table 3Go). These changes were not significantly different between groups. The number of women who developed cholesterol crystals for the first time during treatment were three and none for transdermal and oral estrogen therapy, respectively. Total glycoproteins, bile acids, phospholipids, and total biliary lipids were minimally affected by both treatments.


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  		Table 3. Percent change from baseline for biliary measures and percent change comparison between groups

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, administration of E2 transdermally and conjugated equine estrogens orally elevated circulating E2, E1, and E1S levels, indicating compliance of the participants with the study regimens. It was anticipated that transdermal E2 would raise the level of this hormone substantially more than conjugated equine estrogens, whereas conjugated equine estrogens would increase E1 and E1S more so than transdermal E2 because the major estrogen of this oral preparation is E1S. These changes in hormone levels occurred as anticipated. Although levels of these three estrogens at the end of treatment were very different between the two treatment groups, it was anticipated that the doses of these preparations chosen would elicit similar effects on nonhepatic markers of estrogen action. This was demonstrated by the comparable suppressions of FSH and LH levels by both estrogens at the end of treatment. These findings confirmed previous reports (21).

It was also anticipated that conjugated equine estrogens would have a greater impact than transdermal E2 on hepatic markers of estrogen action because of its oral route of administration. This was confirmed by the significantly greater changes in SHBG and circulating lipids with conjugated equine estrogens than with transdermal E2. These findings also confirmed results reported previously by us and others (21, 34, 35).

Both estrogen treatments significantly increased the biliary saturation of cholesterol and decreased the time required to form cholesterol crystals in bile in vitro (nucleation time). Taken together, these findings support the concept that transcutaneous and oral estrogen administration increases the chances of women developing gallstones by increasing the cholesterol saturation index and promoting nucleation of cholesterol into crystals. An increase in the cholesterol saturation index and a decrease in the nucleation time represent two of the three mechanisms theorized to be responsible for stone formation (1, 2). In addition, significant increases in arachidonate and PGE2 were seen (36). These factors may be responsible for mucus glycoprotein production in bile (37). This last factor decreases nucleation time and enhances probable stone formation. These findings continue to support the concept that estrogens secreted in normal or pregnant women, administered in oral contraceptives, or given as hormone replacement increase the chances of gallstone formation. The only clinical trial of estrogens that reported gallbladder disease found two women each with stones in the placebo and estrogen only group. However, the trial was too small and brief to determine differences in gallstone formation between treatment groups (38).

It must be remembered that the doses of estrogen used in this study (0.1 mg transdermal E2 and 1.25 mg conjugated equine estrogens) are prescribed for estrogen replacement, but are twice as much as the lowest doses required to prevent osteoporosis (39). These doses were chosen to increase the chance of seeing changes in biliary function, which was accomplished. It is likely that lower doses of transdermal E2 and oral conjugated equine estrogens would have less effect on biliary end points.

It is of great interest that the enhanced hepatic actions elicited by oral conjugated equine estrogens in comparison to transdermal E2 were not reflected in the biliary lipid alterations. It is unlikely that these findings were the result of an artifact of the study design, because significant and similar changes in biliary end points occurred with both the transdermal and oral estrogen groups. These findings suggest that the nonoral administration of estrogen does not avoid the biliary changes elicited with oral therapy. There are few reports available in the literature examining gallbladder bile after the administration of transdermal or oral estrogens. Heuman and co-workers (19) studied three postmenopausal women who were given 50 µg ethinyl estradiol daily for 3 weeks followed by intervals of 1 week without therapy for three or four treatment cycles. They found that the treatment resulted in an increased fraction of cholesterol in gallbladder bile and a shift in the bile acid composition favoring cholesterol gallstone formation. A single postmenopausal woman was given percutaneous estradiol valerate (5 mg daily) for 6 weeks and after a 6-week washout period, oral estradiol valerate (2 mg daily) for 6 weeks (40). After both methods of administration, there was an increase in the biliary cholesterol concentration but after oral administration, bile flow also increased, and cholesterol crystals appeared in the bile. Everson and colleagues (41) studied 29 anovulatory women, aged 28–62 yr, given oral conjugated equine estrogens in doses ranging from 0.625–1.25 mg daily for at least 4 weeks. They found that oral estrogens increased the lithogenic index of bile, increased biliary cholesterol secretion, and altered biliary acid composition. The report by Van Erpecum et al. (32) was the first to directly compare transdermal to oral E2 in 17 postmenopausal women. Unfortunately, the small number of patients investigated limited the power of their study.

In summary, transdermal and oral estrogen preparations were administered to postmenopausal women for 8 weeks to determine their impact on a variety of markers of estrogen action. Although the administration of these two medications resulted in very different circulating levels of estrogens, they elicited comparable effects on nonhepatic markers of estrogen action (gonadotropin levels). The oral administration of conjugated equine estrogens induced greater changes in hepatic markers (levels of SHBG and lipids) than transdermal E2. Significant increases in biliary cholesterol saturation index, arachidonate, and PGE2 and a significant decrease in the nucleation time were observed after both the nonoral and oral administration of estrogens. These findings continue to support the hypothesis that estrogens, whether administered transcutaneously or orally, increase the chances of gallstone formation by alteration of biliary lipids and nucleation of cholesterol that have been incriminated in this process.


   Footnotes
 
1 Presented in part at the 43rd Annual Meeting of the Society for Gynecologic Investigation, Philadelphia, PA, March 20–23, 1996. Back

2 Present address: Department of Obstetrics and Gynecology, Loyola University Medical Center, 2160 South First Avenue, Maywood, Illinois 60153. Back

Received June 24, 1997.

Revised October 8, 1997.

Accepted October 20, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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