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ESTROGEN REPLACEMENT INCREASED THE CITRATE AND CALCIUM EXCRETION RATES IN POSTMENOPAUSAL WOMEN WITH RECURRENT UROLITHIASIS
0022-5347/02/1671-0169/0 THE JOURNAL OF UROLOGY® Copyright © 2002 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Vol. 167, 169 –171, January 2002 Printed in U.S.A.
ESTROGEN REPLACEMENT INCREASED THE CITRATE AND CALCIUM EXCRETION RATES IN POSTMENOPAUSAL WOMEN WITH RECURRENT UROLITHIASIS JAYANT DEY, AMERY CREIGHTON, JILL S. LINDBERG, HAROLD A. FUSELIER,* DIRK J. KOK, FRANCIS E. COLE AND LEE L. HAMM From the Departments of Endocrinology, Nephrology, Urology and Research, Ochsner Clinic and Departments of Nephrology, Tulane University and Louisiana State University Medical Center, New Orleans, Louisiana, and Department of Pediatric Urology, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands
ABSTRACT
Purpose: Epidemiological data indicate a sharp increase in urinary calcium stone formation after menopause. We investigated the role of menopausal estrogen replacement therapy on the urinary constituents and characteristics that may influence recurrent calcium oxalate stone disease. Materials and Methods: Urinary constituents in 28 postmenopausal women on estrogen replacement therapy for more than 6 months were compared with those in 41 women who had never been exposed to estrogen after menopause. These 2 groups had a history of recurrent calcium oxalate urolithiasis. A group of age matched, nonstone forming volunteers who were and were not on estrogen served as controls. Results: The 24-hour urine collection revealed significantly higher mean calcium plus or minus standard deviation (188.8 ⫾ 101.5 versus 129.2 ⫾ 80.9 mg./24 hours, p ⬍0.01), citrate (576.6 ⫾ 237.9 versus 306.2 ⫾ 209.9 mg./24 hours, p ⬍0.001) and agglomeration inhibition (203 ⫾ 106 versus 159 ⫾ 81 minutes, p ⬍0.05) in stone forming women who were versus were not on estrogen. Conclusions: Higher urinary citrate and higher agglomeration inhibition in women exposed to estrogen may decrease the risk of subsequent calcium stone formation. KEY WORDS: kidney, kidney calculi, postmenopause, estrogens, calcium oxalate
Female sex hormones may decrease the rate of renal stone formation. In men there is a 2 to 3-fold higher incidence of urolithiasis than in women, in whom the incidence of new stone formation increases after menopause.1 Epidemiological surveys indicate that stones in women may have a biphasic distribution with peaks at about ages 30 and 55 years.2 Intact or sham operated female rats given lithogenic ethylene glycol had a significantly lower incidence of calcium oxalate stone formation than rats that underwent oophorectomy.3 The first prerequisite of stone formation is a period of crystalluria, during which a particle is formed that can become large enough to be trapped within the urinary tract. The risk factors believed to be involved in the formation of large crystals and aggregates are urinary supersaturation with calcium salts and decreased inhibitory activity against further growth and agglomeration. Urinary volume and pH as well as the excretion of various urinary solutes, including proteins, citrate, calcium and oxalate, have a crucial role in the dynamics of stone formation.4 Recent animal data show that estrogen may decrease urinary oxalate and osteopontin excretion, which are stone matrix constituents.5 Citrate, which inhibits the crystallization of calcium salts in urine and, thus, may inhibit calcium urolithiasis, is often lower in calcium stone formers than in normal individuals.6 Prophylactic therapy with oral citrate salts significantly increases agglomeration inhibition and decreases stone formation in recurrent calcium stone formers.6, 7 Citrate levels vary during the menstrual cycle with the highest levels of citrate
during the most estrogenic phase.8 Thus, there appears to be a relationship of estrogen and urinary citrate excretion. To define further the effects of estrogen on the urinary parameters that influence the risk of subsequent stone formation we studied a group of postmenopausal women with idiopathic recurrent calcium oxalate stone disease. We compared those receiving and not receiving estrogen replacement therapy. A control group of postmenopausal women with no history of stone disease was included in the study for comparison. MATERIALS AND METHODS
We studied the urinary constituents of 69 postmenopausal women who presented with recurrent kidney stones, including at least 1 stone within the previous 12 months with a predominantly calcium oxalate composition. Clinical menopause was defined as no menstruation for greater than 6 months in patients older than 50 years old. Of the women 28 were on estrogen replacement therapy with 0.625 or 1.25 mg. conjugated estrogens in tablet form daily, while the remaining 41 had never been exposed to exogenous estrogen after clinical menopause. At study inclusion none was on oral citrate, thiazide, calcium or vitamin D therapy. In each patient the stone burden was evaluated at the initial presentation and subsequently to monitor the effect of therapy. Stone burden evaluation was not usually done at the time of urinalysis and it varied. Our data were not obtained from matched pairs of observations of women who were and were not on estrogen replacement therapy. We have no evidence that the total stone burden varied in the 2 groups. As controls, we recruited 19 age matched healthy menopausal volunteers from the community. None of the controls
Accepted for publication August 3, 2001. Financial interest and/or other relationship with Barr, Abbott, Alza, Pfizer, Merck, TAP, Zeneca and Bayer. 169
170
ESTROGEN REPLACEMENT IN POSTMENOPAUSAL WOMEN WITH UROLITHIASIS
had a history of kidney stones, endocrine or renal disease. In this group 13 women were receiving estrogen replacement and 6 were not. We obtained 24-hour urine samples on an outpatient basis, which were maintained at room temperature. Thymol crystals were added as a preservative before urine collection. Urinary oxalate was determined enzymatically using a commercially available diagnostic kit. Urinary citrate was measured by adapting the citrate lyase enzymatic method.7 Calcium, urate and creatinine were determined by routine clinical procedures at the department of pathology. Crystal agglomeration was measured using the Kok in vitro laboratory method, in which urine at 20% dilution is seeded with calcium oxalate monohydrate crystals at 37C, pH 6.0.7 Agglomeration inhibition was quantitated by measuring the inhibitory effect of urine on the seed crystal uptake of 45calcium tracer. Data were analyzed using commercially available software. Values are presented as the mean plus or minus standard deviation with differences considered significant at p ⬍0.05. The parametric unpaired t test was used for group comparisons. RESULTS
Tables 1 and 2 show the results. The urinary citrate and calcium excretion rates as well as the citrate concentration were higher in estrogen treated postmenopausal women than in those not on estrogen (table 1). Agglomeration inhibition was higher in stone forming and nonstone forming women on estrogen replacement compared with those not on that therapy (tables 1 and 2). There were no significant differences in urinary oxalate, creatinine, urate (data not shown) or total urinary volume in the groups. DISCUSSION
We studied the effect of estrogen on the urinary constituents of postmenopausal women with recurrent calcium oxalate stone disease. Estrogen use was accompanied by increased urine citrate, calcium and agglomeration inhibition but no significant change in oxalate. Agglomeration inhibition also increased with estrogen use in a smaller group of postmenopausal women without a history of kidney stones. Increased urinary citrate would have been expected to decrease the propensity for future stones in these cases, while increased urinary calcium may have the opposite effect. A net beneficial effect on the risk of recurrent stone formation was indicated by improved agglomeration inhibition in patients on estrogen. Estrogen use was associated with significantly higher urinary calcium in stone formers. Postmenopausal women have been reported to have higher urinary calcium than premenopausal women.9 Estrogen therapy has been shown to decrease 24-hour urine calcium excretion in postmenopausal women with primary hyperparathyroidism.10 After menopause variable periods of estrogen administration have been
associated with decreased urinary calcium excretion.11, 12 Thus, the higher urinary calcium excretion rate in estrogen replete versus deficient stone formers was somewhat surprising. This finding may have been due to methodological differences. In other studies urinary calcium was measured before and after estrogen replacement, while in our series women on estrogen for more than 6 months were compared with women who had never received hormone replacement therapy. Differences arising from recall bias in study participants cannot be ruled out. Moreover, urinary calcium was not increased in the estrogen replacement group, whereas citrate was increased. The net effect may be explained by increased agglomeration inhibition. Estrogen has multiple effects on calcium metabolism. After menopause estrogen increases calcium absorption13 from the gut. Calcium absorption decreases after menopause and with aging,14 and increases to premenopausal levels during estrogen replacement.15 Estrogen induced increased calcium absorption of calcium in the gut as well as intrinsic defects in the renal tubular reabsorption of calcium16 may explain increased calcium excretion by recurrent stone formers on estrogen in our study. Despite increased urinary calcium in the group on estrogen a higher level of stone inhibiting urinary citrate may have decreased calcium oxalate urolithiasis. Citrate excreted in urine binds to calcium, forming a soluble salt and, thus, decreasing urinary supersaturation with respect to calcium oxalate. Urinary citrate also interacts with calcium oxalate crystals as an inhibitor of agglomeration, nucleation and crystal growth.17 In postmenopausal women higher urinary citrate and lower calcium oxalate saturation have been associated with higher estrogen after hormone replacement.18 Increased urinary citrate may have been secondary to a decreased acid load in the women on estrogen. Urinary citrate is influenced by the systemic acid-base balance and acid load.19 The decreased acid load and excretion while on estrogen may be reflected by the almost significant increase in urinary pH (p ⫽ 0.083). Daily acid production is the sum of dietary acid or alkali and endogenous acid production by the metabolism. Acid production is balanced by net acid excretion in the urine. To our knowledge an effect of estrogens on the acid-base balance has not previously been documented. Whether dietary acid absorption is decreased or endogenous acid production is inhibited by estrogens has not been determined to our knowledge. A decreased acid load by whatever mechanism would be expected to decrease urinary calcium since acidosis increases calcium release from bone and decreases calcium resorption in the kidneys. Therefore, urinary calcium changes must reflect other mechanisms, as discussed. It has been proposed that elderly individuals are subject to eubicarbinatemic metabolic acidosis, a condition with normal serum bicarbonate but a slightly increased acid load.20 This condition is accompanied by increased muscle catabolism, bone demineralization, increased urinary cal-
TABLE 1. Comparison of 24-hour urinary constituents in stone formers Estrogen No. pts. Mean age ⫾ SD Mean 24-hr. urinary values ⫾ SD: Vol. (l.) pH Calcium (mg./24 hrs.) Citrate (mg./24 hrs.) Oxalate (mmol./24 hrs.) Mins. agglomeration inhibition (No. pts.) Calcium (mg./l.) Citrate (mg./l.) Oxalate (mmol./l.)
28 59.1 ⫾ 9.4 1.96 ⫾ 0.61 6.06 ⫾ 0.48 188.8 ⫾ 101.5 576.6 ⫾ 237.9 0.35 ⫾ 0.13 203 ⫾ 106 (24) 104.08 ⫾ 64.74 223.07 ⫾ 138.24 0.19 ⫾ 0.08
No Estrogen
p Value
41 62.2 ⫾ 9.6 1.88 ⫾ 0.84 5.83 ⫾ 0.59 129.2 ⫾ 80.9 306.2 ⫾ 209.9 0.34 ⫾ 0.19 159 ⫾ 81 (35) 80.65 ⫾ 73.58 186.24 ⫾ 134.40 0.20 ⫾ 0.11
⬍ 0.01 ⬍ 0.001 ⬍ 0.05 ⬍ 0.001
ESTROGEN REPLACEMENT IN POSTMENOPAUSAL WOMEN WITH UROLITHIASIS
171
TABLE 2. Comparison of 24-hour urinary constituents in controls Estrogen No. controls Mean age ⫾ SD Mean 24-hr. urinary values ⫾ SD: Vol. (l.) pH Calcium (mg./24 hrs.) Citrate (mg./24 hrs.) Oxalate (mmol./24 hrs.) Mins. agglomeration inhibition (No. controls) Calcium (mg./l.) Citrate (mg./l.) Oxalate (mmol./l.)
13 55.5 ⫾ 6.9
CONCLUSIONS
Estrogen replacement therapy may have beneficial effects in postmenopausal women with recurrent calcium oxalate urolithiasis. Our results show increased citrate and calcium excretion in postmenopausal women receiving estrogen supplementation. A concern is whether increased urinary calcium in estrogen replete calcium oxalate stone formers may increase the risk of subsequent stone formation. The increased stone inhibitory citrate level and increased agglomeration inhibition imply an overall beneficial effect of estrogen on the risk of calcium oxalate stone recurrence in postmenopausal women. We suggest that the possibility of decreased kidney stone formation may be included in the discussion with postmenopausal women considering estrogen replacement therapy. The number of patients in our study was insufficient to recommend that estrogen replacement therapy should be given to replace or serve as an adjunct to the more accepted medical regimens for recurrent urolithiasis. REFERENCES
1. Morikawa, M., Okuyama, M., Yoshihara, H. et al: [A study of the differences between the sexes in epidemiology of urolithiasis.] Nippon Hinyokika Gakkai Zasshi, 89: 538, 1998 2. Williams, R. E.: The natural history of renal lithiasis. In: Proceedings of the Renal Stone Research Symposium. Edited by A. Hodgkinson and B. C. E. Nordin. London: Churchill, p. 65, 1969 3. Lee, Y. H., Huang, W. C., Huang, J. K. et al: Testosterone enhances whereas estrogen inhibits calcium oxalate stone formation in ethylene glycol treated rats. J Urol, 156: 502, 1996 4. Coe, F. L., Parks, J. H. and Asplin, J. R.: The pathogenesis and treatment of kidney stones. N Engl J Med, 327: 1141, 1992 5. Iguchi, M., Takamura, C., Umekawa, T. et al: Inhibitory effects of female sex hormones on urinary stone formation in rats.
p Value
6 55.3 ⫾ 4.3
1.79 ⫾ 0.5 6.07 ⫾ 0.45 185.42 ⫾ 105.45 568.27 ⫾ 230.37 0.36 ⫾ 0.09 273 ⫾ 90 (11) 110.2 ⫾ 60 339.8 ⫾ 172.8 0.21 ⫾ .05
cium and decreased urinary citrate. Estrogen appears to counteract several of these aspects. Increased agglomeration inhibition in estrogen replete postmenopausal women represents objective evidence that they may be less likely to form calcium oxalate stones even in the presence of increased urinary calcium. Agglomeration inhibition reflects the sum of the stone inhibitory constituents of urine. Previous studies have not addressed the effect of estrogens on agglomeration inhibition. Increased agglomeration inhibition in our study in women on estrogen likely indicates that inhibitory factors, including increased urinary citrate, may be protective.
No Estrogen
2.11 ⫾ 0.6 5.71 ⫾ 0.57 130.32 ⫾ 86.60 497.03 ⫾ 223.92 0.38 ⫾ 0.03 195 ⫾ 11 (4) 77.2 ⫾ 69.2 226.6 ⫾ 80.6 0.19 ⫾ 0.05
⬍ 0.01 ⬍ 0.05
Kidney Int, 56: 479, 1999 6. Fuselier, H. A., Moore, K., Lindberg, J. et al: Agglomeration inhibition reflected stone-forming activity during long-term potassium citrate therapy in calcium stone formers. Urology, 52: 988, 1998 7. Kok, D. J., Papapoulos, S. E. and Bijvoet, O. L. M.: Crystal agglomeration is a major element in calcium oxalate urinary stone formation. Kidney Int, 37: 51, 1990 8. Shorr, R., Bernhein, A. R. and Taussky, H.: The relation of urinary citric acid excretion to the menstrual cycle and the steroidal reproductive hormones. Science, 95: 606, 1942 9. Nordin, B. E., Need, A. G., Morris, H. A. et al: Biochemical variables in pre- and postmenopausal women: reconciling the calcium and estrogen hypotheses. Osteoporosis Int, 9: 351, 1999 10. Marcus, R., Madvig, P., Crim, M. et al: Conjugated estrogens in the treatment of postmenopausal women with hyperparathyroidism. Ann Intern Med, 100: 633, 1984 11. McKane, W. R., Khosla, S., Burritt, M. F. et al: Mechanism of renal calcium conservation with estrogen replacement therapy in women in early postmenopause: a clinical research center study. J Clin Endocrinol Metab, 80: 3458, 1995 12. Reginster, J. Y., Christiansen, C., Dequinze, B. et al: Effect of transdermal 17 beta-estradiol and oral conjugated equine estrogens on biochemical parameters of bone resorption in natural menopause. Calcif Tissue Int, 53: 13, 1993 13. Canniggia, A., Gennari, C., Borrello, G. et al: Intestinal absorption of calcium-47 after treatment with oral oestrogengestogens in senile osteoporosis. Br Med J, 4: 30, 1970 14. Bullamore, J. R., Wilkinson, R., Gallagher, J. C. et al: Effect of age on calcium absorption. Lancet, 2: 535, 1970 15. Gallagher, J. C., Riggs, B. L. and DeLuca, H. F.: Effect of estrogen on calcium absorption and serum vitamin D metabolites in postmenopausal osteoporosis. J Clin Endocrinol Metab, 51: 1359, 1980 16. Lemann, J., Jr., Worcester, E. M. and Gray, R. W.: Hypercalciuria and stones. Am J Kidney Dis, 17: 386, 1991 17. Lieske, J. C. and Coe, F. L.: Urinary inhibitors and renal stone formation. In: Kidney Stones: Medical and Surgical Management. Edited by F. L. Coe. Philadelphia: Lippincot-Raven, p. 65, 1986 18. Puche, R. C., Roveri, E., Perez Jimeno, N. et al: Hypercalciuria and urinary saturation measurements in climacteric women. Maturitas, 16: 39, 1993 19. Kok, D. J., Iestra, J. A., Doorenbos, C. J. et al: The effects of dietary excesses in animal protein and in sodium on the composition and the crystallization kinetics of calcium oxalate monohydrate in urines of healthy men. J Clin Endocrinol Metab, 71: 861, 1990 20. Alpern, R. J., Sakhaee, K.: The clinical spectrum of chronic metabolic acidosis: homeostatic mechanisms produce significant morbidity. Am J Kidney Dis, 29(2): 291, 1997
Vol. 167, 169 –171, January 2002 Printed in U.S.A.
ESTROGEN REPLACEMENT INCREASED THE CITRATE AND CALCIUM EXCRETION RATES IN POSTMENOPAUSAL WOMEN WITH RECURRENT UROLITHIASIS JAYANT DEY, AMERY CREIGHTON, JILL S. LINDBERG, HAROLD A. FUSELIER,* DIRK J. KOK, FRANCIS E. COLE AND LEE L. HAMM From the Departments of Endocrinology, Nephrology, Urology and Research, Ochsner Clinic and Departments of Nephrology, Tulane University and Louisiana State University Medical Center, New Orleans, Louisiana, and Department of Pediatric Urology, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands
ABSTRACT
Purpose: Epidemiological data indicate a sharp increase in urinary calcium stone formation after menopause. We investigated the role of menopausal estrogen replacement therapy on the urinary constituents and characteristics that may influence recurrent calcium oxalate stone disease. Materials and Methods: Urinary constituents in 28 postmenopausal women on estrogen replacement therapy for more than 6 months were compared with those in 41 women who had never been exposed to estrogen after menopause. These 2 groups had a history of recurrent calcium oxalate urolithiasis. A group of age matched, nonstone forming volunteers who were and were not on estrogen served as controls. Results: The 24-hour urine collection revealed significantly higher mean calcium plus or minus standard deviation (188.8 ⫾ 101.5 versus 129.2 ⫾ 80.9 mg./24 hours, p ⬍0.01), citrate (576.6 ⫾ 237.9 versus 306.2 ⫾ 209.9 mg./24 hours, p ⬍0.001) and agglomeration inhibition (203 ⫾ 106 versus 159 ⫾ 81 minutes, p ⬍0.05) in stone forming women who were versus were not on estrogen. Conclusions: Higher urinary citrate and higher agglomeration inhibition in women exposed to estrogen may decrease the risk of subsequent calcium stone formation. KEY WORDS: kidney, kidney calculi, postmenopause, estrogens, calcium oxalate
Female sex hormones may decrease the rate of renal stone formation. In men there is a 2 to 3-fold higher incidence of urolithiasis than in women, in whom the incidence of new stone formation increases after menopause.1 Epidemiological surveys indicate that stones in women may have a biphasic distribution with peaks at about ages 30 and 55 years.2 Intact or sham operated female rats given lithogenic ethylene glycol had a significantly lower incidence of calcium oxalate stone formation than rats that underwent oophorectomy.3 The first prerequisite of stone formation is a period of crystalluria, during which a particle is formed that can become large enough to be trapped within the urinary tract. The risk factors believed to be involved in the formation of large crystals and aggregates are urinary supersaturation with calcium salts and decreased inhibitory activity against further growth and agglomeration. Urinary volume and pH as well as the excretion of various urinary solutes, including proteins, citrate, calcium and oxalate, have a crucial role in the dynamics of stone formation.4 Recent animal data show that estrogen may decrease urinary oxalate and osteopontin excretion, which are stone matrix constituents.5 Citrate, which inhibits the crystallization of calcium salts in urine and, thus, may inhibit calcium urolithiasis, is often lower in calcium stone formers than in normal individuals.6 Prophylactic therapy with oral citrate salts significantly increases agglomeration inhibition and decreases stone formation in recurrent calcium stone formers.6, 7 Citrate levels vary during the menstrual cycle with the highest levels of citrate
during the most estrogenic phase.8 Thus, there appears to be a relationship of estrogen and urinary citrate excretion. To define further the effects of estrogen on the urinary parameters that influence the risk of subsequent stone formation we studied a group of postmenopausal women with idiopathic recurrent calcium oxalate stone disease. We compared those receiving and not receiving estrogen replacement therapy. A control group of postmenopausal women with no history of stone disease was included in the study for comparison. MATERIALS AND METHODS
We studied the urinary constituents of 69 postmenopausal women who presented with recurrent kidney stones, including at least 1 stone within the previous 12 months with a predominantly calcium oxalate composition. Clinical menopause was defined as no menstruation for greater than 6 months in patients older than 50 years old. Of the women 28 were on estrogen replacement therapy with 0.625 or 1.25 mg. conjugated estrogens in tablet form daily, while the remaining 41 had never been exposed to exogenous estrogen after clinical menopause. At study inclusion none was on oral citrate, thiazide, calcium or vitamin D therapy. In each patient the stone burden was evaluated at the initial presentation and subsequently to monitor the effect of therapy. Stone burden evaluation was not usually done at the time of urinalysis and it varied. Our data were not obtained from matched pairs of observations of women who were and were not on estrogen replacement therapy. We have no evidence that the total stone burden varied in the 2 groups. As controls, we recruited 19 age matched healthy menopausal volunteers from the community. None of the controls
Accepted for publication August 3, 2001. Financial interest and/or other relationship with Barr, Abbott, Alza, Pfizer, Merck, TAP, Zeneca and Bayer. 169
170
ESTROGEN REPLACEMENT IN POSTMENOPAUSAL WOMEN WITH UROLITHIASIS
had a history of kidney stones, endocrine or renal disease. In this group 13 women were receiving estrogen replacement and 6 were not. We obtained 24-hour urine samples on an outpatient basis, which were maintained at room temperature. Thymol crystals were added as a preservative before urine collection. Urinary oxalate was determined enzymatically using a commercially available diagnostic kit. Urinary citrate was measured by adapting the citrate lyase enzymatic method.7 Calcium, urate and creatinine were determined by routine clinical procedures at the department of pathology. Crystal agglomeration was measured using the Kok in vitro laboratory method, in which urine at 20% dilution is seeded with calcium oxalate monohydrate crystals at 37C, pH 6.0.7 Agglomeration inhibition was quantitated by measuring the inhibitory effect of urine on the seed crystal uptake of 45calcium tracer. Data were analyzed using commercially available software. Values are presented as the mean plus or minus standard deviation with differences considered significant at p ⬍0.05. The parametric unpaired t test was used for group comparisons. RESULTS
Tables 1 and 2 show the results. The urinary citrate and calcium excretion rates as well as the citrate concentration were higher in estrogen treated postmenopausal women than in those not on estrogen (table 1). Agglomeration inhibition was higher in stone forming and nonstone forming women on estrogen replacement compared with those not on that therapy (tables 1 and 2). There were no significant differences in urinary oxalate, creatinine, urate (data not shown) or total urinary volume in the groups. DISCUSSION
We studied the effect of estrogen on the urinary constituents of postmenopausal women with recurrent calcium oxalate stone disease. Estrogen use was accompanied by increased urine citrate, calcium and agglomeration inhibition but no significant change in oxalate. Agglomeration inhibition also increased with estrogen use in a smaller group of postmenopausal women without a history of kidney stones. Increased urinary citrate would have been expected to decrease the propensity for future stones in these cases, while increased urinary calcium may have the opposite effect. A net beneficial effect on the risk of recurrent stone formation was indicated by improved agglomeration inhibition in patients on estrogen. Estrogen use was associated with significantly higher urinary calcium in stone formers. Postmenopausal women have been reported to have higher urinary calcium than premenopausal women.9 Estrogen therapy has been shown to decrease 24-hour urine calcium excretion in postmenopausal women with primary hyperparathyroidism.10 After menopause variable periods of estrogen administration have been
associated with decreased urinary calcium excretion.11, 12 Thus, the higher urinary calcium excretion rate in estrogen replete versus deficient stone formers was somewhat surprising. This finding may have been due to methodological differences. In other studies urinary calcium was measured before and after estrogen replacement, while in our series women on estrogen for more than 6 months were compared with women who had never received hormone replacement therapy. Differences arising from recall bias in study participants cannot be ruled out. Moreover, urinary calcium was not increased in the estrogen replacement group, whereas citrate was increased. The net effect may be explained by increased agglomeration inhibition. Estrogen has multiple effects on calcium metabolism. After menopause estrogen increases calcium absorption13 from the gut. Calcium absorption decreases after menopause and with aging,14 and increases to premenopausal levels during estrogen replacement.15 Estrogen induced increased calcium absorption of calcium in the gut as well as intrinsic defects in the renal tubular reabsorption of calcium16 may explain increased calcium excretion by recurrent stone formers on estrogen in our study. Despite increased urinary calcium in the group on estrogen a higher level of stone inhibiting urinary citrate may have decreased calcium oxalate urolithiasis. Citrate excreted in urine binds to calcium, forming a soluble salt and, thus, decreasing urinary supersaturation with respect to calcium oxalate. Urinary citrate also interacts with calcium oxalate crystals as an inhibitor of agglomeration, nucleation and crystal growth.17 In postmenopausal women higher urinary citrate and lower calcium oxalate saturation have been associated with higher estrogen after hormone replacement.18 Increased urinary citrate may have been secondary to a decreased acid load in the women on estrogen. Urinary citrate is influenced by the systemic acid-base balance and acid load.19 The decreased acid load and excretion while on estrogen may be reflected by the almost significant increase in urinary pH (p ⫽ 0.083). Daily acid production is the sum of dietary acid or alkali and endogenous acid production by the metabolism. Acid production is balanced by net acid excretion in the urine. To our knowledge an effect of estrogens on the acid-base balance has not previously been documented. Whether dietary acid absorption is decreased or endogenous acid production is inhibited by estrogens has not been determined to our knowledge. A decreased acid load by whatever mechanism would be expected to decrease urinary calcium since acidosis increases calcium release from bone and decreases calcium resorption in the kidneys. Therefore, urinary calcium changes must reflect other mechanisms, as discussed. It has been proposed that elderly individuals are subject to eubicarbinatemic metabolic acidosis, a condition with normal serum bicarbonate but a slightly increased acid load.20 This condition is accompanied by increased muscle catabolism, bone demineralization, increased urinary cal-
TABLE 1. Comparison of 24-hour urinary constituents in stone formers Estrogen No. pts. Mean age ⫾ SD Mean 24-hr. urinary values ⫾ SD: Vol. (l.) pH Calcium (mg./24 hrs.) Citrate (mg./24 hrs.) Oxalate (mmol./24 hrs.) Mins. agglomeration inhibition (No. pts.) Calcium (mg./l.) Citrate (mg./l.) Oxalate (mmol./l.)
28 59.1 ⫾ 9.4 1.96 ⫾ 0.61 6.06 ⫾ 0.48 188.8 ⫾ 101.5 576.6 ⫾ 237.9 0.35 ⫾ 0.13 203 ⫾ 106 (24) 104.08 ⫾ 64.74 223.07 ⫾ 138.24 0.19 ⫾ 0.08
No Estrogen
p Value
41 62.2 ⫾ 9.6 1.88 ⫾ 0.84 5.83 ⫾ 0.59 129.2 ⫾ 80.9 306.2 ⫾ 209.9 0.34 ⫾ 0.19 159 ⫾ 81 (35) 80.65 ⫾ 73.58 186.24 ⫾ 134.40 0.20 ⫾ 0.11
⬍ 0.01 ⬍ 0.001 ⬍ 0.05 ⬍ 0.001
ESTROGEN REPLACEMENT IN POSTMENOPAUSAL WOMEN WITH UROLITHIASIS
171
TABLE 2. Comparison of 24-hour urinary constituents in controls Estrogen No. controls Mean age ⫾ SD Mean 24-hr. urinary values ⫾ SD: Vol. (l.) pH Calcium (mg./24 hrs.) Citrate (mg./24 hrs.) Oxalate (mmol./24 hrs.) Mins. agglomeration inhibition (No. controls) Calcium (mg./l.) Citrate (mg./l.) Oxalate (mmol./l.)
13 55.5 ⫾ 6.9
CONCLUSIONS
Estrogen replacement therapy may have beneficial effects in postmenopausal women with recurrent calcium oxalate urolithiasis. Our results show increased citrate and calcium excretion in postmenopausal women receiving estrogen supplementation. A concern is whether increased urinary calcium in estrogen replete calcium oxalate stone formers may increase the risk of subsequent stone formation. The increased stone inhibitory citrate level and increased agglomeration inhibition imply an overall beneficial effect of estrogen on the risk of calcium oxalate stone recurrence in postmenopausal women. We suggest that the possibility of decreased kidney stone formation may be included in the discussion with postmenopausal women considering estrogen replacement therapy. The number of patients in our study was insufficient to recommend that estrogen replacement therapy should be given to replace or serve as an adjunct to the more accepted medical regimens for recurrent urolithiasis. REFERENCES
1. Morikawa, M., Okuyama, M., Yoshihara, H. et al: [A study of the differences between the sexes in epidemiology of urolithiasis.] Nippon Hinyokika Gakkai Zasshi, 89: 538, 1998 2. Williams, R. E.: The natural history of renal lithiasis. In: Proceedings of the Renal Stone Research Symposium. Edited by A. Hodgkinson and B. C. E. Nordin. London: Churchill, p. 65, 1969 3. Lee, Y. H., Huang, W. C., Huang, J. K. et al: Testosterone enhances whereas estrogen inhibits calcium oxalate stone formation in ethylene glycol treated rats. J Urol, 156: 502, 1996 4. Coe, F. L., Parks, J. H. and Asplin, J. R.: The pathogenesis and treatment of kidney stones. N Engl J Med, 327: 1141, 1992 5. Iguchi, M., Takamura, C., Umekawa, T. et al: Inhibitory effects of female sex hormones on urinary stone formation in rats.
p Value
6 55.3 ⫾ 4.3
1.79 ⫾ 0.5 6.07 ⫾ 0.45 185.42 ⫾ 105.45 568.27 ⫾ 230.37 0.36 ⫾ 0.09 273 ⫾ 90 (11) 110.2 ⫾ 60 339.8 ⫾ 172.8 0.21 ⫾ .05
cium and decreased urinary citrate. Estrogen appears to counteract several of these aspects. Increased agglomeration inhibition in estrogen replete postmenopausal women represents objective evidence that they may be less likely to form calcium oxalate stones even in the presence of increased urinary calcium. Agglomeration inhibition reflects the sum of the stone inhibitory constituents of urine. Previous studies have not addressed the effect of estrogens on agglomeration inhibition. Increased agglomeration inhibition in our study in women on estrogen likely indicates that inhibitory factors, including increased urinary citrate, may be protective.
No Estrogen
2.11 ⫾ 0.6 5.71 ⫾ 0.57 130.32 ⫾ 86.60 497.03 ⫾ 223.92 0.38 ⫾ 0.03 195 ⫾ 11 (4) 77.2 ⫾ 69.2 226.6 ⫾ 80.6 0.19 ⫾ 0.05
⬍ 0.01 ⬍ 0.05
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