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Effect of raloxifene, estrogen, and hormone replacement therapy on serum homocysteine levels in postmenopausal women

2003; Elsevier BV; Volume: 79; Issue: 2 Linguagem: Inglês

10.1016/s0015-0282(02)04673-3

1556-5653

George Christodoulakos, Ιrene Lambrinoudaki, Constantinos Panoulis, Demetrios Rizos, John Coutoukos, George Creatsas,

Eosinophilic Esophagitis

Homocysteine (Hcy) is a sulfur-containing amino acid involved in the remethylation and transulfuration metabolic pathways (1D’Angelo A. Sehlub J. Homocysteine and thrombotic disease.Blood. 1997; 90: 1-11PubMed Google Scholar). Genetic mutations and the deficiency in nutrients and micronutrients may disrupt Hcy metabolism and result in elevated serum levels. Furthermore, total Hcy (tHcy) levels may be determined by demographics, lifestyle, and state of health factors (1D’Angelo A. Sehlub J. Homocysteine and thrombotic disease.Blood. 1997; 90: 1-11PubMed Google Scholar, 2Moustapha A. Robinson K. Homocysteine an emerging age-related cardiovascular risk factor.Geriatrics. 1999; 54: 49-63Google Scholar, 3Van Baal W.M. Smolders R.G.V. van der Mooren M.J. Teerlink T. Kenemans P. Hormone replacement therapy and plasma homocysteine levels.Obstet Gynecol. 1999; 94: 485-491Crossref PubMed Scopus (96) Google Scholar, 4Mijatovic V. Kenemans P. Netelenbos C. Jacobs C. Popp-Snijders C. Peters-Muller E.R. et al.Postmenopausal oral 17b-estradiol continuously combined with dydrogesterone reduces fasting serum homocysteine levels.Fertil Steril. 1998; 69: 876-882Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). Although tHcy levels are reported to be lower in premenopausal women compared with postmenopausal women (5Wouters M.G. Moorrees M.T. van der Mooren M.J. Blom H.J. Boers G.H. Schellekens L.A. et al.Plasma homocysteine and menopausal status.Eur J Clin Invest. 1995; 25: 801-805Crossref PubMed Scopus (209) Google Scholar), there is no consensus on whether they increase after menopause (5Wouters M.G. Moorrees M.T. van der Mooren M.J. Blom H.J. Boers G.H. Schellekens L.A. et al.Plasma homocysteine and menopausal status.Eur J Clin Invest. 1995; 25: 801-805Crossref PubMed Scopus (209) Google Scholar, 6Anderson A. Brattstrom L. Israelsson B. Isaksson A. Hamfelt A. Hultberg B. Plasma homocysteine before and after methionine loading with regard to age, gender and menopausal status.Eur J Clin Invest. 1992; 22: 79-87Crossref PubMed Scopus (303) Google Scholar). Furthermore, it is unclear whether the menopause-associated increase is related to age (2Moustapha A. Robinson K. Homocysteine an emerging age-related cardiovascular risk factor.Geriatrics. 1999; 54: 49-63Google Scholar, 7Christodoulakos G. Panoulis C. Rizos D. Moustakarias T. Phocas I. Creatsas G. Homocysteine and folate levels in postmenopausal women.Maturitas. 2001; 39: 161-167Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar) or to estrogen depletion (2Moustapha A. Robinson K. Homocysteine an emerging age-related cardiovascular risk factor.Geriatrics. 1999; 54: 49-63Google Scholar, 5Wouters M.G. Moorrees M.T. van der Mooren M.J. Blom H.J. Boers G.H. Schellekens L.A. et al.Plasma homocysteine and menopausal status.Eur J Clin Invest. 1995; 25: 801-805Crossref PubMed Scopus (209) Google Scholar). In a previous study, we reported that the increase in tHcy levels among postmenopausal women appears to be age related (7Christodoulakos G. Panoulis C. Rizos D. Moustakarias T. Phocas I. Creatsas G. Homocysteine and folate levels in postmenopausal women.Maturitas. 2001; 39: 161-167Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). Homocysteinemia is risk factor for vascular damage (3Van Baal W.M. Smolders R.G.V. van der Mooren M.J. Teerlink T. Kenemans P. Hormone replacement therapy and plasma homocysteine levels.Obstet Gynecol. 1999; 94: 485-491Crossref PubMed Scopus (96) Google Scholar) and has been associated with cardiocerebrovascular disease and thromboembolism (2Moustapha A. Robinson K. Homocysteine an emerging age-related cardiovascular risk factor.Geriatrics. 1999; 54: 49-63Google Scholar, 8Berger P.B. Herrmann R.R. Dumesic D.A. The effect of estrogen replacement therapy on total plasma homocysteine in healthy postmenopausal women.Mayo Clin Proc. 2000; 75: 18-23Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Data on the effect of estrogen or combined estrogen-progestin (HRT) therapy on serum tHcy concentrations is equivocal. A lowering effect has been reported (3Van Baal W.M. Smolders R.G.V. van der Mooren M.J. Teerlink T. Kenemans P. Hormone replacement therapy and plasma homocysteine levels.Obstet Gynecol. 1999; 94: 485-491Crossref PubMed Scopus (96) Google Scholar, 4Mijatovic V. Kenemans P. Netelenbos C. Jacobs C. Popp-Snijders C. Peters-Muller E.R. et al.Postmenopausal oral 17b-estradiol continuously combined with dydrogesterone reduces fasting serum homocysteine levels.Fertil Steril. 1998; 69: 876-882Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 9Walsh B.W. Paul S. Wild R.A. Dean R.A. Tracy R.P. Cox D.A. et al.The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women a randomized controlled trial.J Clin Endocrinol Metab. 2000; 85: 214-218Crossref PubMed Scopus (350) Google Scholar, 10Barnabei V.M. Philips T.M. Hsia J. Plasma homocysteine in women taking hormone replacement therapy the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.J Womens Health Gend Based Med. 1999; 8: 1167-1172Crossref PubMed Scopus (48) Google Scholar), but this has not been confirmed (8Berger P.B. Herrmann R.R. Dumesic D.A. The effect of estrogen replacement therapy on total plasma homocysteine in healthy postmenopausal women.Mayo Clin Proc. 2000; 75: 18-23Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). The absence of homogenicity within the study groups with respect to the type of hormones, the dose, the mode (continuous or sequential), and the route of administration may explain this discrepancy. Raloxifene is a nonsteroid benzothiophene derivative classified as a selective estrogen receptor modulator (11De Leo V. la Marca A. Morgante G. Lanzetta D. Setacci C. Petraglia F. Randomized controlled study on the effects of raloxifene on serum lipids and homocysteine in older women.Am J Obstet Gynecol. 2001; 184: 350-353Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). The data, although limited, suggest that raloxifene may decrease tHcy levels (9Walsh B.W. Paul S. Wild R.A. Dean R.A. Tracy R.P. Cox D.A. et al.The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women a randomized controlled trial.J Clin Endocrinol Metab. 2000; 85: 214-218Crossref PubMed Scopus (350) Google Scholar, 12Mijatovic V. Netelenbos C. van der Mooren M.J. de Valk-de Roo G.W. Jacobs C. Kenemans P. Randomized, double-blind, placebo-controlled study of the effects of raloxifene and conjugated equine estrogen on plasma homocysteine levels in healthy postmenopausal women.Fertil Steril. 1998; 70: 1085-1089Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). The purpose of this study was to assess the effect of estrogen, two different HRT regimens, and raloxifene on tHcy serum levels in postmenopausal women. Two hundred ten women aged 39–70 years and menopausal for ≥2 years were prospectively studied. Criteria for inclusion were an endometrial thickness ≤5 mm and the absence of a history of gynecological malignancy, ischemic heart disease, thromboembolism, systemic hypertension, diabetes mellitus, or dyslipidemia. Past users of estrogen, HRT, tibolone, or raloxifene were included after a washout period of 12 months. All subjects signed an informed consent form, and Institutional Review Board approval was obtained. Twenty-seven women received 0.625 mg of conjugated equine estrogens (CEE), 41 received 5 mg of CEE combined with medroxyprogesterone acetate (CEE/MPA), 33 received 2 mg of 17β-estradiol combined with 1 mg of norethisterone acetate (E2/NETA), 62 received 60 mg of raloxifene HCl, and 47 women with no indication for therapy served as controls. THcy levels in fasting serum were assessed at baseline and at 6, 12, and 18 months by the Abbott Imx Homocysteine kit (Abbott Laboratories, Abbott Park, IL). The total coefficient of variation (%) and the sensitivity of the kit were 4.3% and 0.5 μmol/L, respectively. Statistical analysis was performed by analysis of variance for repeated measures and analysis of covariance when necessary. Women in the raloxifene group were older (mean 57.1 years) compared with the other groups (51.5–53.3 years). No difference was detected among groups with respect to age of menopause onset, body mass index, baseline tHcy, or smoking. Serum tHcy levels decreased significantly in all therapy groups compared with baseline (Table 1). The decrease appeared to be higher in the subgroup of women with baseline tHcy levels above the median (age and baseline tHcy adjusted change at 18 months: CEE, −24.5%; CEE/MPA, −15.4%; E2/NETA, −32.0%; raloxifene, −28.3%; controls, −2.0%). In this subgroup, changes in all therapy groups were significantly different from the controls.TABLE 1Follow-up serum mean homocysteine levels (SD) in 210 postmenopausal women receiving various regimens of hormone replacement therapy, raloxifene, or no therapy.CEE (n = 27)CEE/MPA (n = 41)E2/NETA (n = 33)RLX (n = 62)Controls (n = 47)Baseline (μmol/L)9.9 (2.4)9.7 (2.1)9.8 (2.4)11.3 (3.4)10.7 (4.2)6 months (μmol/L)9.2 (1.9)9.0 (1.7)9.7 (2.2)9.9 (3.5)10.9 (3.5)% change from baseline (adjusted for age)−1.51.74.1−6.8aP<.05 compared with controls, analysis of covariance; covariate: age.6.912 months9.1 (1.7)8.6 (1.9)9.4 (3.1)9.5 (2.1)11.0 (3.5)% change from baseline (adjusted for age)− 9.7aP<.05 compared with controls, analysis of covariance; covariate: age.0.6−1.9−9.1bP<.01 compared with controls, analysis of covariance; covariate: age.7.018 months8.8 (1.9)8.8 (1.7)8.9 (2.7)8.7 (2.2)10.9 (3.6)% change from baseline (adjusted for age)−7.5−2.6−10.2aP<.05 compared with controls, analysis of covariance; covariate: age.−14.5cP<.001 compared with controls, analysis of covariance; covariate: age.5.1P (linear effect across follow-up visits)dAnalysis of variance for repeated measures, test for linear effect. Christodoulakos. Estrogen, HRT, raloxifene, and homocysteine. Fertil Steril 2003..0001.008.023.0001.81Note: CEE = conjugated equine estrogens; MPA = medroxyprogesterone; NETA = norethisterone acetate; RLX = raloxifene.a P<.05 compared with controls, analysis of covariance; covariate: age.b P<.01 compared with controls, analysis of covariance; covariate: age.c P<.001 compared with controls, analysis of covariance; covariate: age.d Analysis of variance for repeated measures, test for linear effect.Christodoulakos. Estrogen, HRT, raloxifene, and homocysteine. Fertil Steril 2003. Open table in a new tab Note: CEE = conjugated equine estrogens; MPA = medroxyprogesterone; NETA = norethisterone acetate; RLX = raloxifene. Estrogen, HRT, and raloxifene may enhance cardioprotection by favorably modulating lipids-lipoproteins and by promoting vasodilation due to an increase in the nitric oxide/endothelin-1 ratio (13Christodoulakos G. Panoulis C. Kouskouni E. Chondros C. Dendrinos S. Creatsas G. Effects of estrogen-progestin and raloxifene therapy on nitric oxide, prostacyclin and endothelin-1 synthesis.Gynecol Endocrinol. 2002; 16: 9-17PubMed Google Scholar). Furthermore, epidemiological and clinical studies have reported that estrogen HRT may influence Hcy metabolism (2Moustapha A. Robinson K. Homocysteine an emerging age-related cardiovascular risk factor.Geriatrics. 1999; 54: 49-63Google Scholar, 9Walsh B.W. Paul S. Wild R.A. Dean R.A. Tracy R.P. Cox D.A. et al.The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women a randomized controlled trial.J Clin Endocrinol Metab. 2000; 85: 214-218Crossref PubMed Scopus (350) Google Scholar). Estrogen monotherapy with CEE or E2 may decrease tHcy levels by 8% (12Mijatovic V. Netelenbos C. van der Mooren M.J. de Valk-de Roo G.W. Jacobs C. Kenemans P. Randomized, double-blind, placebo-controlled study of the effects of raloxifene and conjugated equine estrogen on plasma homocysteine levels in healthy postmenopausal women.Fertil Steril. 1998; 70: 1085-1089Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar) and 5% (3Van Baal W.M. Smolders R.G.V. van der Mooren M.J. Teerlink T. Kenemans P. Hormone replacement therapy and plasma homocysteine levels.Obstet Gynecol. 1999; 94: 485-491Crossref PubMed Scopus (96) Google Scholar), respectively, or may have no effect (8Berger P.B. Herrmann R.R. Dumesic D.A. The effect of estrogen replacement therapy on total plasma homocysteine in healthy postmenopausal women.Mayo Clin Proc. 2000; 75: 18-23Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). In our study, CEE lowered tHcy levels (7.5%) and the decrease suggested a duration-of-therapy effect. HRT with different estrogens and progestins was associated with significant tHcy decreases ranging from 9.4%–12.6% under sequential administration (3Van Baal W.M. Smolders R.G.V. van der Mooren M.J. Teerlink T. Kenemans P. Hormone replacement therapy and plasma homocysteine levels.Obstet Gynecol. 1999; 94: 485-491Crossref PubMed Scopus (96) Google Scholar, 6Anderson A. Brattstrom L. Israelsson B. Isaksson A. Hamfelt A. Hultberg B. Plasma homocysteine before and after methionine loading with regard to age, gender and menopausal status.Eur J Clin Invest. 1992; 22: 79-87Crossref PubMed Scopus (303) Google Scholar) to 7%–13.5% under continuous administration (4Mijatovic V. Kenemans P. Netelenbos C. Jacobs C. Popp-Snijders C. Peters-Muller E.R. et al.Postmenopausal oral 17b-estradiol continuously combined with dydrogesterone reduces fasting serum homocysteine levels.Fertil Steril. 1998; 69: 876-882Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 9Walsh B.W. Paul S. Wild R.A. Dean R.A. Tracy R.P. Cox D.A. et al.The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women a randomized controlled trial.J Clin Endocrinol Metab. 2000; 85: 214-218Crossref PubMed Scopus (350) Google Scholar). Nevertheless, reports of no change are also present in the literature (14Park J.S. Jung H.H. Yang W.S. Kim S.B. Min W.K. Chi H.S. Effects of hormonal replacement therapy on lipid and haemostatic factors in post-menopausal ESRD patients.Nephrol Dial Transplant. 2000; 15: 1835-1840Crossref PubMed Scopus (32) Google Scholar). The present data do not clarify whether estrogen or HRT is most beneficial in lowering tHcy levels. A decrease of greater magnitude has been related to CEE (10Barnabei V.M. Philips T.M. Hsia J. Plasma homocysteine in women taking hormone replacement therapy the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.J Womens Health Gend Based Med. 1999; 8: 1167-1172Crossref PubMed Scopus (48) Google Scholar), while the presence of progestin has been shown to either attenuate (9Walsh B.W. Paul S. Wild R.A. Dean R.A. Tracy R.P. Cox D.A. et al.The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women a randomized controlled trial.J Clin Endocrinol Metab. 2000; 85: 214-218Crossref PubMed Scopus (350) Google Scholar) or augment (3Van Baal W.M. Smolders R.G.V. van der Mooren M.J. Teerlink T. Kenemans P. Hormone replacement therapy and plasma homocysteine levels.Obstet Gynecol. 1999; 94: 485-491Crossref PubMed Scopus (96) Google Scholar) the effect. In our study, continuous CEE/MPA administration resulted in a decrease of a lesser magnitude (2.6%) compared with CEE. However, the decrease under E2/NETA became progressively steeper compared with baseline (10.2%) and was greater compared with CEE. In agreement to previous reports (3Van Baal W.M. Smolders R.G.V. van der Mooren M.J. Teerlink T. Kenemans P. Hormone replacement therapy and plasma homocysteine levels.Obstet Gynecol. 1999; 94: 485-491Crossref PubMed Scopus (96) Google Scholar, 4Mijatovic V. Kenemans P. Netelenbos C. Jacobs C. Popp-Snijders C. Peters-Muller E.R. et al.Postmenopausal oral 17b-estradiol continuously combined with dydrogesterone reduces fasting serum homocysteine levels.Fertil Steril. 1998; 69: 876-882Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar), we found that the magnitude of tHcy reduction was greater among the subgroup of women with higher baseline levels. The effect of the duration of treatment in modulating tHcy is not yet clear (3Van Baal W.M. Smolders R.G.V. van der Mooren M.J. Teerlink T. Kenemans P. Hormone replacement therapy and plasma homocysteine levels.Obstet Gynecol. 1999; 94: 485-491Crossref PubMed Scopus (96) Google Scholar, 4Mijatovic V. Kenemans P. Netelenbos C. Jacobs C. Popp-Snijders C. Peters-Muller E.R. et al.Postmenopausal oral 17b-estradiol continuously combined with dydrogesterone reduces fasting serum homocysteine levels.Fertil Steril. 1998; 69: 876-882Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 10Barnabei V.M. Philips T.M. Hsia J. Plasma homocysteine in women taking hormone replacement therapy the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.J Womens Health Gend Based Med. 1999; 8: 1167-1172Crossref PubMed Scopus (48) Google Scholar), and the absence of a significant change of tHcy under estrogen or HRT (8Berger P.B. Herrmann R.R. Dumesic D.A. The effect of estrogen replacement therapy on total plasma homocysteine in healthy postmenopausal women.Mayo Clin Proc. 2000; 75: 18-23Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar) could be due to the short duration of the observation. In our series, we observed a linear duration-of-therapy effect. Raloxifene decreases tHcy levels, which may be related to the dose administered (9Walsh B.W. Paul S. Wild R.A. Dean R.A. Tracy R.P. Cox D.A. et al.The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women a randomized controlled trial.J Clin Endocrinol Metab. 2000; 85: 214-218Crossref PubMed Scopus (350) Google Scholar, 12Mijatovic V. Netelenbos C. van der Mooren M.J. de Valk-de Roo G.W. Jacobs C. Kenemans P. Randomized, double-blind, placebo-controlled study of the effects of raloxifene and conjugated equine estrogen on plasma homocysteine levels in healthy postmenopausal women.Fertil Steril. 1998; 70: 1085-1089Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar) and the duration of therapy (11De Leo V. la Marca A. Morgante G. Lanzetta D. Setacci C. Petraglia F. Randomized controlled study on the effects of raloxifene on serum lipids and homocysteine in older women.Am J Obstet Gynecol. 2001; 184: 350-353Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). With 60 mg of raloxifene, the decrease ranged from a nonsignificant 2% (12Mijatovic V. Netelenbos C. van der Mooren M.J. de Valk-de Roo G.W. Jacobs C. Kenemans P. Randomized, double-blind, placebo-controlled study of the effects of raloxifene and conjugated equine estrogen on plasma homocysteine levels in healthy postmenopausal women.Fertil Steril. 1998; 70: 1085-1089Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar) to a significant 6% (9Walsh B.W. Paul S. Wild R.A. Dean R.A. Tracy R.P. Cox D.A. et al.The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women a randomized controlled trial.J Clin Endocrinol Metab. 2000; 85: 214-218Crossref PubMed Scopus (350) Google Scholar) and 19.5% (11De Leo V. la Marca A. Morgante G. Lanzetta D. Setacci C. Petraglia F. Randomized controlled study on the effects of raloxifene on serum lipids and homocysteine in older women.Am J Obstet Gynecol. 2001; 184: 350-353Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). We found that a 60-mg dose of raloxifene had a stronger lowering effect on tHcy (14.5%) compared with the other regimens and that the magnitude of the decrease appeared to be related to the duration of therapy. In conclusion, estrogen, HRT, and raloxifene are associated with a decrease in serum tHcy levels, which appears to be related to the duration of therapy. The magnitude of the decrease may be more prominent in women with higher baseline levels.