Simone J.M. Neele

A 2-year, randomized, comparative, placebo-controlled study on the effects of raloxifene on lipoprotein(a) and homocysteine

OBJECTIVES Lipoprotein(a) (Lp(a)) and homocysteine (Hcy) are independent cardiovascular risk factors, which have been shown to be lowered by hormone replacement therapy (HRT). In this 2-year study, the long-term effects of raloxifene (Rlx) in two doses, on Lp(a) and Hcy, were studied and compared with the effects of continuously combined hormone replacement therapy (ccHRT). METHODS In a prospective, randomized, double-blind, placebo-controlled 2-year study, 95 healthy, non-hysterectomized, early postmenopausal women, received daily either oral Rlx 60 mg (N=24) or 150 mg (N=23), ccHRT (conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg; N=24) or placebo (N=24). Fasting serum Lp(a) and plasma Hcy concentrations were measured at baseline and at 6, 12 and 24 months. RESULTS The mean individual changes compared to baseline after 24 months were for Lp(a): Rlx 60: - 5%, Rlx 150: -7%, ccHRT: -34%, placebo: +1% and for Hcy: Rlx 60: -3%, Rlx 150: -4%, ccHRT: -4%, placebo: +6%. ANCOVA was significant for Lp(a) under ccHRT versus placebo (P=0.001) and for Lp(a) under ccHRT versus each of the two Rlx groups (P<0.05). CONCLUSIONS Long-term treatment with Rlx was not as effective as ccHRT in lowering Lp(a). Although not significant and without an obvious dose-related response, the Hcy values showed the same trend for each treatment arm, which is in line with data reported earlier.

Raloxifene reduces procarboxypeptidase U, an antifibrinolytic marker. A 2-year randomized, placebo-controlled study in healthy early postmenopausal women.

Objective The aim of this study was to compare the long-term effects of two dosages of raloxifene with oral hormone therapy (HT; conjugated equine estrogens combined with medroxyprogesterone acetate) on procarboxypeptidase U. Design In a randomized, double-blind, placebo-controlled, 2-year study, 95 healthy, nonhysterectomized, early postmenopausal women received either daily raloxifene 60 mg (n = 24), raloxifene 150 mg (n = 23), HT (conjugated equine estrogens 0.625 mg + medroxyprogesterone acetate 2.5 mg, n = 24), or placebo (n = 24). At baseline and after 6, 12, and 24 months, fasting plasma procarboxypeptidase U concentrations were measured. Results Six months of treatment with raloxifene 60 mg and raloxifene 150 mg were associated with significant decreases in plasma procarboxypeptidase U concentrations, which were sustained after 12 and 24 months. Raloxifene 60 mg: t = 0, 619 ± 89 U/L (mean ± SD); t = 6, 574 ± 87 U/L; t = 12, 571 ± 96 U/L; t = 24, 568 ± 92 U/L; ANCOVA versus placebo, P = 0.026. Raloxifene 150 mg: t = 0, 608 ± 67 U/L; t = 6, 580 ± 73 U/L; t = 12, 578 ± 70 U/L; t = 24, 562 ± 61 U/L; ANCOVA versus placebo, P = 0.039. No significant changes were found in the HT group. Conclusion Long-term treatment with raloxifene reduced procarboxypeptidase U plasma concentrations.

Raloxifene treatment increases plasma levels of β-endorphin in postmenopausal women: a randomized, placebo-controlled study

OBJECTIVE To evaluate the effect of the selective estrogen receptor modulator raloxifene hydrochloride (Evista, Eli Lilly and Company, Indianapolis, IN) on plasma levels of beta-endorphin, and to determine whether beta-endorphin levels and menopausal symptoms are related. DESIGN A randomized, double-blind, placebo-controlled pilot study. SETTING Endocrinology outpatient department. PATIENT(S) Forty postmenopausal women. INTERVENTION(S) The women received raloxifene, 60 mg/d, or placebo for 3 months. A questionnaire on climacteric symptoms was administered before and after treatment. MAIN OUTCOME MEASURE(S) Circulating levels of beta-endorphin, climacteric symptom score, and correlation with beta-endorphin levels. RESULT(S) Raloxifene treatment significantly increased levels of beta-endorphin and did not significantly affect climacteric symptoms, with the exception of worsening vasomotor symptoms. No significant relation was seen between plasma levels of beta-endorphin and climacteric symptoms. CONCLUSION(S) Raloxifene modulates plasma levels of beta-endorphin without concomitantly relieving climacteric symptoms, as seen with hormone replacement therapy.

Effect of estrogen on intestinal strontium absorption in postmenopausal women

OBJECTIVES there is considerable uncertainty about the underlying cause of decreased intestinal calcium absorption that occurs in postmenopausal women. In a previous study, estrogen treatment did not result in an increased intestinal calcium absorption using strontium as a marker. A possible explanation could be that the calcium/strontium load given to the women was too high ( approximately 600 mg Ca), which might result in an insensitive test with respect to the possible stimulation of active strontium transport by estrogen. Therefore, the purpose of this study was to reinvestigate the effect of estrogen on active intestinal strontium absorption using a load of 2.5 mmol of strontium only. METHODS the effect of estrogen on intestinal strontium absorption was measured in eight normal postmenopausal women. The study included two baseline strontium absorption tests, which were performed with an interval of 10 days for calculating the within subject variation (SER). Thereafter the effect of 2 months of estrogen treatment on intestinal strontium absorption was assessed. Fractional absorption (FC(240)) and the area under the concentration time curve (AUC) 4 h after an oral strontium load of 2.5 mmol were calculated. RESULTS the within subject SER of FC(240) and AUC(0-240) were 2.3+/-0.76 and 1.2+/-0.41, respectively. FC(240) and AUC(0-240) of strontium were unchanged after treatment with estrogen. CONCLUSIONS in normal postmenopausal women, we did not find a modulating effect of short-term treatment with a (supra) physiological dose of estrogen on intestinal calcium absorption as measured by the strontium absorption test.

Effect of raloxifene on activated protein C (APC) resistance in postmenopausal women and on APC resistance and homocysteine levels in elderly men: two randomized placebo-controlled studies.

Raloxifene, a selective estrogen receptor modulator, like hormonal replacement therapy increases the risk of venous thromboembolism in postmenopausal women. A possible explanation for the increased thrombotic risk could be an increase in acquired resistance to activated protein C (APC). In two randomized, placebo-controlled, double-blind studies we determined the effect of raloxifene on the normalized APC sensitivity ratios (nAPCsr). The nAPCsr were determined with the thrombin generation-based APC resistance test. In the first study 83 postmenopausal women (age, 51.1 ± 2.7 years) randomly received daily 0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate (n = 17), 60 mg raloxifene (n = 23), 150 mg raloxifene (n = 20) or placebo (n = 23) for 24 months. At baseline and after 6, 12 and 24 months the nAPCsr were measured. In the second study 30 elderly men (age, 64.4 ± 2.4 years) randomly received 120 mg raloxifene (n = 15) or placebo (n = 15) for 3 months. At baseline and after 3 months the nAPCsr and fasting homocysteine levels were measured. In postmenopausal women conjugated equine estrogen/medroxyprogesterone acetate significantly increased the nAPCsr from 1.26 ± 0.82 to 2.87 ± 0.86 at 24 months (P < 0.0005 compared with placebo). Raloxifene had no significant effect on nAPCsr compared with placebo in both women and men. The results did not change after excluding carriers of factor V Leiden. Also fasting homocysteine levels were not affected by raloxifene in the aging men. It is concluded that raloxifene, in contrast to combined hormonal replacement therapy, does not increase APC resistance.

III.5 Saline infusion sonohysterography is a good approach for additional assessment of the endometrium

Abstract We describe the results of endometrial assessment with transvaginal ultrasound (TVU) and saline infusion sonohysterography (SIS) in healthy, asymptomatic early postmenopausal women. We used cross-sectional data obtained from women who were screened prior to participation in a clinical trial for prevention of osteoporosis, with either hormone replacement therapy, placebo or a selective oestrogen receptor modulator.