Raloxifene - 2nd Generation SERM (Specific Estrogen Receptor Modulator)
Brand Name - Evista (Raloxifene HCL)
Halflife - 27.7 hours
A few studies:
Effects of raloxifene on gonadotrophins, sex hormones, bone turnover and lipids in healthy elderly men
EJ Duschek, LJ Gooren, and C Netelenbos
Department of Endocrinology, VU University Medical Centre, Amsterdam, The Netherlands. e.duschek@vumc.nl
OBJECTIVE: To explore effects on serum lipids, pituitary-gonadal axis, prostate and bone turnover of the administration of the mixed oestrogen agonist/antagonist raloxifene in healthy elderly men. PARTICIPANTS: Thirty healthy men aged 60-70 years randomly received raloxifene 120 mg/day (n=15) or placebo (n=15) for 3 months. MEASUREMENTS: In this double-blind, placebo-controlled study, serum gonadotrophins, sex hormones, prostate specific antigen (PSA), a marker of bone turnover, urinary hydroxyproline (OHPro) and cholesterol were measured at baseline and after 3 months. RESULTS: Raloxifene significantly increased serum concentrations of LH and FSH (by 29% and 21%), total testosterone (20%), free testosterone (16%) and bioavailable testosterone (not bound to sex hormone-binding globulin (SHBG; 20%). In parallel with testosterone, 17 beta-oestradiol also increased by 21%. SHBG increased by 7%. Total cholesterol (TChol) decreased significantly, from 5.7 to 5.5 mmol/l (P=0.03). Low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) showed a trend to decrease. Overall, there was no change in urinary OHPro/creatinine ratio as a marker for bone resorption. However, the raloxifene-induced increases in both serum testosterone and 17 beta-oestradiol were significantly related to a lower OHPro/creatinine ratio. Total PSA increased by 17% without significant changes in free PSA or free/total PSA ratio. Participants reported no side effects and raloxifene was well tolerated. CONCLUSION: In healthy elderly man, raloxifene 120 mg/day for 3 months increased LH, FSH and sex steroid hormones. Potentially beneficial effects were the small but significant decrease in TChol and the trend towards a decrease in LDL-c. Negative effects were the trend towards a decrease in HDL-c and the significant increase in serum PSA. A decrease in markers of bone resorption during raloxifene treatment was found only in men with relatively high increases in serum testosterone and 17 beta-oestradiol. Overall, there were no clear beneficial effects of administration of raloxifene to ageing men in this preliminary investigation.
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A study showing raloxifenes use in treating pre-existing gynocomastia
from Superior muscle
Selective estrogen receptor modulators (SERMs) are a relatively new family of drugs designed to act as estrogens on some, but not all, tissues.2 Tamoxifen is a first-generation SERM. Raloxifene, a second-generation SERM, has been extensively studied on postmenopausal women, and is indicated for the treatment of postmenopausal osteoporosis.3 It is an alternative to estrogen replacement therapy in women with a history of breast cancer.4, 5 Its anti-proliferative effect on mammary tissue is such that prolonged use reduces the risk of breast cancer among osteoporotic women.6
In a recent placebo-controlled short-term trial, the drug was administered to 34 healthy males (mean age, 48 years) at the dose of 60 mg/day for one month; no subject developed gynocomastia. Besides, serum testosterone increased 20%, and serum estradiol decreased slightly.7
We decided to evaluate the effect of raloxifene in a series of patients with gynocomastia. Twelve patients aged 18-84 years were treated. Breast enlargement was unilateral in 5 cases; its duration ranged from a few weeks (7 cases) to several years (5 cases). Four patients were hypogonadal by clinical criteria, and had low serum testosterone. In two patients there was a possible drug effect (prasterone in one, ranitidine in the other). The size of breast tissue ranged between 1.5 and 6.0 cm. All patients had normal testes by palpation, and normal serum levels of estradiol, LH, FSH, prolactin, and alpha-hCG. Liver function tests and serum creatinine also were normal. The dose of raloxifene was 60 mg every other day in 4 elderly patients (age 70 years or more), and 60 mg daily in the remaining; the medication was given for 2-12 months. Hypogonadal patients received, in addition, i.m. injections of testosterone enanthate, 100 mg twice a month.
Raloxifene was well tolerated; only one young patient reported a slight decrease in sexual potency. No subject complained of hot flushes; there were no episodes of thrombophlebitis during follow-up. The analgesic effect of treatment was fast (2-4 weeks) and sustained among 9 patients with pain and tenderness. The size of the gynocomastia was evaluated monthly by means of a caliper (all patients), and ultrasonography (7 patients). All patients responded: there was an average reduction in size of 61% (range: 34-100%); in 2 patients gynocomastia disappeared. Six of 8 eugonadal patients (75%) had a reduction in the size of breast tissue of at least 50% (average, 73%). Among hypogonadal patients (all of them followed with ultrasonography) gynocomastia disappeared in one, and size reduction in the remaining subjects ranged between 46 and 67% (this is particularly noteworthy, since testosterone replacement not infrequently causes or aggravates gynocomastia due to local aromatization to estrogens by mammary tissue). Maximal effect was observed during the first 2 months of treatment.
This open, observational study suggests that raloxifene may be a safe, well tolerated and effective therapeutic alternative for drug-induced or idiopathic gynocomastia in men of all ages.
Zulema Man, MD.
TIEMPO, Buenos Aires, Argentina
Ariel S??nchez, MD, PhD;
Hugo Carretto, MD;
Ricardo Parma, MD.
Centro de Endocrinolog??a, Rosario, Argentina
References
1. Khan HN, Blamey RW. Endocrine treatment of physiological gynaecomastia. Br Med J 2003;327:301-2.
2. Compston JE. Selective oestrogen receptor modulators: potential therapeutic implications. Clin Endocrinol 1998;48:389-91.
3. Agnusdei D, Iori N. Raloxifene: results from the MORE study. J Musculoskel Neuron Interact 2000;1:127-32.
4. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnasson NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC. The effect of raloxifene on risk of breast cancer in postmenopausal women. J Am Med Ass 1999;281:2189-97.
5. Mincey BA, Morahan TJ, Perez EA. Prevention and treatment of osteoporosis in women with breast cancer. Mayo Clin Proc 2000;75:821-9.
6. Cauley JA, Norton L, Lippman ME, Eckert S, Krueger KA, Purdie DW, Farrerons J, Karasik A, Mellstrom D, Ng KW, Stepan JJ, Powles TJ, Morrow M, Costa A, Silfen SL, Walls EL, Schmitt H, Muchmore DM, Jordan VC. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Breast Cancer Res Treatment 2001;65:125-34.
7. Uebelhart B, Bonjour JP, Draper MW, Pavo I, Basson R, Rizzoli R. Effects of selective estrogen receptor modulator raloxifene on the pituitary gonadal axis in healthy males (Abstract). J Bone Miner Res 2000;15(Suppl 1):S453.
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Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia.
Lawrence SE, Faught KA, Vethamuthu J, Lawson ML.
Department of Pediatrics, University of Ottawa, Ontario, Canada. slawrence@cheo.on.ca
OBJECTIVES: To assess the efficacy of the anti-estrogens tamoxifen and raloxifen in the medical management of persistent pubertal gynecomastia.
STUDY DESIGN: Retrospective chart review of 38 consecutive patients with persistent pubertal gynecomastia who presented to a pediatric endocrinology clinic. Patients received reassurance alone or a 3- to 9-month course of an estrogen receptor modifier (tamoxifen or raloxifene).
RESULTS: Mean (SD) age of treated subjects was 14.6 (1.5) years with gynecomastia duration of 28.3 (16.4) months. Mean reduction in breast nodule diameter was 2.1 cm (95% CI 1.7, 2.7, P <.0001) after treatment with tamoxifen and 2.5 cm (95% CI 1.7, 3.3, P <.0001) with raloxifene. Some improvement was seen in 86% of patients receiving tamoxifen and in 91% receiving raloxifene, but a greater proportion had a significant decrease (>50%) with raloxifene (86%) than tamoxifen (41%). No side effects were seen in any patients.
CONCLUSION: Inhibition of estrogen receptor action in the breast appears to be safe and effective in reducing persistent pubertal gynecomastia, with a better response to raloxifene than to tamoxifen. Further study is required to determine that this is truly a treatment effect.
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A study documenting the long term use of Raloxifen
Effects of Long-Term Use of Raloxifene, a Selective Estrogen Receptor Modulator, on Thyroid Function Test Profiles
Sandy H.-J. Hsu, Wern-Cherng Cheng, Men-Wang Jang and Keh-Sung Tsai
Estrogen (1)(2)(3)(4)(5) may increase hepatic production of thyroxine-binding globulin (TBG) and decrease TBG clearance (6), thus increasing serum total thyroxine (tT4) (3)(4) and, to a lesser extent, total triiodothyronine (tT3) (3)(4). As a result, increased tT4 and tT3 are seen in states of excessive estrogen and/or progestin, such as pregnancy, estrogen replacement therapy (HRT) (5), and oral contraceptive usage (1). This phenomenon may cause problems in clinical diagnoses when tT4 or tT3 is used for these patients. On the other hand, estrogen has been shown to increase thyroid-stimulating hormone (TSH) and to decrease free thyroxine (fT4) through a mild inhibitory effect on the thyroid gland (4). Compound that are analogs of estrogens, such as tamoxifen, have been shown to increase TSH without decreasing fT4 (7)(
. Recently, a new category of therapeutic agents, collectively termed selective estrogen receptor modulators (SERMs), has been developed to treat patients with postmenopausal osteoporosis (9). Raloxifene is one SERM. It decreases bone resorption (9)(10) and serum LDL-cholesterol (9)(11)(12), but it does not stimulate breast (13) or endometrium (14) at the recommended dosage of 60 mg daily. This agent is becoming one of the first-line pharmaceutical agents for postmenopausal osteoporosis and is currently administered to a large number of patients. However, the effect of long-term raloxifene usage on TBG, T3 uptake, tT3, tT4, fT4, and TSH has not been well documented. To investigate whether raloxifene causes changes in serum concentrations of these markers, we compared the effects of 1 year of treatment with either raloxifene or combined continuous estrogen and progesterone (CCEP) on the thyroid function test profiles, estradiol 2 (E2), and follicle-stimulating hormone (FSH).
We studied 60 euthyroid postmenopausal women (age range, 40–75 years) with relatively low bone mineral density. The t-score, using the mean and SD of healthy premenopausal Taiwanese women as reference (15), ranged from +1 to -2.49. These 60 women were divided into two groups in a double-blind, randomized fashion. Fifty women received raloxifene (60 mg daily) before breakfast, and 10 women received combined conjugated equine estrogen (premarin®; 0.625 mg) and medroxyprogesterone acetate (provera®; 5 mg) daily. Fasting serum samples were collected for all participants at baseline and after 1 year of treatment. All of the serum samples were stored at -70 °C, thawed simultaneously, and measured on the same day. All participants completed the treatment program. The compliance was good for both groups. Pill counting showed that each patient consumed 85–100% of the tablets/capsules.
Serum tT3, tT4, fT4, TBG, third-generation TSH, T3 uptake, E2, and FSH were all measured using commercial chemiluminescent immunoassays and instruments (Immulite; DPC). The within-day imprecision (CVs) of these assays was 3–7%.
We used two-way ANOVA for repeated measures to compare the concentrations of E2 and FSH and the thyroid function profiles between the two therapeutic groups, before and after treatment. The data were analyzed by the general linear model procedure (PROG GLM) included in the SAS package (SAS, Ver. 6.12; SAS Institute).
The anthropometric data and the mean value (± SE) for each thyroid function test item before and after treatment in the CCEP and raloxifene groups are shown in Table 1 . At baseline, there was no significant difference in height, weight, age, years since menopause, or thyroid function test items between these two groups. CCEP significantly increased serum TBG (17%), tT3 (5.7%), and tT4 (19%) and decreased T3 uptake (9%), whereas it did not change TSH. The mean fT4 concentration decreased by 3%, but the change was not statistically significant. Raloxifene also increased serum TBG (7.8%), tT3 (4.4%), and tT4 (5.7%) and decreased T3 uptake (3.7%). The mean fT4 concentration decreased by 3%, but this change was not statistically significant (Table 1 ). The changes in these five markers were apparently smaller than those caused by CCEP but did not reach statistical significance.
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