RESUMEN
OBJECTIVE: To study cardiovascular risk markers in women taking estradiol/trimegestone or estradiol/dydrogesterone. DESIGN: Multicenter, randomized, prospective, double-blind study of 184 healthy post-menopausal women randomized to 6 cycles of either estradiol (2mg)+trimegestone (0.5mg) (T-group) or estradiol (2mg)+dydrogesterone (10mg) (DYDR group). Cardiovascular risk markers were measured before, after cycle 1, 3 and 6 and at 4 weeks post-treatment. RESULTS: Fibrinogen was reduced in both groups but more markedly in the DYDR group. Factor VIIc activity levels decreased in both groups with a greater change in the T-group. Factor VII antigen was increased in both groups with a greater increase in the DYDR group. Factor VIIa was increased in the DYDR group only. Plasminogen levels were also increased in both groups with a greater increase in the T-group. There were no statistically significant changes in lipid variables between the different regimens. Changes in total cholesterol and LDL cholesterol were correlated positively with changes in factor VIIc in the DYDR group and negatively with changes in factor VIIc in the T-group. Trigemestone was associated with a better bleeding pattern. CONCLUSIONS: Trimegestone was associated with less procoagulant changes in factor VIIa and factor VIIc activity and larger decrease in PAI-1 activity compared with the dydrogesterone preparation. These results reflect less androgenic properties of the trimegestone preparation. The fibrinogen level and Lp(a) were more decreased during dydrogesterone treatment. Further investigation is required to clarify the relative importance of beneficial effects with respect to cardiovascular risk.
Asunto(s)
Factores de Coagulación Sanguínea/metabolismo , Enfermedades Cardiovasculares/prevención & control , Didrogesterona/uso terapéutico , Estradiol/uso terapéutico , Estrógenos/uso terapéutico , Lípidos/sangre , Progestinas/uso terapéutico , Promegestona/análogos & derivados , Adulto , Anciano , Biomarcadores/sangre , Método Doble Ciego , Quimioterapia Combinada , Terapia de Reemplazo de Estrógeno , Femenino , Fibrinólisis/efectos de los fármacos , Humanos , Persona de Mediana Edad , Posmenopausia , Promegestona/uso terapéutico , Factores de Riesgo , Tromboembolia/etiología , Hemorragia Uterina/inducido químicamenteRESUMEN
Trimegestone (TMG) is a novel, 19-norpregnane progestin with potent and selective properties. In preclinical studies, TMG has been shown to provide high endometrial selectivity. Further, TMG has high affinity and selectivity for the progesterone receptor and lacks the agonist effects of other steroid hormones. In clinical studies, TMG has been shown to have high endometrial safety and an improved bleeding profile along with improved tolerability compared with other progestins. In addition, TMG also does not impede the beneficial effects of estrogen, especially on bone, and does not compromise quality of life. The preclinical findings of lack of mineralocorticoid activity of TMG were supported in clinical findings, with neutral effect on body weight. Similarly, the smaller effect of TMG on the GABA-ergic (gamma-aminobutyric acid) system in preclinical studies is consistent with the improvement of central nervous system-related effects on depressed mood and sleep quality in clinical studies. Low-dose estradiol/TMG regimens provide rapid relief from menopausal symptoms, reducing the number and severity of hot flushes as effectively as 2 mg 17beta-estradiol/1 mg norethisterone acetate. Therefore, it may be concluded that TMG provides a clinically proven option in hormone therapy for both clinicians and patients.
Asunto(s)
Promegestona/análogos & derivados , Afecto/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Fenómenos Químicos , Química , Depresión/psicología , Quimioterapia Combinada , Endometrio/efectos de los fármacos , Estradiol/uso terapéutico , Femenino , Sofocos/tratamiento farmacológico , Humanos , Progestinas/farmacología , Progestinas/uso terapéutico , Promegestona/efectos adversos , Promegestona/metabolismo , Promegestona/farmacología , Promegestona/uso terapéutico , Receptores de Progesterona/metabolismo , Sueño/efectos de los fármacos , Hemorragia Uterina/inducido químicamente , Ácido gamma-Aminobutírico/metabolismoRESUMEN
OBJECTIVES: To compare the efficacy of a continuous combined regimen of 1mg 17beta-estradiol (17beta-E2) and 0.125 mg trimegestone (TMG) with two continuous combined 17beta-E2/norethisterone acetate (NETA) combinations in the relief of climacteric symptoms in postmenopausal women. STUDY DESIGN: This was a randomized, double-blind, multicenter study conducted in 13 countries over a 2-year period. Healthy postmenopausal women with an intact uterus were treated with 1 mg 17beta-E2/0.125 mg TMG, 2 mg 17beta-E2/1 mg NETA or 1 mg 17beta-E2/0.5 mg NETA for up to 26 cycles, each of 28 days. RESULTS: The 1 mg 17beta-E2/0.125 mg TMG combination was effective in significantly reducing the mean daily number and severity of hot flushes and in reducing the number of night sweats from cycle 1 onward. No overall significant differences between this regimen and the comparators were detected. Other efficacy variables, including the Kupperman index, psychofunctional disorders and quality-of-life sub-scales, experienced a similar improvement from baseline with all treatments. CONCLUSION: Continuous combined 1 mg 17beta-E2/0.125 mg TMG provides relief of menopausal symptoms that is non-inferior to both 17beta-E2/NETA combinations. Furthermore, trimegestone appeared to provide a better improvement of depressive mood than 0.5 mg NETA when combined with 1 mg 17beta-estradiol.
Asunto(s)
Estradiol/uso terapéutico , Terapia de Reemplazo de Estrógeno , Sofocos/tratamiento farmacológico , Noretindrona/análogos & derivados , Posmenopausia/efectos de los fármacos , Promegestona/análogos & derivados , Administración Oral , Adulto , Afecto/efectos de los fármacos , Método Doble Ciego , Esquema de Medicación , Combinación de Medicamentos , Estradiol/administración & dosificación , Terapia de Reemplazo de Estrógeno/métodos , Femenino , Humanos , Persona de Mediana Edad , Noretindrona/administración & dosificación , Noretindrona/uso terapéutico , Acetato de Noretindrona , Promegestona/administración & dosificación , Promegestona/uso terapéutico , Estudios Prospectivos , Calidad de Vida , Sudoración/efectos de los fármacosRESUMEN
OBJECTIVE: To compare the efficacy of two sequential 17beta-estradiol (17beta-E2)/trimegestone (TMG) combinations with the sequential estradiol valerate (E2V)/norethisterone (NET) regimen in relieving climacteric symptoms. STUDY DESIGN: This was a double-blind, randomized, multicenter study conducted among 1218 Caucasian (99%) postmenopausal women with an intact uterus in seven European countries and Israel, over 13 cycles (each of 28 days). Study duration was extended further for 13 cycles, with 531 women receiving treatment for up to 26 cycles. Treatments consisted of 1 mg 17beta-E2 on days 1-14 and 1 mg 17beta-E2/0.125 mg TMG or 0.25 mg TMG on days 15-28, and 1 mg E2V on days 1-16 and 1 mg E2V/1 mg NET on days 17-28. RESULTS: Rapid and significant reductions in the mean daily number and severity of hot flushes and in the mean daily number of nocturnal sweats were established in most women with 1 mg 17beta-E2/0.25 mg TMG and E2V/NET. These treatments also induced a significant improvement in the quality-of-life assessments. CONCLUSION: The 1 mg 17beta-E2/0.25 mg TMG regimen provides rapid and effective relief of menopausal symptoms, with a reduction in the number of hot flushes "at least as good as" that of the E2V/NET comparator.
Asunto(s)
Estradiol/análogos & derivados , Estradiol/uso terapéutico , Terapia de Reemplazo de Estrógeno , Sofocos/tratamiento farmacológico , Noretindrona/análogos & derivados , Posmenopausia/efectos de los fármacos , Promegestona/análogos & derivados , Administración Oral , Adulto , Método Doble Ciego , Esquema de Medicación , Combinación de Medicamentos , Estradiol/administración & dosificación , Estradiol/efectos adversos , Terapia de Reemplazo de Estrógeno/efectos adversos , Terapia de Reemplazo de Estrógeno/métodos , Femenino , Humanos , Persona de Mediana Edad , Noretindrona/administración & dosificación , Noretindrona/uso terapéutico , Acetato de Noretindrona , Promegestona/administración & dosificación , Promegestona/uso terapéutico , Estudios Prospectivos , Calidad de Vida , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Sudoración/efectos de los fármacos , Hemorragia Uterina/inducido químicamenteRESUMEN
OBJECTIVE: To compare the bleeding profiles and endometrial protection of two sequential regimens of 17beta-estradiol (17beta-E2) and trimegestone (TMG) with a sequential estradiol valerate (E2V)/norethisterone (NET) regimen. STUDY DESIGN: This was a randomized, double-blind, multicenter study conducted in eight countries in healthy, postmenopausal women with an intact uterus. A total of 1218 women were enrolled into the initial 1-year study (13 cycles), and subsequently 531 of these received treatment for a further year (26 cycles). Treatment regimens were 1 mg 17beta-E2 on days 1-14 and 1 mg 17beta-E2/0.125 mg TMG or 1 mg 17beta-E2/0.25 mg TMG on days 15-28, and 1 mg E2V on days 1-16 and 1 mg E2V/1 mg NET on days 17-28. RESULTS: Mean percentage of women reporting onset of withdrawal bleeding episodes during the week following discontinuation of progestogen was higher in the 1 mg 17beta-E2/0.25 mg TMG group than in the other two treatments, showing a more efficient progestogen effect on the endometrium and good predictability of bleeding onset with this treatment. The mean numbers and average lengths of bleeding episodes were similar in the three treatment groups. Overall, the bleeding profile was more favorable with 1 mg 17beta-E2/0.25 mg TMG than with the lower-dose TMG preparation. Both of the TMG regimens demonstrated a good protective effect on endometrial proliferation, with the 0.25 mg TMG dose showing a lower incidence of proliferative endometrium. CONCLUSION: The 1 mg 17beta-E2/0.25 mg TMG regimen showed an adequate protection of the endometrium, with an overall favorable bleeding profile.
Asunto(s)
Estradiol/análogos & derivados , Estradiol/efectos adversos , Terapia de Reemplazo de Estrógeno , Noretindrona/análogos & derivados , Promegestona/análogos & derivados , Hemorragia Uterina/inducido químicamente , Administración Oral , Adulto , Peso Corporal/efectos de los fármacos , Método Doble Ciego , Esquema de Medicación , Combinación de Medicamentos , Hiperplasia Endometrial/prevención & control , Endometrio/efectos de los fármacos , Endometrio/patología , Estradiol/administración & dosificación , Estradiol/uso terapéutico , Terapia de Reemplazo de Estrógeno/métodos , Femenino , Humanos , Persona de Mediana Edad , Noretindrona/administración & dosificación , Noretindrona/efectos adversos , Noretindrona/uso terapéutico , Acetato de Noretindrona , Posmenopausia/efectos de los fármacos , Promegestona/administración & dosificación , Promegestona/efectos adversos , Promegestona/uso terapéutico , Estudios ProspectivosRESUMEN
BACKGROUND: It has been proposed that hormonal supplementation during prolonged GnRH agonist therapy prevents hypoestrogenic side effects, including bone loss. The optimal combination for long-term treatments with safe metabolic profile remains questionable. A norprogesterone derivative, promegestone, was assessed for the first time in a double-blind trial. METHODS: Seventy-eight patients with endometriosis with rAFS (Revised American Society for Reproductive Medicine) scores of III-IV were randomly assigned to monthly leuprorelin 3.75 mg (1 year) which, after the third injection was used in combination with promegestone 0.5 mg (P) plus either estradiol placebo (PL) or estradiol 2 mg (E) per day. Bone mineral density (BMD) was determined at baseline, 6 and 12 months, and biological and clinical quarterly assessments were performed. Analysis was by the intention to treat method. RESULTS: At month 12, BMD changes from baseline were -6.1 +/- 3.7 and -4.9 +/- 4.0% in the PL-P group, at the spine and hip, respectively. This bone loss was prevented in the E-P group: -1.9 +/- 3.1 and -1.4 +/- 2.3%, respectively (P < 0.0001 inter-group comparisons). The BMD decrease in the E-P group was explained by the changes occurring during the first 6 months of treatment. There was no deleterious change in lipid parameters. Clinical improvement was observed without an inter-group difference. CONCLUSIONS: Estradiol 2 mg and promegestone 0.5 mg per day is an effective and safe add-back therapy, which can be proposed for prolonged leuprorelin treatment over 6 months in severe endometriosis.
Asunto(s)
Endometriosis/tratamiento farmacológico , Estradiol/administración & dosificación , Leuprolida/administración & dosificación , Promegestona/administración & dosificación , Absorciometría de Fotón , Adulto , Densidad Ósea/efectos de los fármacos , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Endometriosis/metabolismo , Estradiol/efectos adversos , Estradiol/uso terapéutico , Femenino , Humanos , Leuprolida/efectos adversos , Leuprolida/uso terapéutico , Vértebras Lumbares/metabolismo , Vértebras Lumbares/efectos de la radiación , Promegestona/efectos adversos , Promegestona/uso terapéutico , Resultado del TratamientoRESUMEN
Trimegestone (TMG) is a novel, 19-norpregnane progestin, which demonstrates endometrial selectivity with a reduced progestin-related side effect profile when compared to several other currently marketed progestins. TMG has been studied in combination with 17beta-estradiol (17beta-E2) and conjugated equine estrogens (CEE). TMG-containing HRT agents were effective in relieving vasomotor symptoms and providing protection from endometrial hyperplasia with < or =1% hyperplasia. In clinical trials with sequential regimens, TMG provided predictable withdrawal bleeding associated with a low incidence of irregular and prolonged bleeding. Clinical studies of continuous combined regimens of estrogen/TMG combinations demonstrated high levels of amenorrhea. Both 17beta-E2 and CEE/TMG combinations have shown improved bone mineral density and quality-of-life assessments. Both continuous combined and sequential regimens of 17beta-E2/TMG and CEE/TMG have a favorable clinical profile. TMG provides an important new option for the treatment of postmenopausal symptoms and the prevention of osteoporosis.
Asunto(s)
Ensayos Clínicos como Asunto , Terapia de Reemplazo de Hormonas , Progestinas/uso terapéutico , Promegestona/análogos & derivados , Promegestona/uso terapéutico , Adulto , Densidad Ósea , Estradiol/metabolismo , Femenino , Humanos , Menopausia/efectos de los fármacos , Persona de Mediana Edad , Posmenopausia , Factores de TiempoRESUMEN
In a prospective, randomized, placebo-controlled 12-wk study, we investigated the effect of oral hormone replacement therapy on asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), and an independent risk factor for coronary heart disease. The effects on arginine and symmetric dimethylarginine were also investigated. Sixty healthy early postmenopausal women received daily placebo (n = 16) or oral 17beta-estradiol 2 mg, either unopposed (E(2); n = 16) or sequentially combined with dydrogesterone 10 mg (E(2)+D; n = 14) or trimegestone 0.5 mg (E(2)+T; n = 14). ADMA levels reduced in all active treatment groups. Compared with baseline and placebo, the largest reduction in ADMA levels was observed in the E(2)+T group [-18.7% (95% confidence interval [CI], -25.4 to -11.9%) and -21.1% (95% CI, -26.2 to -16.1%), at 4 and 12 wk, respectively]. At 4 and 12 wk in the E(2)+T group, arginine levels were significantly reduced as well [-30.9% (95% CI, -41.1 to -20.7%) and -36.3% (95% CI, -43.1 to -29.5%), respectively], whereas symmetric dimethylarginine levels were significantly lower in the E(2)+D group after 12 wk [-11.6% (95% CI, -19.9 to -3.3%)]. In conclusion, unopposed oral estradiol and estradiol combined with dydrogesterone or trimegestone reduced plasma levels of the NOS inhibitor ADMA. Whether the reduction of the NOS substrate arginine in the E(2)+T group counteracts the potentially beneficial effect of ADMA reduction or reflects increased NO production remains to be investigated.
Asunto(s)
Arginina/análogos & derivados , Arginina/sangre , Enfermedades Cardiovasculares/prevención & control , Terapia de Reemplazo de Estrógeno , Promegestona/análogos & derivados , Biomarcadores , Cromatografía Líquida de Alta Presión , Didrogesterona/uso terapéutico , Estradiol/uso terapéutico , Femenino , Humanos , Isomerismo , Persona de Mediana Edad , Congéneres de la Progesterona/uso terapéutico , Promegestona/uso terapéutico , Factores de Riesgo , Espectrometría de FluorescenciaRESUMEN
BACKGROUND: Hormone replacement therapy (HRT) increases the risk of cardiovascular morbidity in postmenopausal women under certain circumstances. Part of this effect may be the result of the influence of HRT on blood platelets. We studied the effect of short-term oral hormone replacement therapy (unopposed oestradiol or sequentially combined oestradiol and trimegestone or dydrogesterone) on platelet activation parameters in healthy postmenopausal women. DESIGN: We designed a prospective, randomised, placebo-controlled 12-week study. Sixty healthy, normotensive, nonhysterectomised, postmenopausal women received daily micronised oestradiol (E2) 2 mg (n = 16), or 2 mg E2 daily sequentially combined with either trimegestone 0.5 mg daily (n = 14) or dydrogesterone 10 mg daily (n = 14), or placebo (n = 16). Data on platelet activation were collected at baseline and after 12 weeks of treatment using flow cytometry. RESULTS: Twelve weeks of treatment with combined HRT was associated with an increase in platelet activation parameters P-selectin and glycoprotein 53 (by 17% and 14%, respectively, P = 0.04 vs. the placebo group for both comparisons), suggesting alpha granule and lysosome degranulation. E2 replacement therapy was associated with an increase in P-selectin labelling by 22% (P = 0.04 vs. the placebo group). CONCLUSION: Short-term treatment with oestradiol or combined HRT increases the amount of circulating activated platelets as measured by flow cytometry. This could be a mechanism by which short-term HRT might increase the risk of thrombosis.
Asunto(s)
Arteriosclerosis/inducido químicamente , Estradiol/uso terapéutico , Terapia de Reemplazo de Estrógeno/efectos adversos , Activación Plaquetaria/efectos de los fármacos , Promegestona/análogos & derivados , Antígenos CD/sangre , Biomarcadores/sangre , Didrogesterona/uso terapéutico , Femenino , Citometría de Flujo , Humanos , Persona de Mediana Edad , Selectina-P/sangre , Glicoproteínas de Membrana Plaquetaria , Congéneres de la Progesterona/uso terapéutico , Promegestona/uso terapéutico , Estudios Prospectivos , Tetraspanina 30RESUMEN
BACKGROUND: Abnormal bleeding pattern is one major reason for non-compliance with hormone replacement therapy (HRT) in post-menopausal women. We have previously documented that the dose of trimegestone is the main determinant of the pattern of bleeding in women treated with estradiol (E(2)) and sequential combined trimegestone administered in four doses. The objectives of this study were to test the effect of changing the dose of trimegestone and the duration of treatment on the pattern of bleeding in these women who then entered a 6 month extension phase where a single dose of trimegestone was given sequentially combined with E(2). METHODS: The menstrual diaries of 134 post-menopausal women who completed a dose-ranging study of trimegestone and then entered a 6 month extension phase were analysed. In the 6 month extension study, all women were given one dose of trimegestone (0.25 mg) in a sequential fashion (day 15-28) combined with continuous E(2) (2 mg/day). RESULTS: Women who had received trimegestone 0.25 mg/day during the first 6 months experienced no change in the bleeding pattern in the 6 month extension. Women who had been treated with 0.5 mg/day dose experienced earlier onset, and more prolonged bleeding (P < 0.0001) following the change to 0.25 mg/day. Women who previously received trimegestone doses of 0.05 and 0.1 mg experienced a later onset of bleeding, which was lighter and of shorter duration (P < 0.001) during the extension phase as compared with the first 6 months. CONCLUSION: The dose of trimegestone, and not the duration of treatment, appears to be the important determinant of the pattern of bleeding in post-menopausal women on this HRT regimen.
Asunto(s)
Terapia de Reemplazo de Estrógeno/efectos adversos , Promegestona/administración & dosificación , Promegestona/uso terapéutico , Hemorragia Uterina/inducido químicamente , Hemorragia Uterina/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Endometrio/patología , Femenino , Humanos , Incidencia , Registros Médicos , Persona de Mediana Edad , Progestinas/efectos adversos , Promegestona/análogos & derivados , Índice de Severidad de la Enfermedad , Factores de Tiempo , Hemorragia Uterina/epidemiología , Hemorragia Uterina/fisiopatologíaRESUMEN
OBJECTIVE: This randomized, double-blind, multicenter study was planned to compare the efficacy and tolerance of a novel oral regimen containing estradiol (2.0 mg) sequentially combined with trimegestone, at a daily dose of either 0.25 mg or 0.5 mg, with a standard hormone replacement therapy containing estradiol and norethisterone acetate (E2 + NETA) in the treatment of climacteric symptoms. METHODS: The study was conducted over 13 cycles, each of 28 days, and involved 487 subjects, of whom 349 completed the study. RESULTS: All three treatments were equally effective in alleviating hot flushes and showed a progressive and significant reduction in the value of the Kupperman index. The treatments diminished equally effectively urogenital signs and symptoms. All treatments were well tolerated and the incidences of adverse events associated with each treatment were similar across the treatment groups. The duration of expected withdrawal bleeding was shorter in the estradiol + trimegestone 0.5 mg group than in the estradiol + trimegestone 0.25 mg or E2 + NETA group. CONCLUSION: All treatments were effective and well tolerated, providing significant relief from climacteric symptoms. Treatment with estradiol + trimegestone 0.5 mg provided the most favorable bleeding pattern.
Asunto(s)
Estradiol/uso terapéutico , Terapia de Reemplazo de Estrógeno , Sofocos/tratamiento farmacológico , Noretindrona/análogos & derivados , Noretindrona/uso terapéutico , Promegestona/uso terapéutico , Hemorragia Uterina/fisiopatología , Argentina , Método Doble Ciego , Endometrio/efectos de los fármacos , Endometrio/patología , Estradiol/administración & dosificación , Estradiol/farmacología , Europa (Continente) , Femenino , Humanos , Persona de Mediana Edad , Noretindrona/administración & dosificación , Noretindrona/farmacología , Acetato de Noretindrona , Satisfacción del Paciente , Promegestona/administración & dosificación , Promegestona/análogos & derivados , Promegestona/farmacología , Resultado del TratamientoRESUMEN
OBJECTIVE: To assess the value of identifying endometrial structural abnormalities at baseline hysteroscopy in predicting the pattern of bleeding in postmenopausal women treated with hormone replacement therapy. DESIGN: A randomised, double-blind, dose-ranging study. SETTING: A teaching hospital in the UK. POPULATION: One hundred and seventy-six healthy postmenopausal women. METHODS: Women were randomised to receive one of four doses of oral trimegestone (0.05, 0.1, 0.25 and 0.5 mg per day), from day 15-28, and a daily dose of 2 mg oral micronised oestradiol for six treatment cycles. Women completed diaries in which the bleeding episodes were recorded. Hysteroscopy under local anaesthesia and endometrial biopsy were performed at baseline and on day 24 of the last treatment cycle. RESULTS: Women with submucous fibroids had more prolonged (P = 0.026) and heavier (P = 0.002) progestogen-associated bleeding (odds ratio 4.54). The incidence of intermenstrual bleeding, but not its duration or severity, was higher in women with submucous fibroids (P = 0.017). There was a clear dose-dependent effect of trimegestone, with a consistently later onset of progestogen-associated bleeding occurring with increasing doses of trimegestone (P < 0.001), and such episodes became progressively lighter and of shorter duration over time (P < 0.001). CONCLUSION: Hysteroscopic evaluation of the endometrial cavity in women treated with hormone replacement therapy, predicts the occurrence of heavy and unscheduled bleeding.
Asunto(s)
Leiomioma/tratamiento farmacológico , Congéneres de la Progesterona/uso terapéutico , Promegestona/análogos & derivados , Hemorragia Uterina/tratamiento farmacológico , Neoplasias Uterinas/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Endometrio , Femenino , Terapia de Reemplazo de Hormonas/métodos , Humanos , Leiomioma/complicaciones , Persona de Mediana Edad , Posmenopausia , Promegestona/uso terapéutico , Neoplasias Uterinas/complicacionesAsunto(s)
Drogas en Investigación/uso terapéutico , Osteoporosis/tratamiento farmacológico , Progestinas/uso terapéutico , Promegestona/análogos & derivados , Anciano , Drogas en Investigación/efectos adversos , Drogas en Investigación/farmacología , Femenino , Humanos , Persona de Mediana Edad , Osteoporosis Posmenopáusica/tratamiento farmacológico , Progestinas/efectos adversos , Progestinas/farmacología , Promegestona/efectos adversos , Promegestona/farmacología , Promegestona/uso terapéuticoRESUMEN
OBJECTIVE: To compare the effects of 4 and 12 weeks of combined estradiol-progestogen replacement with unopposed estradiol therapy on fasting plasma total homocysteine concentrations in healthy postmenopausal women. METHODS: In this prospective, 12-week study in healthy postmenopausal women, we randomly assigned 59 women to sequentially combined daily 2 mg estradiol (E2) plus either trimegestone 0.5 mg daily or dydrogesterone 10 mg daily (n = 28), or to unopposed daily 2 mg estradiol (n = 16), or to placebo (n = 15). RESULTS: Fasting plasma total homocysteine concentrations decreased by 9.4% in the combined estradiol-progestogen group and by 5.1% in the estradiol-only group, and they increased by 2.4% in the placebo group (analysis of covariance: combined hormone replacement therapy compared with placebo (P = .02); combined therapy compared with estradiol (P = .23); and estradiol compared with placebo (P = .26). Reductions were detectable after 4 weeks of combined estradiol-progestogen treatment. The data suggest an additional progestogen-related reduction in homocysteine levels of 0.7 micromol/L and 0.4 micromol/L after 4 and 12 weeks, respectively. Women with a baseline homocysteine concentration in the highest quartile had significantly greater reductions in homocysteine compared with women with an initial homocysteine value in the lowest quartile. CONCLUSION: Fasting total homocysteine concentrations were significantly reduced by combined estradiol-progestogen replacement. Women with high homocysteine levels at baseline benefit the most. The progestogens used in this study did not have an unfavorable effect on homocysteine metabolism.
Asunto(s)
Didrogesterona/uso terapéutico , Estradiol/uso terapéutico , Homocisteína/sangre , Terapia de Reemplazo de Hormonas , Congéneres de la Progesterona/uso terapéutico , Promegestona/análogos & derivados , Ayuno , Femenino , Humanos , Persona de Mediana Edad , Promegestona/uso terapéutico , Estudios Prospectivos , Factores de TiempoRESUMEN
Histomorphometric changes in the endometrium were evaluated under the effect of a trimegestone-based sequential hormone replacement therapy (HRT) regimen, and the findings were compared to those in endometrium of the natural cycle. Endometrial samples were taken from postmenopausal women who completed a randomized, double blind, dose-ranging study of oral trimegestone (0.05, 0.1, 0.25 and 0.5 mg per day) from day 15 to day 28 with continuous micronized oestradiol 2 mg daily for six treatment cycles. The HRT-treated endometrium, irrespective of the dose, had a smaller mean total glandular area, smaller average glandular diameter, smaller mean total vascular space area and diameter than the luteal phase. Stromal cellularity was similar in the four dose groups. There were reduced glandular secretions in the endometrium from the high dose group. The relative weighting of these histological parameters was evaluated by linear discriminant analysis. The weighted values were dose independent, and may therefore represent either a specific effect of trimegestone, number of days administered, or both. We have constructed an equation to assign a value for a histological parameter which determines the position on linear discriminant functions. These assigned values can be used in other sequential HRT regimens to determine the relative influence of a given progestogen on endometrial morphology in relation to different phases of the natural cycle.
Asunto(s)
Endometrio/efectos de los fármacos , Terapia de Reemplazo de Hormonas , Ciclo Menstrual/fisiología , Promegestona/análogos & derivados , Anciano , Análisis Discriminante , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Endometrio/ultraestructura , Femenino , Humanos , Persona de Mediana Edad , Posmenopausia , Promegestona/uso terapéuticoRESUMEN
The effect of trimegestone-based sequential hormone replacement therapy (HRT) on the distribution of endometrial leukocytes and Ki-67 expression was investigated and the findings compared with the endometrium of the natural cycle. Endometrial cells positive for CD45(+), CD56(+), CD3(+), Ki-67(+) and CD45(+)/Ki-67(+) antigens were immunohistochemically evaluated in samples from postmenopausal women who completed a randomized, double-blind, dose-ranging study of oral trimegestone (0.05, 0.1, 0.25 and 0.5 mg per day) from days 15 to 28 with continuous micronized oestradiol 2 mg daily for six treatment cycles. The control samples were luteinizing hormone (LH)-dated endometrial biopsies. Cell counts were interpreted using linear discriminant analysis and unpaired t-test. The dose of trimegestone did not significantly affect the mean count of CD45(+), CD56(+), CD3(+), Ki-67(+) and CD45(+)/Ki-67(+) cells in the endometrial biopsies obtained from treated women. Endometrial sections from women who bled on the day of the biopsy contained higher numbers of CD45(+) and CD56 cells. In the trimegestone-treated endometrium, CD45(+), CD56(+) and CD3(+) cell expression was similar to the proliferative and early secretory phases of the natural cycle. However the expression Ki-67 and CD45(+)/Ki-67(+) cells was similar to the menstrual phase of the natural cycle endometrium. Women treated with four doses of trimegestone exhibited four different bleeding patterns. Therefore the endometrial infiltration with these cells did not explain the pattern of bleeding in women on this HRT regimen.
Asunto(s)
Endometrio/efectos de los fármacos , Ciclo Menstrual/fisiología , Promegestona/análogos & derivados , Anciano , Biomarcadores/sangre , División Celular/fisiología , Análisis Discriminante , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Endometrio/citología , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Posmenopausia , Promegestona/uso terapéuticoRESUMEN
Trimegestone is a norpregnane progestogen which is being developed in combination with oral oestradiol as postmenopausal hormone replacement therapy (HRT). In this multicentre dose-ranging study using randomized parallel groups, four doses of trimegestone were used to compare data on the patterns of uterine bleeding, the endometrial histology, and the control of menopausal symptoms in 203 women who completed treatment for 6 months. The treatment consisted of micronized oestradiol (2 mg/day) and one of four doses of trimegestone, which was administered sequentially for days 15-28 of the treatment cycle. Higher doses of trimegestone were associated with later onset of bleeding, which was lighter and of shorter duration than that observed with lower doses. The variability of the day of onset of bleeding in individual women was greater when bleeding occurred before the end of the progestogen phase (early bleeders) than when it occurred afterwards (late bleeders). All women enrolled in the study experienced good control of menopausal symptoms, with minimal progestogenic adverse effects, there being no statistically significant difference between the four dose groups.
Asunto(s)
Terapia de Reemplazo de Estrógeno , Posmenopausia , Promegestona/análogos & derivados , Hemorragia Uterina , Anciano , Biopsia , Endometrio/patología , Estradiol/administración & dosificación , Estradiol/uso terapéutico , Femenino , Humanos , Hiperplasia , Persona de Mediana Edad , Promegestona/administración & dosificación , Promegestona/efectos adversos , Promegestona/uso terapéuticoRESUMEN
In spite of the nearly total effectiveness of classic estrogen-progestogen oral contraception and its good overall tolerance, in a not inconsiderable number of situations yet, it is not possible to resort to it. These situations are the following: high blood pressure, hyperlipemia, diabetes, minor mastopathy, premenstrual tension either spontaneous or under estroprogestogen therapy. Macroprogestational contraception using either pregnanes (chlormadinone acetate) or nor-pregnanes, promegestone, nomegestrol acetate, can be then the right solution. Clinical and metabolic tolerance is excellent. In the occurrence of hypoestrogeny symptoms, a combination of nomegestrol acetate-estradiol 17 beta, transdermally administered, has given top results in a preliminary study.
Asunto(s)
Acetato de Clormadinona/uso terapéutico , Megestrol , Norpregnadienos/uso terapéutico , Congéneres de la Progesterona/uso terapéutico , Promegestona/uso terapéutico , Administración Cutánea , Adulto , Acetato de Clormadinona/metabolismo , Acetato de Clormadinona/farmacología , Anticonceptivos Orales Combinados/metabolismo , Anticonceptivos Orales Combinados/farmacología , Anticonceptivos Orales Combinados/uso terapéutico , Estradiol/sangre , Estradiol/metabolismo , Estradiol/farmacología , Estradiol/uso terapéutico , Femenino , Humanos , Incidencia , Trastornos de la Menstruación/inducido químicamente , Trastornos de la Menstruación/epidemiología , Norpregnadienos/metabolismo , Norpregnadienos/farmacología , Congéneres de la Progesterona/metabolismo , Congéneres de la Progesterona/farmacología , Promegestona/metabolismo , Promegestona/farmacologíaRESUMEN
Oestrogen deficiency is the main physiopathological factor of postmenopausal osteoporosis. The repercussions on bone metabolism of decrease in other sex steroid levels (progesterone, androgens) remains imperfectly known. Several studies on both animals and man have demonstrated that androgens and progestogens derived from testosterone have an anabolic effect on bone tissue. The latest data from studies conducted in non-menopausal women treated with progesterone suggest that this hormone might prevent bone loss. The mechanism of action of this effect on cells remain to be determined, even though progesterone has been shown to exert a mitogenic activity in vitro. Altogether, these data suggest that side by side with oestrogen deficiency the decrease of other sex steroid levels might also play a role in the physiopathology of postmenopausal bone loss.
Asunto(s)
Osteoporosis Posmenopáusica/etiología , Congéneres de la Progesterona/uso terapéutico , Progesterona/deficiencia , Adulto , Femenino , Humanos , Factor II del Crecimiento Similar a la Insulina/biosíntesis , Persona de Mediana Edad , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteoporosis Posmenopáusica/prevención & control , Progesterona/farmacología , Promegestona/uso terapéutico , Estimulación QuímicaRESUMEN
One hundred thirty-two women between the ages of 19 and 50, with various forms of benign breast diseases received 1 mg promegestone, or 0.5 mg promegestone, or 10 mg lynestrenol daily (double-blind), for 15 days per cycle, during three cycles. The groups were identical before treatment, with the exception of a longer history of mastodynia and mastopathies in the 1 mg promegestone group than in the lynestrenol group (P = 0.04) and a greater proportion of mastosis zones in the lynestrenol group as compared to the 0.500 mg promegestone group (P = 0.05). The effectiveness of lynestrenol both in terms of symptomatology (evaluated as good or excellent in 66.6% of the cases) and of clinical observations (evaluated as good or excellent in 59% of the cases) is not significantly different statistically from that of promegestone at 1 mg, whose effectiveness on symptomatology was good or excellent in 65.9% and 57.1% of the cases, respectively, or from that of promegestone at 0.5 mg/day (with 65% and 51.3% effectiveness, respectively). Clinical tolerance was rated good or excellent for 73.9% of the women on 1 mg promegestone and for 59.5% of the women on 0.500 mg promegestone, compared to 66.7% of the women on lynestrenol. No statistically significant difference was observed, neither between lynestrenol and promegestone 1 mg nor between lynestrenol and promegestone 0.5 mg. This study shows a clear improvement in functional and physical signs in patients treated with promegestone. Promegestone's efficacy is close to that of lynestrenol, a nonsteroidal progestin.2+ off