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1.
Clin Oral Implants Res ; 31(7): 655-668, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32279374

RESUMO

OBJECTIVES: The objective of the study was to evaluate and compare the effect of different drugs such as simvastatin, alendronate, and tibolone for titanium implant osseointegration enhancement. MATERIALS AND METHODS: Eighty female albino Wistar rats were equally divided into five groups: Group I (ovariectomy), Group II (sham ovariectomy), Group III (alendronate + ovariectomy), Group IV (simvastatin + ovariectomy), and Group V (tibolone + ovariectomy). Three months after ovariectomy, we performed bilateral titanium intramedullary nailing in all groups, followed by oral administration of alendronate, simvastatin, or tibolone for 12 weeks. Examinations included micro-CT, mechanical pull-out test, histology, and bone serum markers. RESULTS: Peri-implant micro-CT analysis showed a significantly higher overall bone tissue in tibolone compared to the ovariectomy group, while no significant difference was found between the treatment groups. Sham ovariectomy, alendronate, and tibolone groups had a higher body mass density compared to ovariectomy and simvastatin groups. All treatment groups had a greater thickness of the peri-implant compact bone layer compared to ovariectomy group, but the results were not statistically significant. Tibolone presented the highest values in pull-out test, but alendronate showed more consistently positive results compared to other groups. Osteocalcin had in the tibolone group almost three times the value in the ovariectomy group, but the results were not statistically significant. CONCLUSION: The hypothesis that alendronate, simvastatin, and tibolone enhance the osseointegration process of intramedullary titanium implants in ovariectomized rats has been accepted, while tibolone could offer the best results.


Assuntos
Implantes Dentários , Osseointegração , Alendronato , Animais , Densidade Óssea , Feminino , Humanos , Norpregnenos , Ovariectomia , Ratos , Sinvastatina , Titânio
2.
Ecotoxicol Environ Saf ; 188: 109912, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31706240

RESUMO

Synthetic progestins are emerging contaminants of the aquatic environment with endocrine disrupting potential. The main aim of the present study was to investigate the effects of the synthetic progestins gestodene, and drospirenone on sex differentiation in common carp (Cyprinus carpio) by histological analysis. To gain insights into the mechanisms behind the observations from the in vivo experiment on sex differentiation, we analyzed expression of genes involved in hypothalamus-pituitary-gonad (HPG) and hypothalamus-pituitary-thyroid (HPT) axes, histology of hepatopancreas, and in vitro bioassays. Carp were continuously exposed to concentrations of 2 ng/L of single progestins (gestodene or drospirenone) or to their mixture at concentration 2 ng/L of each. The exposure started 24 h after fertilization of eggs and concluded 160 days post-hatching. Our results showed that exposure of common carp to a binary mixture of drospirenone and gestodene caused increased incidence of intersex (32%) when compared to clean water and solvent control groups (both 3%). Intersex most probably was induced by a combination of multiple modes of action of the studied substances, namely anti-gonadotropic activity, interference with androgen receptor, and potentially also with HPT axis or estrogen receptor.


Assuntos
Androstenos/toxicidade , Carpas/crescimento & desenvolvimento , Disruptores Endócrinos/toxicidade , Norpregnenos/toxicidade , Diferenciação Sexual/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Gônadas/efeitos dos fármacos , Hepatopâncreas/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipófise/efeitos dos fármacos , Diferenciação Sexual/genética
3.
Arch Med Res ; 50(4): 187-196, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31499479

RESUMO

BACKGROUND: Ovarian steroid hormones are involved in modulating the growth of glioblastomas (the most common, aggressive, and lethal brain tumor) through the interaction with their intracellular receptors. Activation of sex hormone receptors is involved in glioblastomas progression. Tibolone (TIB) is a selective tissue estrogenic activity regulator widely prescribed to treat menopausal symptoms and to prevent bone lost. The effects of TIB on the growth of glioblastoma are unknown. AIM OF THE STUDY: To evaluate the effects of TIB on cell number, migration, and invasion of two derived human glioblastoma cell lines (U251 MG and U87), as well as the role of this steroid in estrogen and progesterone receptors activity and content. METHODS: U251-MG and U87 human glioblastoma cell lines were grown with different doses of TIB. The number of cells was determined and migration and invasion tests were carried out. Protein expression was performed by Western blot. RESULTS: We observed that TIB (10 nM) increased the number of cells by inducing proliferation with no effects on cell migration or invasion. The increase in cell proliferation induced by TIB was blocked by estrogen (ERs) or progesterone receptor (PRs) antagonists, ICI 182, 780 and RU 486, suggesting that these receptors mediate proliferating actions of TIB; TIB also modified the content of ERs and PRs by increasing ER-α, ER-ß, and PR-B, while decreased PR-A. CONCLUSION: Our results suggest that TIB increases cell number and proliferation of human glioblastoma cells through the regulation of ERs and PRs actions and content.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Receptor alfa de Estrogênio/metabolismo , Glioblastoma/tratamento farmacológico , Norpregnenos/uso terapêutico , Receptores de Progesterona/metabolismo , Antineoplásicos Hormonais/farmacologia , Linhagem Celular Tumoral , Feminino , Glioblastoma/patologia , Humanos , Norpregnenos/farmacologia
4.
Medicina (Kaunas) ; 55(8)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416164

RESUMO

Hormonal replacement therapy (HRT) is effective in treating the symptoms of menopause. Endometriosis is defined as the presence of functional endometrial tissue outside the uterine cavity with a tendency towards invasion and infiltration. Being an estrogen-dependent disease, it tends to regress after menopause. Nevertheless, it affects up to 2.2% of postmenopausal women. Conclusive data are not available in the literature on the appropriateness of HRT in women with endometriosis or a past history of the disease. The hypothesis that exogenous estrogen stimulation could reactivate endometriotic foci has been proposed. The aim of this state-of-the-art review was to revise the current literature about endometriosis in perimenopause and menopause and to investigate the possible role of HRT in this setting of patients. An electronic databases search (MEDLINE, Scopus, ClinicalTrials.gov, EMBASE, Sciencedirect, the Cochrane Library at the CENTRAL Register of Controlled Trials, Scielo) was performed, with the date range of from each database's inception until May 2019. All of the studies evaluating the impact of different HRT regimens in patients with a history of endometriosis were selected. 45 articles were found: one Cochrane systematic review, one systematic review, five narrative reviews, two clinical trials, two retrospective cohort studies, 34 case reports and case series. Some authors reported an increased risk of malignant transformation of endometriomas after menopause in patients assuming HRT with unopposed estrogen. Low-quality evidence suggests that HRT can be prescribed to symptomatic women with a history of endometriosis, especially in young patients with premature menopause. Continuous or cyclic combined preparations or tibolone are the best choices. HRT improves quality of life in symptomatic post-menopausal women, who should not be denied the replacement therapy only due to their history of endometriosis. Based on low-grade literature evidence, we recommend to prescribe combined HRT schemes; tibolone could be considered.


Assuntos
Endometriose/epidemiologia , Terapia de Reposição Hormonal , Menopausa/fisiologia , Moduladores de Receptor Estrogênico/administração & dosagem , Feminino , Humanos , Norpregnenos/administração & dosagem , Estudos Retrospectivos
5.
Cas Lek Cesk ; 158(3-4): 107-111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31416316

RESUMO

Tibolon is the only therapeutic approach to climacteric symptoms, prevention of osteoporosis and urogenital atrophy with the same efficacy as hormone replacement therapy. Tibolon has more positive effects on sexuality and mood changes in menopausal women. It decreases the mammographic density. Its safety for breast cancer is the same as for only estrogen therapy and better than for estrogen-gestagen therapy. Tibolon is the first choice for postmenopausal women with mood and sexuality disorders, women with mastodynia and high mammographic density.


Assuntos
Moduladores de Receptor Estrogênico , Norpregnenos , Osteoporose , Neoplasias da Mama/induzido quimicamente , Clima , Moduladores de Receptor Estrogênico/efeitos adversos , Moduladores de Receptor Estrogênico/uso terapêutico , Estrogênios , Feminino , Humanos , Menopausa , Norpregnenos/efeitos adversos , Norpregnenos/uso terapêutico , Osteoporose/prevenção & controle , Progestinas
6.
Rev Bras Ginecol Obstet ; 41(7): 449-453, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31344719

RESUMO

OBJECTIVE: To analyze the effects of estrogen alone or in combination with progestogens and tibolone (TIB) on the expression of the extracellular matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), of perlecan, and of heparanase (HPSE) of the vascular walls of the carotid arteries. METHODS: A total of 30 250-day-old ovariectomized Wistar rats were orally treated for 5 weeks with: a) 1 mg/kg of estradiol benzoate (EB); b) EB + 0.2 mg/kg of medroxyprogesterone acetate (MPA); c) EB + 0.2mg/kg of norethisterone acetate (NETA); d) EB + 2 mg/kg of dydrogesterone (DI); e) 1 mg/kg of TIB; f) placebo (CTR). Following treatment, the expression of mRNA for MMP-2, MMP-9, and HPSE was analyzed by real-time polymerase chain-reaction (PCR), and the expression of MMP-2, of MMP-9, of tissue inhibitor of metalloproteinase 2 (TIMP-2), and of perlecan was quantified by immunohistochemistry in the carotid arteries. RESULTS: The groups showed significant differences on mRNA HPSE expression (p = 0.048), which was higher in the EB, EB + MPA, and TIB groups. There was no statistically significant difference in mRNA MMP-2 or MMP-9 expression. The immunohistochemical expression of MMP-2, of TIMP-2, of MMP-9, of HPSE, and of perlecan showed no differences between groups. CONCLUSION: Estradiol alone or associated with MPA and TIB treatment can increase mRNA HSPE expression of the walls of the carotid arteries in ovariectomized rats.


Assuntos
Artérias Carótidas/enzimologia , Contraceptivos Hormonais/farmacologia , Estradiol/análogos & derivados , Heparina Liase/efeitos dos fármacos , Norpregnenos/farmacologia , Progestinas/farmacologia , Administração Oral , Animais , Artérias Carótidas/efeitos dos fármacos , Contraceptivos Hormonais/administração & dosagem , Estradiol/administração & dosagem , Estradiol/farmacologia , Terapia de Reposição de Estrogênios , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Proteoglicanas de Heparan Sulfato/genética , Proteoglicanas de Heparan Sulfato/metabolismo , Heparina Liase/genética , Heparina Liase/metabolismo , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Modelos Animais , Norpregnenos/administração & dosagem , Ovariectomia , Progestinas/administração & dosagem , Ratos , Ratos Wistar
7.
Molecules ; 24(13)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261651

RESUMO

To further explore the scope of our recently developed "fluorination on Sep-Pak" method, we prepared two well-known positron emission tomography (PET) tracers 21-[18F]fluoro-16α,17α-[(R)-(1'-α-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione furanyl norprogesterone ([18F]FFNP) and 16ß-[18F]fluoro-5α-dihydrotestosterone ([18F]FDHT). Following the "fluorination on Sep-Pak" method, over 70% elution efficiency was observed with 3 mg of triflate precursor of [18F]FFNP. The overall yield of [18F]FFNP was 64-72% (decay corrected) in 40 min synthesis time with a molar activity of 37-81 GBq/µmol (1000-2200 Ci/mmol). Slightly lower elution efficiency (~55%) was observed with the triflate precursor of [18F]FDHT. Fluorine-18 labeling, reduction, and deprotection to prepare [18F]FDHT were performed on Sep-Pak cartridges (PS-HCO3 and Sep-Pak plus C-18). The overall yield of [18F]FDHT was 25-32% (decay corrected) in 70 min. The molar activity determined by using mass spectrometry was 63-148 GBq/µmol (1700-4000 Ci/mmol). Applying this quantitative measure of molar activity to in vitro assays [18F]FDHT exhibited high-affinity binding to androgen receptors (Kd~2.5 nM) providing biological validation of this method.


Assuntos
Di-Hidrotestosterona/química , Radioisótopos de Flúor/química , Norpregnenos/química , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Feminino , Halogenação , Humanos , Masculino , Espectrometria de Massas , Estrutura Molecular
8.
J Obstet Gynaecol ; 39(5): 633-638, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31001993

RESUMO

This is a cohort study which included 100 cases with pre-eclampsia (PE) and 100 controls, done to compare the antepartum and postpartum uterine artery (UtA) Doppler velocimetry between them. UtA PI and RI were measured before and within 48-72 h after delivery. There was a highly significant difference between the cases and controls, regarding the UtA RI (0.70 ± 0.10 and 0.72 ± 0.10, versus 0.59 ± 0.12 and 0.60 ± 0.11) and PI (1.41 ± 0.89 and 1.45 ± 0.90 versus 0.85 ± 0.30 and 0.90 ± 0.34) measured at the antepartum and postpartum periods, respectively. Age and gestational age were significantly related to the postpartum and changes in the UtA PI. The gestational age was also correlated to UtA RI changes. Both the antepartum and postpartum mean blood pressure were correlated with postpartum UtA RI and PI and PI changes after delivery. We concluded that uterine artery Doppler indices changes are more common in women with PE, than in normotensive women with significant correlations with age and gestational age. Impact statement What is already known on this subject? After delivery, the haemodynamic changes that occurred with pregnancy reverse. Both the heart rate and the cardiac output decreased to reach the non-pregnant state. Impedance to flow in the uterine artery rises as the nutritional needs are decreased abruptly. What do the results of this study add? Both the antepartum and postpartum measurement of uterine artery Doppler indices is significantly higher in women with PE when compared to control women. The persistent uterine artery impedance is a result of inadequate trophoblastic invasion within the basal part of the decidua basalis and myometrium or persistently increased maternal vascular tone. What are the implications of these findings for clinical practice and/or further research? The uterine artery Doppler parameters return to the non-pregnant values in normal pregnancies. Knowing such information may help in understanding the haemodynamics of the uterine vasculature during puerperium in hypertensive patients.


Assuntos
Período Pós-Parto , Pré-Eclâmpsia/fisiopatologia , Artéria Uterina/fisiopatologia , Adulto , Velocidade do Fluxo Sanguíneo , Pressão Sanguínea , Estudos de Casos e Controles , Estudos de Coortes , Egito , Impedância Elétrica , Feminino , Humanos , Norpregnenos , Gravidez , Diagnóstico Pré-Natal , Fluxo Pulsátil , Ultrassonografia Doppler , Ultrassonografia Pré-Natal
9.
Mol Cell Endocrinol ; 486: 65-78, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30822454

RESUMO

Palmitic acid (PA) induces several metabolic and molecular changes in astrocytes, and, it is involved in pathological conditions related to neurodegenerative diseases. Previously, we demonstrated that tibolone, a synthetic steroid with estrogenic, progestogenic and androgenic actions, protects cells from mitochondrial damage and morphological changes induced by PA. Here, we have evaluated which estrogen receptor is involved in protective actions of tibolone and analyzed whether tibolone reverses gene expression changes induced by PA. Tibolone actions on astrocytic cells were mimicked by agonists of estrogen receptor α (ERα) and ß (ERß), but the blockade of both ERs suggested a predominance of ERß on mitochondria membrane potential. Expression analysis showed a significant effect of tibolone on genes associated with inflammation such as IL6, IL1B and miR155-3p. It is noteworthy that tibolone attenuated the increased expression of TERT, TERC and DNMT3B genes induced by palmitic acid. Our results suggest that tibolone has anti-inflammatory effects and can modulate pathways associated with DNA methylation and telomeric complex. However, future studies are needed to elucidate the role of epigenetic mechanisms and telomere-associated proteins on tibolone actions.


Assuntos
Astrócitos/metabolismo , Receptor alfa de Estrogênio/metabolismo , Inflamação/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Norpregnenos/farmacologia , Ácido Palmítico/toxicidade , Astrócitos/efeitos dos fármacos , Linhagem Celular , Epigênese Genética/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/antagonistas & inibidores , Receptor beta de Estrogênio/metabolismo , Humanos , Inflamação/genética , Nitrilos/farmacologia , Fenóis , Substâncias Protetoras/farmacologia , Pirazóis , Telomerase/genética , Telomerase/metabolismo , Telômero/metabolismo , Fatores de Transcrição/metabolismo
10.
J Clin Endocrinol Metab ; 104(5): 1595-1622, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30907953

RESUMO

OBJECTIVE: The objective is to formulate clinical practice guidelines for the pharmacological management of osteoporosis in postmenopausal women. CONCLUSIONS: Evidence from clinical trials and insights from clinical experience with pharmacologic therapies for osteoporosis were critically evaluated in formulating this guideline for the management of postmenopausal osteoporosis. Patient preferences, data on adherence and persistence, and risks and benefits from the patient and provider perspectives were also considered in writing committee deliberations. A consensus by the Writing Committee members was achieved for four management principles: (i) The risk of future fractures in postmenopausal women should be determined using country-specific assessment tools to guide decision-making. (ii) Patient preferences should be incorporated into treatment planning. (iii) Nutritional and lifestyle interventions and fall prevention should accompany all pharmacologic regimens to reduce fracture risk. (iv) Multiple pharmacologic therapies are capable of reducing fracture rates in postmenopausal women at risk with acceptable risk-benefit and safety profiles.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Denosumab/uso terapêutico , Difosfonatos/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Absorciometria de Fóton , Acidentes por Quedas/prevenção & controle , Calcitonina/uso terapêutico , Cálcio/uso terapêutico , Tomada de Decisão Clínica , Moduladores de Receptor Estrogênico/uso terapêutico , Terapia de Reposição de Estrogênios , Feminino , Humanos , Norpregnenos/uso terapêutico , Osteoporose Pós-Menopausa/diagnóstico por imagem , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Preferência do Paciente , Cloridrato de Raloxifeno/uso terapêutico , Medição de Risco , Comportamento de Redução do Risco , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Teriparatida/uso terapêutico , Vitamina D/uso terapêutico
11.
J Clin Endocrinol Metab ; 104(5): 1623-1630, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30907957

RESUMO

BACKGROUND: Osteoporosis and osteopenia are associated with increased fracture incidence in postmenopausal women. We aimed to determine the comparative effectiveness of various available pharmacological therapies. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ISI Web of Science, and Scopus for randomized controlled trials that enrolled postmenopausal women with primary osteoporosis and evaluated the risk of hip, vertebral, or nonvertebral fractures. A network meta-analysis was conducted using the multivariate random effects method. RESULTS: We included 107 trials (193,987 postmenopausal women; mean age, 66 years; 55% white; median follow-up, 28 months). A significant reduction in hip fractures was observed with romosozumab, alendronate, zoledronate, risedronate, denosumab, estrogen with progesterone, and calcium in combination with vitamin D. A significant reduction in nonvertebral fractures was observed with abaloparatide, romosozumab, denosumab, teriparatide, alendronate, risedronate, zoledronate, lasofoxifene, tibolone, estrogen with progesterone, and vitamin D. A significant reduction in vertebral fractures was observed with abaloparatide, teriparatide, parathyroid hormone 1-84, romosozumab, strontium ranelate, denosumab, zoledronate, risedronate, alendronate, ibandronate, raloxifene, bazedoxifene, lasofoxifene, estrogen with progesterone, tibolone, and calcitonin. Teriparatide, abaloparatide, denosumab, and romosozumab were associated with the highest relative risk reductions, whereas ibandronate and selective estrogen receptor modulators had lower efficacy. The evidence for the treatment of fractures with vitamin D and calcium remains limited despite numerous large trials. CONCLUSIONS: This network meta-analysis provides comparative effective estimates for the various available treatments to reduce the risk of fragility fractures in postmenopausal women.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Fraturas do Quadril/prevenção & controle , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Fraturas da Coluna Vertebral/prevenção & controle , Doenças Ósseas Metabólicas/tratamento farmacológico , Calcitonina/uso terapêutico , Moduladores de Receptor Estrogênico/uso terapêutico , Terapia de Reposição de Estrogênios , Feminino , Humanos , Metanálise em Rede , Norpregnenos/uso terapêutico , Pós-Menopausa , Vitamina D/uso terapêutico
12.
J Cataract Refract Surg ; 45(1): 101-104, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30448005

RESUMO

We describe the association of rapid progression of keratoconus in a 49-year-old woman on selective tissue estrogenic activity regulator (STEAR) therapy for endometriosis. Approximately 4 months after initiation of therapy with STEAR therapy and 3 months after ovariectomy, Scheimpflug images showed a massive increase in the previously stable ectasia. During this period, the maximum increase in the keratometry values was 2.7 diopters (D) in the right eye and 3.8 D in the left eye. Corneal crosslinking (CXL) was performed in both eyes. This resulted in excessive flattening of 5.5 D in the right eye and 6.1 D in the left eye at 9 months postoperatively. Patients having STEAR therapy must be monitored closely for corneal changes.


Assuntos
Endometriose/tratamento farmacológico , Moduladores de Receptor Estrogênico/efeitos adversos , Ceratocone/induzido quimicamente , Ceratocone/diagnóstico , Norpregnenos/efeitos adversos , Colágeno/metabolismo , Substância Própria/metabolismo , Topografia da Córnea , Reagentes para Ligações Cruzadas , Progressão da Doença , Feminino , Humanos , Ceratocone/tratamento farmacológico , Pessoa de Meia-Idade , Ovariectomia , Fármacos Fotossensibilizantes/uso terapêutico , Riboflavina/uso terapêutico , Raios Ultravioleta , Acuidade Visual
13.
Blood Coagul Fibrinolysis ; 30(1): 17-23, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30507711

RESUMO

: Postmenopausal hormone therapy increases the risk of venous thrombosis. Sex hormone binding globulin (SHBG) is a suggested marker of 'total estrogenicity'. The study objective was to evaluate the impact of hormone therapy on SHBG and the association with coagulation variables. The study populations comprised 202 healthy postmenopausal women randomized to treatment with low-dose or conventional-dose hormone therapy, tibolone or raloxifene (RET-study) and 140 women with a history of venous thrombosis randomized to conventional-dose hormone therapy or placebo (EVTET-study). SHBG was determined in serum collected at baseline and after 12 weeks. In healthy women, conventional-dose hormone therapy increased SHBG with mean 9.7 (95% confidence interval 4.8-14.5) nmol/l, low-dose hormone therapy by mean 5.9 (0.4-11.5) nmol/l, raloxifene by mean 7.2 (3.9-10.4) nmol/l, while tibolone reduced SHBG with mean -25.1 (-29.9 to -20.4) nmol/l. SHBG correlated with protein S, tissue factor pathway inhibitor (TFPI) and protein C at baseline, and with protein S and TFPI after 12 weeks, but the change in SHBG from baseline to 12 weeks was only associated with the change in activated protein C (APC) resistance. In women with a history of venous thrombosis, the mean increase in SHBG was 13.6 (8.4-18.9) nmol/l in the conventional-dose hormone therapy group, with no change in the placebo group. Baseline SHBG was higher among women who developed recurrent venous thrombosis on conventional-dose hormone therapy. SHBG correlated with several coagulation inhibitors, but the change in SHBG induced by postmenopausal hormone therapy was only associated with the change in APC resistance.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Terapia de Reposição de Estrogênios/métodos , Globulina de Ligação a Hormônio Sexual/efeitos dos fármacos , Trombose Venosa/tratamento farmacológico , Resistência à Proteína C Ativada/sangue , Moduladores de Receptor Estrogênico/farmacologia , Moduladores de Receptor Estrogênico/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Norpregnenos , Pós-Menopausa/sangue , Cloridrato de Raloxifeno , Globulina de Ligação a Hormônio Sexual/análise
14.
Exp Clin Endocrinol Diabetes ; 127(6): 396-404, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30107623

RESUMO

In addition to oxidative stress due to the increase of free radicals, estrogen deficiency is associated with changes in enzymatic activity, glutathione redox ratio (GSH/GSSG), and the content of oxidative markers such as malondialdehyde. Tibolone, a synthetic steroid, has been used as an elective treatment for the relief of menopausal symptoms. However, the acute effects of hormonal therapy with tibolone on metabolic parameters and oxidative stress markers associated with the first stages of estrogen deficiency are still unknown. The study aimed to evaluate if the acute administration of tibolone reduces oxidative stress in ovariectomized rats fed high-fat-and-fructose diet. Rats were fed a standard diet or a diet consisting of 10% lard-supplemented chow and 20% high-fructose syrup in the drinking water plus tibolone or vehicle for seven days. Weight, cholesterol, triglycerides, and glucose levels, as well as antioxidant enzymes and oxidative stress markers were quantified in the serum of each experimental group. It was observed that seven days of diet and tibolone treatment in the ovariectomized group reduced weight, triglycerides, cholesterol, glucose levels and advanced glycation end products but did not change GSH/GSSG ratio nor the enzymatic activity of superoxide dismutase. Also, both glutathione peroxidase and glutathione reductase activity decreased, as well as malondialdehyde levels. These results suggest that the acute treatment with tibolone prevented the changes in the metabolic parameters analyzed as well as the increase in the levels of malondialdehyde and AGEs induced by ovariectomy and high-fat diet.


Assuntos
Carboidratos da Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Frutose/efeitos adversos , Norpregnenos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Carboidratos da Dieta/farmacologia , Gorduras na Dieta/farmacologia , Feminino , Frutose/farmacologia , Ovariectomia , Ratos , Ratos Sprague-Dawley
15.
Int Urogynecol J ; 30(2): 251-256, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29946829

RESUMO

INTRODUCTION AND HYPOTHESIS: The impact of estradiol-based hormone therapy (HT) on the incidence of stress urinary incontinence (SUI) is unknown. Therefore, we compared the use of such HT regimens and tibolone in women with and without SUI. METHODS: The women with a history of SUI operation (N = 15,002) were identified from the Finnish National Hospital Discharge Register, and the control women without such an operation (N = 44,389) from the Finnish Central Population Register. The use of HT was traced from the National Drug Reimbursement Register, and the odd ratios (ORs) with 95% confidence intervals (95% CIs) for SUI were calculated by using the conditional logistic regression analysis. RESULTS: The cases had used any HT more often than the controls. The use of systemic estradiol-only or estradiol-progestin therapy was accompanied by an increased SUI risk (OR 3.8, 95% CI: 3.6-4.0 and OR 2.7, 95% CI: 2.6-2.9 respectively). The use of estradiol with noretisterone acetate showed a higher risk of increase than that with medroxyprogesterone acetate. Age over 55 years at the initiation of systemic HT was accompanied by a higher SUI risk increase than that under 55 years of age. The use of tibolone, an estradiol + levonorgestrel-releasing intrauterine device, or vaginal estradiol also increased the risk. CONCLUSIONS: The use of HT regimens may predispose to the de novo development or worsening of pre-existing SUI. Thus, caution is needed when these regimens are prescribed to women with mild stress-related urine leakage or with established SUI risk factors.


Assuntos
Estradiol/efeitos adversos , Terapia de Reposição de Estrogênios/efeitos adversos , Estrogênios/efeitos adversos , Norpregnenos/efeitos adversos , Incontinência Urinária por Estresse/epidemiologia , Terapia de Reposição de Estrogênios/métodos , Feminino , Finlândia/epidemiologia , Humanos , Pessoa de Meia-Idade , Pós-Menopausa/efeitos dos fármacos , Sistema de Registros , Fatores de Risco , Incontinência Urinária por Estresse/induzido quimicamente
16.
Gynecol Obstet Fertil Senol ; 46(12): 834-844, 2018 12.
Artigo em Francês | MEDLINE | ID: mdl-30385358

RESUMO

OBJECTIVES: To synthesize knowledge on cancer risks related to hormonal contraception and to propose recommendations on contraception during treatment and after cancer. METHODS: A systematic review of the literature about hormonal contraception and cancer was conducted on PubMed/Medline and the Cochrane Library. RESULTS: Overall, there is no increase in cancer (all types together) incidence or mortality among hormonal contraceptive users. Estroprogestin combined contraceptive use is associated with an increased risk of breast cancer (during use), and with a reduced risk of endometrial, ovarian, lymphatic or hematopoietic cancers that persist after discontinuation, and a decreased risk of colorectal cancer. Information on cancer risk is part of the systematic information given to patients wishing contraception. However, these data will not influence its prescription, considering the positive risk/benefit balance in women without specific cancer risk factor. Contraception is required during and after cancer treatment in every non-menopausal woman at cancer diagnosis. Specific thromboembolic, immunologic or vomiting risks due to the oncological context should be taken into account before the contraceptive choice. All hormonal contraceptives are contra-indicated after breast cancer, regardless of the delay since treatment, hormone receptor status and histological subtype. There is no data in the literature to limit hormonal or non-hormonal contraceptive use after colorectal or thyroid cancer. There was insufficient data in the literature to propose recommendations on contraceptive choice after cervical cancer, melanoma, lung cancer, tumor of the central nervous system, or after thoracic irradiation. If an emergency contraception is needed in a woman previously treated for a hormone-sensitive cancer, a non-hormonal copper intrauterine device should be preferred. CONCLUSIONS: Information on cancer risk is part of the patient's information but does not influence the prescription of contraception in the absence of any specific risk factor. Contraception should be proposed in every woman treated or previously treated for cancer. The whole context should be taken into account to choose a tailored contraception.


Assuntos
Anticoncepcionais Femininos/efeitos adversos , Anticoncepcionais Orais Hormonais/efeitos adversos , Neoplasias/epidemiologia , Neoplasias/terapia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Anticoncepção Pós-Coito , Combinação de Medicamentos , Etinilestradiol/efeitos adversos , Feminino , França , Humanos , Dispositivos Intrauterinos de Cobre , MEDLINE , Neoplasias/induzido quimicamente , Norpregnenos/efeitos adversos , Fatores de Risco
17.
Gynecol Obstet Fertil Senol ; 46(12): 823-833, 2018 12.
Artigo em Francês | MEDLINE | ID: mdl-30389542

RESUMO

Venous thromboembolism and arterial ischemic events are the main deleterious diseases associated with the use of combined hormonal contraceptives (CHC). Even though their composition has been substantially improved, the vascular risk persists with the most recent CHCs use. If the vascular risk associated with CHCs containing 50µg EE is significantly higher than with those containing less than 50µg, there is no evidence that the CHCs containing either 30 or 20µg of EE induce different venous risks. CHC containing gestodene, desogestrel, drospirenone or cyproterone acetate are associated with a higher risk of venous thrombosis compared with levonorgestrel-containing CHCs. CHC containing norgestimate are associated with similar venous thrombosis risk than CHC containing levonorgestrel. Venous thrombosis risk of non-oral routes of administration of CHC appears to be equivalent to the risk of CHC containing gestodene or desogestrel, but this result is based on a small number of epidemiological studies. Before prescribing a CHC, it is important to determine all vascular risk factors. Family history of ischemic arterial event or venous thromboembolism disease should be routinely sought before any CHC prescription. All CHCs are contraindicated in women with biological thrombophilia, in women with combined vascular risk factors, in women with first-degree family history of arterial or venous event (under age 50) as well as in women suffering of migraine with aura. Progestin-only contraceptives are not associated with vascular risk (arterial or venous) outside of medroxyprogesterone acetate. In women with higher vascular risk, progestin-only contraceptives (administered by oral, sous-cutaneous or intra-uterine routes) can be prescribed.


Assuntos
Anticoncepcionais Orais Hormonais/efeitos adversos , Doenças Vasculares/induzido quimicamente , Tromboembolia Venosa/induzido quimicamente , Androstenos/efeitos adversos , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/efeitos adversos , Anticoncepcionais Orais Combinados/efeitos adversos , Acetato de Ciproterona/efeitos adversos , Desogestrel/efeitos adversos , Feminino , França , Humanos , Levanogestrel/efeitos adversos , Norpregnenos/efeitos adversos , Progestinas , Fatores de Risco , Tromboembolia Venosa/epidemiologia
18.
Microsc Res Tech ; 81(12): 1489-1500, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30365192

RESUMO

There are several possible mechanisms by which combined oral contraceptives (COC) use increase venous thromboembolism (VTE) risk. Melodene® is a monophasic COC containing the third-generation progestin Gestodene (GSD), which is associated with increased risk of VTE. Therefore, the aim of this study was to investigate the possible alterations in viscoelastic parameters of whole blood and plasma clots along with the biophysical characteristics of erythrocytes and specifically fibrin fibers in females using a COC containing GSD. GSD appeared to have a significant impact on the biophysical characteristics of fibrin fiber networks. When GSD is combined with ethinylestradiol the viscoelastic properties of whole blood clots tend to become more prothrombotic. The alterations to and aggregation of erythrocytes accompanied with spontaneous formation of a fibrin "blanket" provides a possible mechanism for the increased occurrence of "red" clots, which can lead to occlusions in the vascular system. Thus, the increased risk of VTE associated with these COCs can be attributed to these erythrocyte-and-fibrin-rich-clots occluding venous vessels. However, our findings also propose that these changes to the biophysical properties of both erythrocytes and fibrin, specifically spontaneous expansion of deformed fibrin networks, can also occlude vessels in the microcirculation, which could have lasting, subclinical complications for female users. We recommend that a thorough risk assessment, with specific focus on coagulation and other factors affecting fibrin formation, be done for each female before prescribing a GSD-containing COC. Females that "qualify" then need to be monitored on a regular basis to lower the risk of thrombotic events. RESEARCH HIGHLIGHTS: Gestodene in combination with ethinyl estradiol significantly impacts the biophysical characteristics of erythrocytes and fibrin fiber networks. These changes, specifically spontaneous expansion of deformed fibrin networks, can occlude vessels in the microcirculation, which could have lasting, subclinical complications for the female user. The changes observed for specifically erythrocytes and fibrin show that the hormone formulation investigated contribute to a thrombogenic profile for female users.


Assuntos
Anticoncepcionais Orais Combinados/efeitos adversos , Norpregnenos/efeitos adversos , Trombose/etiologia , Adulto , Coagulação Sanguínea/efeitos dos fármacos , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Feminino , Fibrina/metabolismo , Humanos , Trombose/sangue , Trombose/metabolismo , Adulto Jovem
19.
JAMA Cardiol ; 3(9): 877-882, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30073300

RESUMO

Importance: Women are at higher risk of drug-induced torsade de pointes (TdP) than men. Androgens are protective. Influence of oral contraception on drug-induced TdP and QT prolongation is controversial. Objective: To determine if the extent of sotalol-induced corrected QT (QTc) prolongation and specific T-wave morphological changes, which are biomarkers for the risk of drug-induced TdP, differ in patients according to the androgenic activity of the type of oral contraceptive (OCs) they take compared with patients who took no pills. Design, Setting, and Participants: A cohort of 498 healthy, nonmenopausal women received 80 mg of oral sotalol, a drug with known risk of drug-induced TdP, during this study in a clinical investigation center. The participants also took either no oral contraception or received OCs with different types of progestin: levonorgestrel (which has high androgenic potency), desogestrel or gestodene (which has intermediate androgenic potency), or drospirenone (which has antiandrogenic properties). Women were enrolled from February 2008 to February 2012, and data analysis took place from September 2014 to May 2018. Main Outcomes and Measures: Electrocardiographic changes 3 hours after sotalol administration. Results: A total of 137 women received levonorgestrel, 41 received desogestrel, 51 received gestodene, and 62 received drospirenone; another 207 received no OCs. Baseline QTc duration, plasma sotalol levels, and potassium levels did not significantly differ among groups. However, 3 hours after sotalol exposure, QTc prolongation was greater in women taking drospirenone (mean [SD] increase, 31.2 [12.6] milliseconds from baseline) than in women taking no OCs (mean [SD] increase, 24.6 [12.5] milliseconds; P = .005) or those taking levonorgestrel (mean [SD] increase, 24.2 [13.7] milliseconds; P = .005). The frequency of sotalol-induced T-wave alteration was higher in women taking drospirenone (n = 13 of 61 [21.0%]) than those taking levonorgestrel (n = 20 of 137 [14.6%]) or women taking no OCs (n = 24 of 207 [11.6%]; P = .01). Disproportionality analysis using the European pharmacovigilance database showed a higher reporting rate of OC-induced prolonged QT and ventricular arrhythmias in women taking drospirenone than levonorgestrel (drug-induced long QT syndrome: reporting odds ratio [ROR], 6.2 [95% CI, 1.3-30.8]; P = .01; ventricular arrhythmia: ROR, 3.3 [95% CI, 1.7-6.3]; P < .001). Conclusions and Relevance: Contraceptive pills are associated with variable drug-induced alterations of ventricular repolarization in healthy nonmenopausal women. Drospirenone, an antiandrogenic pill, was associated with increased sotalol-induced QTc prolongation, although absolute QTc prolongation was modest. This finding was supported by the European pharmacovigilance database, which showed a higher reporting rate of suspected OC-induced ventricular arrhythmias on drospirenone compared with levonorgestrel. More data are required on whether antiandrogenic OCs lead to clinically significant adverse events in patients taking QTc-prolonging drugs.


Assuntos
Antagonistas de Androgênios/efeitos adversos , Androstenos/efeitos adversos , Síndrome do QT Longo/epidemiologia , Sotalol/efeitos adversos , Administração Oral , Adulto , Antagonistas de Androgênios/administração & dosagem , Androstenos/administração & dosagem , Estudos de Coortes , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/efeitos adversos , Desogestrel/administração & dosagem , Desogestrel/efeitos adversos , Europa (Continente) , Feminino , Humanos , Levanogestrel/administração & dosagem , Levanogestrel/efeitos adversos , Modelos Logísticos , Síndrome do QT Longo/induzido quimicamente , Norpregnenos/administração & dosagem , Norpregnenos/efeitos adversos , Sotalol/administração & dosagem , Adulto Jovem
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