RESUMO
The aim of this study was to explore the mechanisms of action of alsevirone in prostate cancer (PC) in vitro and in vivo: CYP17A1 inhibition, cytotoxic, apoptotic, and antitumor effects in comparison with abiraterone. The CYP17A1-inhibitory activity was investigated in rat testicular microsomes using high-performance liquid chromatography. Testosterone levels were evaluated using enzyme-linked immunoassay. IC50 values were calculated for PC3, DU-145, LNCaP, and 22Rv1 cells using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test. The antitumor effect in vivo was studied in DU-145 and 22Rv1 subcutaneous xenografts in Balb/c nude mice. Alsevirone reduced the CYP17A1-inhibitory activity by 98% ± 0.2%. A statistically significant reduction in the testosterone concentration in murine blood was recorded after the 7th administration of 300 mg/kg alsevirone at 0.31 ± 0.03 ng/ml (p < .001) versus 0.98 ± 0.22 ng/ml (p = .392) after abiraterone administration and 1.52 ± 0.49 ng/ml in control animals. Alsevirone was more cytotoxic than abiraterone in DU-145, LNCaP, and 22Rv1 cells, with IC50 values of 23.80 ± 1.18 versus 151.43 ± 23.70 µM, 22.87 ± 0.54 versus 28.80 ± 1.61 µM, and 35.86 ± 5.63 versus 109.87 ± 35.15 µM, respectively. Alsevirone and abiraterone significantly increased annexin V-positive, caspase 3/7-positive, and activated Bcl-2-positive cells. In 22Rv1 xenografts, alsevirone 300 mg/kg × 10/24 h per os inhibited tumor growth: on Day 9 of treatment, tumor growth inhibition = 59% (p = .022). Thus, alsevirone demonstrated significant antitumor activity associated with CYP17A1 inhibition, apoptosis in PC cells, and testosterone reduction.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Norpregnadienos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Norpregnadienos/administração & dosagem , Células PC-3 , Ratos , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Testosterona/sangue , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: To analyse the effect of ulipristal acetate (UPA) as emergency contraception (EC) on the gene expression of human endometrial cell line (HEC-1A) and endometrium from fertile women treated with UPA after ovulation. MATERIALS AND METHODS: HEC-1A cells were treated with UPA, and endometrial tissue from four healthy women was collected in cycles before, during and 2 months after post-ovulation pill intake. Ovulation and luteal phase were monitored, and endometrial biopsies were obtained at day LH + 7 in each cycle. In all cases, we analysed the expression profile of 192 genes associated to endometrial receptivity. RESULTS: We observed a significant change in total transcriptomic activity of UPA-treated HEC-1A cells compared to controls. In vivo, we also observed a trend to down-regulation of genes in the UPA-treated cycle that was partially restored in the post-treatment cycle. Altogether, our results supported a partially reversible effect of UPA in gene expression associated with uterine receptivity. CONCLUSIONS: When UPA was administered after ovulation, it seems to induce a down-regulation of the main genes involved in conditioning the endometrium for implantation. This effect is partially restored two months after pill intake. The action of UPA on the endometrium for users of EC should be further investigated.
Assuntos
Anticoncepção Pós-Coito , Norpregnadienos , Anticoncepção Pós-Coito/métodos , Endométrio , Feminino , Humanos , Norpregnadienos/farmacologia , TranscriptomaRESUMO
Muscle wasting caused by catabolic reactions in skeletal muscle is commonly observed in patients with sepsis. Myostatin, a negative regulator of muscle mass, has been reported to be upregulated in diseases associated with muscle atrophy. However, the behavior of myostatin during sepsis is not well understood. Herein, we sought to investigate the expression and regulation of myostatin in skeletal muscle in mice inoculated with gram-negative bacteria. Interestingly, the protein level of myostatin was found to increase in the muscle of septic mice simultaneously with an increase in the levels of follistatin, NF-κΒ, myogenin, MyoD, p- FOXO3a, and p-Smad2. Furthermore, the inhibition of myostatin by YK11 repressed the levels of pro-inflammatory cytokines and organ damage markers in the bloodstream and in the major organs of mice, which originally increased in sepsis; thus, myostatin inhibition by YK11 decreased the mortality rate due to sepsis. The results of this study suggest that YK11 may help revert muscle wasting during sepsis and subdue the inflammatory environment, thereby highlighting its potential as a preventive agent for sepsis-related muscle wasting.
Assuntos
Infecções por Escherichia coli/tratamento farmacológico , Escherichia coli/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/prevenção & controle , Miostatina/antagonistas & inibidores , Norpregnadienos/farmacologia , Sepse/tratamento farmacológico , Animais , Caquexia/metabolismo , Caquexia/patologia , Caquexia/prevenção & controle , Citocinas/metabolismo , Modelos Animais de Doenças , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Masculino , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , NF-kappa B/metabolismo , Sepse/metabolismo , Sepse/patologiaRESUMO
PURPOSE: "Real-world" data incorporates studies performed outside of controlled environments, allowing for a better understanding of the effects of treatment in routine clinical practice. We, therefore, performed a systematic review to summarise available "real-world studies" reporting on the use of ulipristal acetate (UPA) for management of uterine fibroids. METHODS: We designed a prospective protocol according to PRISMA guidelines and registered it with PROSPERO (ID: CRD42019151393). We searched all major databases for relevant citations until 20th September 2019. Our screen included studies for risk of bias using an adapted structured quality assessment tool. Random-effects meta-analysis was used to calculate proportion estimates for each outcome including 95% confidence interval. Reported heterogeneity was assessed using I2. RESULTS: Initial search yielded 755 studies and 13 were included in the final synthesis. Administration of UPA resulted in reduction in the size of fibroids in 56.5% of women, improved menorrhagia in 83% of women, improved perception of pain in 80.1% of women and lead to an improvement in global symptom scores in 85.2% of women. Mean reduction in surgical blood loss and surgical time with use of UPA was 59.85 ml and 12.47 min, respectively. Qualitative analysis suggested that there was no difference in overall surgical experience for patients treated with UPA compared to those without pre-treatment. CONCLUSIONS: Our findings are consistent with previously reported data that UPA is an acceptable management option for women with fibroids. However, it provides limited benefits when used as a pre-operative adjunct, in terms of blood loss and surgical time.
Assuntos
Contraceptivos Hormonais/uso terapêutico , Leiomioma/tratamento farmacológico , Norpregnadienos/uso terapêutico , Contraceptivos Hormonais/farmacologia , Feminino , Humanos , Leiomioma/cirurgia , Norpregnadienos/farmacologia , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
The use of emergency contraception (EC) methods is increasing worldwide as it constitutes an effective way to prevent unplanned pregnancy after unprotected sexual intercourse. During the last decade, ulipristal acetate (UPA), a selective progesterone receptor modulator, has emerged as the most effective EC pill, and it is now recommended as first-line hormonal treatment for EC in several countries. Its principal mechanism of action involves inhibition or delay of follicular rupture, but only when administered during the follicular phase before the luteinizing hormone (LH) peak. However, considering the high efficacy of UPA, it is possible that it also exerts contraceptive effects besides ovulation. In the present review, we summarize and discuss the existing evidence obtained on the effect of UPA on sperm function and post-ovulatory events as potential additional mechanisms to prevent pregnancy. The bulk of evidence collected so far indicates that UPA would not affect gamete function; however, it could impair embryo-uterine interaction. Thus, besides the described effects on ovarian function, UPA contraceptive effectiveness might also be attributed to post-ovulatory effects, depending on the moment of the female cycle in which the drug is administered.
Assuntos
Anticoncepção Pós-Coito , Contraceptivos Hormonais/farmacologia , Norpregnadienos/farmacologia , Oviductos/efeitos dos fármacos , Útero/efeitos dos fármacos , Animais , Implantação do Embrião/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Humanos , Masculino , Ovulação/efeitos dos fármacos , Espermatozoides/efeitos dos fármacosRESUMO
Ulipristal acetate (UPA) is a selective progesterone receptor modulator used for emergency contraception that has proven to be highly effective in preventing pregnancy when taken up to 120 h after unprotected sexual intercourse. Even though it may act mainly by delaying or inhibiting ovulation, additional effects of UPA on post-fertilization events cannot be excluded. Therefore, the aim of this study was to determine whether a single post-ovulatory dose of UPA could prevent pregnancy using the mouse as a pre-clinical model. Mated females received a single dose of UPA (40 mg/kg) on Day E1.5 or E2.5 (E0.5: copulatory plug detection) and post-fertilization events were evaluated. Our studies revealed that UPA administration produced a significant decrease in the number of conceptuses compared to control. Moreover, UPA-treated females exhibited a lower number of early implantation sites on Day E5.5, despite normal in vivo embryo development and transport to the uterus at E3.5. Administration of UPA produced histological and functional alterations in the uterine horns, i.e., a dyssynchronous growth between endometrial glands and stroma, with non-physiological combination of both fractions compared to controls, and a completely impaired ability to respond to an artificial decidualization stimulus. Altogether, our results show that the administration of a single post-ovulatory dose of UPA impairs mouse pregnancy probably due to an effect on embryo-uterine interaction, supporting additional effects of the drug on post-fertilization events. Although these studies cannot be performed with human samples, our results with the mouse model provide new insights into the mechanism of action of UPA as an emergency contraception method.
Assuntos
Contraceptivos Hormonais/farmacologia , Implantação do Embrião/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Fertilização/fisiologia , Norpregnadienos/farmacologia , Ovário/efeitos dos fármacos , Animais , Anticoncepção Pós-Coito/métodos , Copulação/fisiologia , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Implantação do Embrião/fisiologia , Desenvolvimento Embrionário/fisiologia , Feminino , Humanos , Masculino , Camundongos , Ovário/fisiologia , Ovulação/fisiologia , GravidezRESUMO
RESEARCH QUESTION: Can patient and/or uterine fibroid characteristics predict the volume reduction of fibroids under ulipristal acetate (UPA) treatment? DESIGN: This was a monocentric observational prospective cohort study of women with symptomatic fibroids who were willing to undergo surgery after a 3-month treatment of daily 5 mg doses of UPA. Patients underwent magnetic resonance imaging before and after treatment, and the volumes of the three largest fibroids were assessed. The reduction in volume was assessed qualitatively: fibroids decreasing in volume were considered to be 'responsive' to treatment, and fibroids that were stable or increased in volume were considered to be 'non-responsive'. Comparisons were made of patient (age and body mass index) and fibroid (initial volume, number and location) characteristics between fibroids that were responsive and non-responsive to UPA treatment. RESULTS: Fifty-three women were included in the final analysis and 116 fibroids were measured. The initial number and initial volume of the fibroids were statistically associated with the response to UPA treatment (adjusted odds ratio [OR] 0.645, 95% confidence interval [CI] 0.461-0.903, Pâ¯=â¯0.0115 for number of fibroids, and adjusted OR 1.447, 95% CI 1.063-1.970, Pâ¯=â¯0.0195 for initial volume, with a log-linear relationship). Submucosal fibroids had a higher response rate to treatment (i.e. a decrease in volume) than intramural fibroids (21/25 [84.0%] versus 15/28 [53.6%]; Pâ¯=â¯0.0490; adjusted OR 4.478, 95% CI 1.007-19.918). CONCLUSIONS: The location, initial volume and number of fibroids may allow prediction of the outcome of a single 3-month treatment course of daily 5 mg doses of UPA in terms of reduction in volume before surgery.
Assuntos
Leiomioma/diagnóstico por imagem , Leiomioma/tratamento farmacológico , Norpregnadienos/farmacologia , Adulto , Índice de Massa Corporal , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
RESEARCH QUESTION: What are the effects of ulipristal acetate (UPA) on the expression of endometrial proliferation and maturation markers? DESIGN: A total of 45 endometrium-containing blocks of hysterectomy samples from non-menopausal women with a diagnosis of moderate to severe symptoms of uterine fibroids: 14 women operated on at the end of a 3-month course of UPA; four women who had discontinued UPA treatment 1-12 months before surgery; 27 control unexposed samples (14 in the proliferative and 13 in the secretory phase). Immunohistochemical staining of Ki67, vascular endothelial growth factor-receptor 2 (VEGFR2), oestradiol receptor, progesterone receptor, interleukin-15 (IL-15), indoleamin-2,3-dioxygenase (IDO) and C-C motif chemokine ligand-2 (CCL2) markers were analysed in both endometrial compartments and layers. RESULTS: Under UPA, oestradiol receptor and progesterone receptor expression is similar to the proliferative phase in both layers, although with a decrease in cell proliferation. IL-15, IDO and CCL2 expressions are similar to the proliferative phase, suggesting a progesterone-antagonist effect of UPA. VEGFR2 staining suggests a trend to a mixed agonist-antagonist effect. No significant difference is observed in the post-UPA proliferative phase group compared with the control group in both layers of the endometrium. CONCLUSION: The effect of 3-month UPA treatment is mostly progesterone receptor antagonist-like. After treatment is discontinued, there are no signs of any long-term effects of this molecule on endometrial proliferation and maturation. Therefore, UPA may be administered to women willing to conceive in the short term without consequences for further implantation.
Assuntos
Contraceptivos Hormonais/farmacologia , Endométrio/efeitos dos fármacos , Leiomioma/tratamento farmacológico , Norpregnadienos/farmacologia , Neoplasias Uterinas/tratamento farmacológico , Adulto , Proliferação de Células/efeitos dos fármacos , Contraceptivos Hormonais/uso terapêutico , Endométrio/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Norpregnadienos/uso terapêutico , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Ulipristal acetate (UPA) is used for medical treatment of uterine fibroids. The aim of this study was to describe the effects on painful symptoms and the sonographic uterine modifications in patients with adenomyosis erroneously treated with UPA. This is an observational study on six women affected by adenomyosis and treated with three months of UPA (5 mg/24h). The baseline ultrasonography (US) was not performed at out center nor was the diagnosis of fibroids. The patients came to our attention after the treatment with UPA, prescribed by an external physician. During our post-treatment scan we found aspects of adenomyosis, while no fibroids were detected. Symptoms, myometrial and endometrial ultrasound features were evaluated. All patients reported an increase in pelvic pain. At US evaluation intramyometrial cystic areas were found in all six cases (100%). All patients showed an enhancement of adenomyosis features.The intra-myometrial cysts appeared enlarged and the vascularization enhanced when compared to the images of the pretreatment scan. In patients with adenomyosis treated with UPA due to an erroneous diagnosis of uterine fibroids we observed a worsening of the US features of adenomyosis and of the painful symptoms.
Assuntos
Adenomiose/diagnóstico por imagem , Leiomioma/tratamento farmacológico , Norpregnadienos/uso terapêutico , Ultrassonografia , Neoplasias Uterinas/tratamento farmacológico , Útero/diagnóstico por imagem , Erros de Diagnóstico , Progressão da Doença , Feminino , Humanos , Leiomioma/diagnóstico por imagem , Pessoa de Meia-Idade , Norpregnadienos/farmacologia , Neoplasias Uterinas/diagnóstico por imagem , Útero/efeitos dos fármacosRESUMO
Nomegestrol acetate (NOMAc) is a synthetic progesterone analog and classified as a fourth-generation progestin. It has been approved in many countries for oral contraception, hormonal replacement therapy (HRT), and treatment of various gynecological disorders. There are several synthetic routes reported for the synthesis of NOMAc and they all share the very similar last three to five steps toward the conversion of 6-methylene to 6-methyl-6,7-unsaturated structure. Therefore the final product from different processing routes may have similar impurity profiles. In the analysis of NOMAc, we identified two impurities, impurity A (listed in EP 8.0) and impurity B (not specified in EP 8.0). Both impurities were further confirmed by synthesis. In addition, both impurities and NOMAc were evaluated for their in vitro cytotoxicities against L02 liver cells, mesenchymal stem cells, MCF-7 breast cancer cells, and C33A cervical cancer cells. These three analogs are not cytotoxic to the four cell lines at low concentrations (<20 µM). NOMAc and impurity A showed cytotoxicity to L02, MCF-7, and C33A cells at high concentrations, while impurity B did not show significant cytotoxicity to any of the cell lines tested.
Assuntos
Antineoplásicos Hormonais/síntese química , Descoberta de Drogas/métodos , Megestrol/síntese química , Norpregnadienos/síntese química , Congêneres da Progesterona/síntese química , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Contaminação de Medicamentos , Humanos , Megestrol/química , Megestrol/farmacologia , Estrutura Molecular , Norpregnadienos/química , Norpregnadienos/farmacologia , Congêneres da Progesterona/química , Congêneres da Progesterona/farmacologiaRESUMO
This study investigated the effect of a novel progestin and its combination with metformin on the growth of endometrial cancer (EC) cells. Inhibitory effects of four progestins, including nomegestrol acetate (NOMAC), medroxyprogesterone acetate, levonorgestrel, and cyproterone acetate, were evaluated in RL95-2, HEC-1A, and KLE cells using cell counting kit-8 assay. Flow cytometry was performed to detect cell cycle and apoptosis. The activity of Akt (protein kinase B), mTOR (mammalian target of rapamycin) and its downstream substrates 4EBP1 (4E-binding protein 1) and eIF4G (Eukaryotic translation initiation factor 4G) were assayed by Western blotting. Nude mice were used to assess antitumor effects in vivo. NOMAC inhibited the growth of RL95-2 and HEC-1A cells, accompanied by arresting the cell cycle at G0/G1 phase, inducing apoptosis, and markedly down-regulating the level of phosphorylated mTOR/4EBP1/eIF4G in both cell lines (p < 0.05). Metformin significantly increased the inhibitory effect of and apoptosis induced by NOMAC and strengthened the depressive effect of NOMAC on activity of mTOR and its downstream substrates, compared to their treatment alone (p < 0.05). In xenograft tumor tissues, metformin (100 mg/kg) enhanced the suppressive effect of NOMAC (100 mg/kg) on mTOR signaling and increased the average concentration of NOMAC by nearly 1.6 times compared to NOMAC treatment alone. Taken together, NOMAC suppressing the growth of EC cells likely correlates to down-regulating the activity of the mTOR pathway and metformin could strengthen this effect. Our findings open a new window for the selection of progestins in hormone therapy of EC.
Assuntos
Regulação para Baixo/efeitos dos fármacos , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/patologia , Megestrol/farmacologia , Metformina/farmacologia , Norpregnadienos/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Fator de Iniciação Eucariótico 4G/metabolismo , Feminino , Humanos , Megestrol/química , Metformina/química , Camundongos Nus , Norpregnadienos/química , Fosforilação/efeitos dos fármacos , Receptores de Progesterona/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
To observe and investigate the in vitro effect of ulipristal acetate (UPA) on human sperm parameters and function. The 20 patients with normal semen parameters and average age of (32.5±8.5) years old, who were treated in our hospital from January 2018 to August 2018, were selected as research objects. They were subjected to density gradient centrifugation, and then four groups were incubated for about an hour in a culture medium containing different concentrates of ulipristal acetate and the other two groups were set as blank control group and dimethylsulphoxide (DMSO) control group. Indicators including sperm motility, sperm hyperactivation and sperm concentration of free calcium ions of each group were tested. Under the ulipristal acetate concentration of 0.0.4 mol/L, the proportion of sperm damage was increased, the length of tail was increased, and the proportion of sperm hyperactivation was decreased, p<0.05. In addition, the acrosome reaction was inhibited, which significantly reduced the calcium concentration in the sperm, p<0.05. Ulipristal acetate can significantly inhibit acrosome reaction and hyperactivation of sperm in vitro, and can reduce the concentration of calcium ions in sperm, thus causing sperm damage.
Assuntos
Norpregnadienos/farmacologia , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Reação Acrossômica/efeitos dos fármacos , Adulto , Cálcio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Contraceptivos Hormonais/farmacologia , Dano ao DNA/efeitos dos fármacos , Humanos , Masculino , Progesterona/farmacologia , Motilidade dos Espermatozoides/efeitos dos fármacosRESUMO
RESEARCH QUESTION: Does ulipristal acetate (UPA) modify the expression of genes related to apoptosis or the extracellular matrix in uterine myomas and are any modifications associated with a clinical response? DESIGN: Targeted analysis of 176 apoptosis- or extracellular-matrix-related genes was conducted using polymerase chain reaction (PCR) arrays. Relevant results were validated by quantitative PCR. Four groups were established: responsive short-term (one course, n = 9), responsive long-term (two to four courses, n = 9), non-responsive (n = 9), and the control group who was not given any hormone therapy (n = 9). The clinical response was monitored by medical imagery and considered significant when volume reduction was greater than 25%. RESULTS: Compared with untreated myomas, significant changes in expression of four genes were found in UPA-treated myomas. Gene expression of integrin subunit beta 4 was repressed by UPA treatment (fold change [FC] = -12.50, P < 0.001, q < 0.001), tenascin-C expression was downregulated in UPA-responsive patients (FC = -2.50, P = 0.010, q = 0.090), survivin was repressed in short-term UPA-responsive tumours (FC = -7.69, P < 0.001, q = 0.010), and catenin delta 2 gene expression was upregulated in non-responsive myomas (FC = +7.36, P < 0.001, q = 0.010). CONCLUSION: This characterization provides the first molecular distinction between myomas responsive or non-responsive to UPA treatment.
Assuntos
Expressão Gênica/efeitos dos fármacos , Leiomioma/tratamento farmacológico , Norpregnadienos/uso terapêutico , Neoplasias Uterinas/tratamento farmacológico , Útero/efeitos dos fármacos , Feminino , Humanos , Leiomioma/genética , Leiomioma/patologia , Pessoa de Meia-Idade , Norpregnadienos/farmacologia , Resultado do Tratamento , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Útero/patologiaRESUMO
INTRODUCTION: Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Current management strategies involve mainly surgical interventions, but the choice of treatment is guided by patient age and desire to preserve fertility or avoid 'radical' surgery such as hysterectomy. Areas covered: There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids, leading to increasing use of selective progesterone receptor modulators (SPRMs) such as ulipristal acetate. We searched all published studies on medical management of fibroids with SPRMs. Expert opinion: The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. These options now exist, with SPRMs proven to treat fibroid symptoms effectively. Gynecologists now have new tools in their armamentarium, opening up novel strategies for the management of uterine fibroids.
Assuntos
Desenho de Fármacos , Leiomioma/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Feminino , Preservação da Fertilidade/métodos , Humanos , Leiomioma/patologia , Norpregnadienos/farmacologia , Norpregnadienos/uso terapêutico , Receptores de Progesterona/efeitos dos fármacos , Receptores de Progesterona/metabolismo , Neoplasias Uterinas/patologiaRESUMO
Ulipristal acetate (UPA) is used to treat leiomyomas, and its effect on the endometrium has been studied in biopsy material. Reversible histologic modifications were found, named progesterone receptor modulators-associated endometrial changes (PAEC). However, hysterectomies from patients treated with UPA have not been analyzed. For the first time, we examined surgical specimens from 100 leiomyoma-treated patients for UPA-related endometrial changes. We analyzed the distribution of lesions, involution after treatment, and the relationship between type and extent of lesions and dosage. Clinically, 72 patients were treated with 1 cycle of UPA; 23 patients with 2 cycles, and 5 with 3 cycles. A total of 66 patients underwent surgery in the first 4 wk after treatment, 24 were operated between 5 and 12 wk after discontinuation of UPA, and 10 after more than 12 wk after the last cycle, up to a maximum of 32 wk. Histologically normal endometria were found in 41 cases and PAEC in 59 cases. PAEC consisted of irregular, cystic glands showing a flattened secretory-like epithelium with vacuolation, coexisting mitoses and apoptosis, and were found focally within cyclic endometria in 51 cases. Only in 8 cases did diffuse PAEC involve the whole endometrium, transforming it into a thick spongy cushion. PAEC also occurred in adenomyosis. There was no relationship between dosage and type and extent of lesions. Diffuse PAEC, which usually presents differential diagnoses with hyperplasia, occurred in only 8 cases, being only present during the first 4 wk after discontinuation of treatment and was independent of the number of cycles administered.
Assuntos
Endométrio/patologia , Leiomioma/patologia , Norpregnadienos/uso terapêutico , Neoplasias Uterinas/patologia , Adulto , Endométrio/efeitos dos fármacos , Endométrio/cirurgia , Feminino , Humanos , Leiomioma/tratamento farmacológico , Leiomioma/cirurgia , Pessoa de Meia-Idade , Norpregnadienos/farmacologia , Perimenopausa , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/cirurgiaRESUMO
Androgens are key regulators that play a critical role in the male reproductive system and have anabolic effects on bone mineral density and skeletal muscle mass. We have previously reported that YK11 is a novel selective androgen receptor modulator (SARM) and induces myogenic differentiation and selective gene regulation. In this study, we show that treatment of YK11 and dihydrotestosterone (DHT) accelerated cell proliferation and mineralization in MC3T3-E1 mouse osteoblast cells. Further, YK11-treated cells increased osteoblast specific differentiation markers, such as osteoprotegerin and osteocalcin, compared to untreated cells. These observations were attenuated by androgen receptor (AR) antagonist treatment. To clarify the effect of YK11, we investigated rapid non-genomic signaling by AR. The phosphorylated Akt protein level was increased by YK11 and DHT treatment, suggesting that YK11 activates Akt-signaling via non-genomic signaling of AR. Because it is known Akt-signaling is a key regulator of androgen-mediated osteoblast differentiation, YK11 has osteogenic activity as well as androgen.
Assuntos
Androgênios/farmacologia , Norpregnadienos/farmacologia , Osteoblastos/efeitos dos fármacos , Células 3T3 , Animais , Calcificação Fisiológica/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Camundongos , Proteína Oncogênica v-akt/biossíntese , Proteína Oncogênica v-akt/genética , Osteogênese/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
Selective progesterone receptor modulators (SPRMs) are steroid progesterone receptor ligands able to induce agonistic or antagonistic activities. Mifepristone, the class leader, was primarily used for pregnancy termination from the 1980s. Emergency contraception with extended activity was the second major development 30 years later, with mifepristone in some countries and ulipristal acetate world-wide. More recently, ulipristal acetate was released for the treatment of myoma-related uterine bleeding. In addition to a very rapid cessation of bleeding, SPRMs allow a decrease in myoma volume, as do gonadotropin releasing hormone analogs. However, estradiol secretion is not blunted by SPRMs. This offers new alternatives for myoma treatment, especially in women close to menopause. In conclusion, use of SPRMs has allowed significant progress in emergency contraception and treatment of myoma-related symptoms. Numerous future perspectives in women's health care are currently under evaluation.
Assuntos
Leiomioma/tratamento farmacológico , Norpregnadienos/farmacologia , Receptores de Progesterona/agonistas , Receptores de Progesterona/antagonistas & inibidores , Neoplasias Uterinas/tratamento farmacológico , Aborto Induzido/métodos , Endometriose/tratamento farmacológico , Feminino , Humanos , Mifepristona/farmacologia , Gravidez , Progesterona/metabolismo , Hemorragia Uterina/tratamento farmacológico , Hemorragia Uterina/etiologiaRESUMO
STUDY QUESTION: What is the impact of administration of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA) on the endometrium of women with fibroids? SUMMARY ANSWER: UPA administration altered expression of sex-steroid receptors and progesterone-regulated genes and was associated with low levels of glandular and stromal cell proliferation. WHAT IS KNOWN ALREADY: Administration of all SPRM class members results in PAEC (progesterone receptor modulator associated endometrial changes). Data on the impact of the SPRM UPA administration on endometrial sex-steroid receptor expression, progesterone (P)-regulated genes and cell proliferation are currently lacking. STUDY DESIGN SIZE, DURATION: Observational study with histological and molecular analyses to delineate impact of treatment with UPA on endometrium. Endometrial samples (n = 9) were collected at hysterectomy from women aged 39 to 49 with uterine fibroids treated with UPA (oral 5 mg daily) for 9-12 weeks. Control proliferative (n = 9) and secretory (n = 9) endometrium from women aged 38-52 with fibroids were derived from institutional tissue archives. PARTICIPANTS/MATERIALS, SETTING, METHODS: Study setting was a University Research Institute. Endometrial biopsies were collected with institutional ethical approval and written informed consent. Concentrations of mRNAs encoded by steroid receptors, P-regulated genes and factors in decidualised endometrium were quantified with qRT-PCR. Immunohistochemistry was employed for localization of progesterone (PR, PRB), androgen (AR), estrogen (ERα) receptors and expression of FOXO1, HAND2, HOXA10, PTEN homologue. Endometrial glandular and stromal cell proliferation was objectively quantified using Ki67. MAIN RESULTS AND THE ROLE OF CHANCE: UPA induced morphological changes in endometrial tissue consistent with PAEC. A striking change in expression patterns of PR and AR was detected compared with either proliferative or secretory phase samples. There were significant changes in pattern of expression of mRNAs encoded by IGFBP-1, FOXO1, IL-15, HAND2, IHH and HOXA10 compared with secretory phase samples consistent with low agonist activity in endometrium. Expression of mRNA encoded by FOXM1, a transcription factor implicated in cell cycle progression, was low in UPA-treated samples. Cell proliferation (Ki67 positive nuclei) was lower in samples from women treated with UPA compared with those in the proliferative phase. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: A small number of well-characterized patients were studied in-depth. The impacts on morphology, molecular and cellular changes with SPRM, UPA administration on symptom control remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS: P plays a pivotal role in endometrial function. P-action is mediated through interaction with the PR. These data provide support for onward development of the SPRM class of compounds as effective long-term medical therapy for heavy menstrual bleeding. STUDY FUNDING/COMPETING INTEREST(S): H.O.D.C. received has clinical research support for laboratory consumables and staff from Bayer Pharma Ag and provides consultancy advice (no personal remuneration) for Bayer Pharma Ag, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc.; A.R.W.W. has received consultancy payments from Bayer, Gedeon Richter, Preglem SA, HRA Pharma; L.H.R.W., A.A.M., R.M., G.S. and P.T.K.S. have no conflicts of interest. Study funded in part from each of: Medical Research Council (G1002033; G1100356/1; MR/N022556/1); National Health Institute for Health Research (12/206/520) and TENOVUS Scotland.
Assuntos
Anticoncepcionais Femininos/farmacologia , Endométrio/efeitos dos fármacos , Leiomioma/metabolismo , Norpregnadienos/farmacologia , Receptores de Progesterona/metabolismo , Células Estromais/efeitos dos fármacos , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Proteínas Homeobox A10 , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Interleucina-15/genética , Interleucina-15/metabolismo , Pessoa de Meia-Idade , Receptores de Progesterona/genética , Células Estromais/metabolismoRESUMO
This observational study was conducted in healthy premenopausal women, who presented themselves for contraceptive advice at the outpatient Family Planning Clinics of the Department of Obstetrics and Gynecology of the University of Cagliari, Hospital-University of Cagliari (Italy). After a screening period of three menstrual cycles, 48 women without contraindications to estroprogestin contraceptives (OCs) were included in the study. The primary purposes of the study were to evaluate whether a 12-month-treatment with the combined OC containing micronized estradiol (1.5 mg, E2) plus nomegestrol acetate (2.5 mg, NOMAC) (E2/NOMAC) interfere on anthropometric indices (AI), body composition (BC) and psychological status (PS). In subjects with dysmenorrhea (#36), its intensity was evaluated using the visuo analogic scale (VAS), both before and during the 12-month-treatment with E2/NOMAC. E2/NOMAC did not modify neither AI nor BC in the 40 subjects who concluded the study. The PS and the VAS of dysmenorrhea were significantly (p < 0.0001) improved from the first cycle of treatment and throughout the E2/NOMAC treatment in comparison with basal values. The study suggests that E2/NOMAC is devoid of negative effects on AI and BC, with additional benefits on PS and dysmenorrhea.
Assuntos
Composição Corporal/efeitos dos fármacos , Anticoncepcionais Orais Hormonais/farmacologia , Emoções/efeitos dos fármacos , Estradiol/farmacologia , Megestrol/farmacologia , Norpregnadienos/farmacologia , Adolescente , Adulto , Antropometria , Anticoncepcionais Orais Hormonais/uso terapêutico , Dismenorreia/tratamento farmacológico , Estradiol/uso terapêutico , Feminino , Humanos , Megestrol/uso terapêutico , Norpregnadienos/uso terapêutico , Psicometria , Adulto JovemRESUMO
Nomegestrol acetate (NOMAC) has been successfully used for the treatment of some gynecological disorders, and as a combined oral contraceptive with approval in many countries. In this study, we investigated the effects of NOMAC on human endometrial cancer cells in vitro and in vivo. The proliferation of human endometrial cancer cells (RL95-2 and KLE) were assessed using CCK-8 and EdU incorporation assays. Whole-genome cDNA microarray analysis was used to identify the effects of NOMAC on gene expression profiles in RL95-2 cells. RL95-2 xenograft nude mice were treated with NOMAC (50, 100, and 200 mg/kg) or medroxyprogesterone acetate (MPA; 100 and 200 mg/kg) for 28 consecutive days. The results showed that NOMAC significantly inhibited the growth of RL95-2 cells in a concentration-dependent manner, but not in KLE cells. Further investigation demonstrated that NOMAC produced a stronger inhibition of tumor growth (inhibition rates for 50, 100, and 200 mg/kg NOMAC were 24.74%, 47.04%, and 58.06%, respectively) than did MPA (inhibition rates for 100 and 200 mg/kg MPA were 41.06% and 27.01%, respectively) in the nude mice bearing the cell line of RL95-2. NOMAC altered the expression of several genes related to cancer cell proliferation, including SUFU and Wnt7a. The upregulation of SUFU and Wnt7a was confirmed using real-time quantitative polymerase chain reaction and Western blotting in RL95-2 cells and RL95-2 xenograft tumor tissues, but not in KLE cells. These data indicate that NOMAC can inhibit the proliferation of RL95-2 cell in vitro and suppress the growth of xenografts in the nude mice bearing the cell line of RL95-2 in vivo. This effect could be related to the upregulating expression of SUFU and Wnt7a.