RESUMO
Two adrenalectomies py -45erformed fourteen years apart notoriously alleviated insulin resistance in a female teenager with Congenital Generalized Lipoatrophy (CGL, 1988) and in a murine model of CGL (2002). Following a successful therapeutic trial with anti-glucocorticoids, we performed the first surgical procedure on an 18-year-old girl. Before surgery, the anti-glucocorticoid therapy produced a rapid and striking drop in fasting serum insulin levels (from over 400 to 7.0 mU/L) and a slower -but impressive- fall in fasting serum triglycerides from 7,400 to 220-230 mg/dL. In contrast, fasting serum glucose levels dropped more slowly, from 225-290 to 121-138 mg/dL. Two weeks following total adrenalectomy, the fasting serum glucose level was 98 mg/dL, with a corresponding serum insulin level of 10 mU/L. During an Oral Glucose Tolerance Test, the 2-hour serum glucose was 210 mg/dL, and serum insulin values during the test did not exceed 53 mU/L. In 2002, the A-ZIP/F1 hypoleptinemic mouse had its adrenal glands removed. Even though this CGL model does not respond well to leptin replacement, an infusion of recombinant leptin reduced the characteristic hypercorticosteronemia of this murine model of CGL. Adrenalectomy in this transgenic mouse improved insulin sensitivity in the liver and muscle. In summary, adrenalectomy -in both a human and a mouse case of CGL- limited adipose tissue exposure to corticosteroid action and led to a notorious metabolic improvement. On a broader scenario, given that leptin restrains the adrenal axis, the reduced leptin activity of the leptin resistance displayed by obese subjects should lead to adrenal axis overactivity. This overactivity should result in elevated serum levels of free cortisol, free fatty acids, and glycerol. In this manner, leptin resistance should lead to peripheral (adipose tissue, liver, and muscle) insulin resistance and islet beta-cell apoptosis, paving the way to Type 2 diabetes.
Assuntos
Diabetes Mellitus Lipoatrófica , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Insulinas , Lipodistrofia Generalizada Congênita , Adolescente , Animais , Feminino , Humanos , Camundongos , Adrenalectomia , Modelos Animais de Doenças , Glucose , Leptina , Relatos de Casos como AssuntoRESUMO
Several brain structures responsible for controlling stress responses reach maturity during adolescence. Therefore, acute or chronic stress in prepuberty may negatively affect stress responses as well as behavior in adulthood. The hypothalamus-pituitary-adrenal axis (HPA) is part of the stress system whose inhibitory control is regulated by glucocorticoids through mineralocorticoid (MR) and glucocorticoid (GR) receptors. In this study, we aimed to determine whether MR or GR blockade after stress in adolescence prevents changes in exploratory behavior and HPA axis control in adult female rats. Adolescent female rats (26 days old) were submitted to one or seven daily restraint sessions followed by administration of MR (spironolactone) or GR (RU-486) antagonists. At 60 days old, animals were evaluated in the elevated plus maze and at 61 days old rats were subjected to acute stress to evaluate the HPA response. The chronic restraint in the adolescence induced an anxiogenic effect in the adult animals that was reverted by either MR or GR antagonist. In the same way chronic stress reduced the HPA axis activity by blunted corticosterone (CORT) secretion and decreased the activation of Corticotropin Releasing Hormone (CRH) neurons in the paraventricular nucleus. The post-stress blocking of GR independently restored the CORT secretion without effect on central activation. The acute stress in the adolescence had minor enduring effects. We concluded that the use of RU-486 and spironolactone after stress in the early adolescence can improve behavioral changes induced by stress whereas RU-486 only showed effect on the HPA axis response in adulthood.
Assuntos
Ansiedade , Sistema Hipotálamo-Hipofisário , Antagonistas de Receptores de Mineralocorticoides , Sistema Hipófise-Suprarrenal , Receptores de Glucocorticoides , Animais , Corticosterona/farmacologia , Hormônio Liberador da Corticotropina/metabolismo , Feminino , Glucocorticoides/farmacologia , Mifepristona/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Ratos , Receptores de Glucocorticoides/antagonistas & inibidores , Espironolactona/farmacologia , Estresse PsicológicoRESUMO
A growing body of research indicates that cortisol, the glucocorticoid product of the activation of the hypothalamic-pituitary-adrenal axis, plays a role in the pathophysiology of metabolic syndrome. In this regard, chronic exposure to cortisol is associated with risk factors related to metabolic syndrome like weight gain, type 2 diabetes, hypertension, among others. Mifepristone is the only FDA-approved drug with antiglucocorticoids properties for improved the glycemic control in patients with type 2 patients secondary to endogenous Cushing's syndrome. Mifepristone also have been shown positive effects in rodents models of diabetes and patients with obesity due to antipsychotic treatment. However, the underlying molecular mechanisms are not fully understood. In this perspective, we summarized the literature regarding the beneficial effects of mifepristone in metabolic syndrome from animal studies to clinical research. Also, we propose a potential mechanism for the beneficial effects in insulin sensitivity which involved the regulation of mitochondrial function in muscle cells.
RESUMO
RU486 (mifepristone), a glucocorticoid and progesterone receptor antagonist, has been reported to exert antiproliferative effects on tumor cells. Experiments were performed to analyze the effects of RU486 on the proliferation of the human neuroblastoma, both in vitro and in vivo, using the human neuroblastoma SK-N-SH cell line. The exposure in vitro of SK-N-SH cells to RU486 revealed a dose-dependent inhibition of 3H-thymidine incorporation due to a rapid but persistent inhibition of MAPKinase activity and ERK phosphorylation. A significant decrease of SK-N-SH cell number was evident after 3, 6, and 9 days of treatment (up to 40% inhibition), without evident cell death. The inhibitory effect exerted by RU486 was not reversed by the treatment of the cells with dexamethasone or progesterone. Moreover, RU486 induced a shift in SK-N-SH cell phenotypes, with an almost complete disappearance of the neuronal-like and a prevalence of the epithelial-like cell subtypes. Finally, the treatment with RU486 of nude mice carrying a SK-N-SH cell xenograft induced a strong inhibition (up to 80%) of tumor growth. These results indicated a clear effect of RU486 on the growth of SK-N-SH neuroblastoma cells that does not seem to be mediated through the classical steroid receptors. RU486 acted mainly on the more aggressive component of the SK-N-SH cell line and its effect in vivo was achieved at a concentration already used to inhibit oocyte implantation.
Assuntos
Humanos , Animais , Coelhos , Neuroblastoma/tratamento farmacológico , Progesterona , Mifepristona/farmacologia , Glucocorticoides , Camundongos NusRESUMO
Mifepristone is the only FDA-approved drug for glycaemia control in patients with Cushing's syndrome and type 2 diabetes. Mifepristone also has beneficial effects in animal models of diabetes and patients with antipsychotic treatment-induced obesity. However, the mechanisms through which Mifepristone produces its beneficial effects are not completely elucidated. PURPOSE: To determine the effects of mifepristone on insulin-stimulated glucose uptake on a model of L6 rat-derived skeletal muscle cells. RESULTS: Mifepristone enhanced insulin-dependent glucose uptake, GLUT4 translocation to the plasma membrane and Akt Ser473 phosphorylation in L6 myotubes. In addition, mifepristone reduced oxygen consumption and ATP levels and increased AMPK Thr172 phosphorylation. The knockdown of AMPK prevented the effects of mifepristone on insulin response. CONCLUSIONS: Mifepristone enhanced insulin-stimulated glucose uptake through a mechanism that involves a decrease in mitochondrial function and AMPK activation in skeletal muscle cells.
Assuntos
Glucose/metabolismo , Insulina/farmacologia , Mifepristona/farmacologia , Células Musculares/metabolismo , Músculo Esquelético/citologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adenilato Quinase/metabolismo , Animais , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , Células Musculares/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , RatosRESUMO
Estrogen action is necessary for evidencing the stimulatory action of mifepristone and naloxone on prolactin (PRL) secretion during late pregnancy. Our aim is to determine the mechanism mediating this facilitator action of estrogens. To investigate the hypothalamic mechanisms involved in estrogen actions in PRL secretion at the end of pregnancy, we measured the effect of pretreatment with the estrogen antagonist tamoxifen on the expression of tyrosine hydroxylase (TH), hormone receptors (ERα and ß, PRs, PRLR(long)), and µ- and κ- opioid receptors (ORs) at mRNA (by semiquantitative RT-PCR) and protein (by western blot for TH, PRLR(long), ERα, PRs, µ- and ORs) levels in extracts of medial basal hypothalamus (MBH) and serum PRL, E2 and P4 levels (by RIA) in mifepristone- and naloxone-treated rats. Tamoxifen administration partially prevented PRL release induced by the combined treatment. TH expression diminished and ERα expression increased in mifepristone-treated rats at mRNA and protein levels and tamoxifen partially prevented these changes with no effect on PRs expression. Mifepristone increased PRLR(long) mRNA levels; this increase was blocked by tamoxifen. Combined tamoxifen and mifepristone treatment decreased µ- and k-ORs mRNA but not protein levels. In conclusion, E2 induces neuroadaptive mechanisms necessary to facilitate PRL release preceding delivery. Acting through ERα, E2 modulates hypothalamic dopaminergic neurons activity, regulating TH, µ- and κ-ORs and PRLR(long) expression, and is necessary for evidencing the effects of P4 withdrawal. Its presence on days 14 and 15 of pregnancy is crucial to facilitate the opioid system modulation of PRL secretion at the end of pregnancy in the rat.
Assuntos
Estradiol/metabolismo , Prenhez/fisiologia , Prolactina/metabolismo , Animais , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Hipotálamo Médio/metabolismo , Mifepristona/farmacologia , Naloxona/farmacologia , Gravidez , Prenhez/efeitos dos fármacos , Progesterona/metabolismo , Ratos Wistar , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Receptores de Progesterona/metabolismo , Receptores da Prolactina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Astrocytomas are the most common and aggressive primary brain tumors in humans. Invasiveness of these tumors has been attributed in part to deregulation of cell motility-dependent cytoskeletal dynamics that involves actin-binding proteins such as cofilin. Progesterone (P4) has been found to induce migration and invasion of cells derived from breast cancer and endothelium. However, the role of P4 in migration and invasion of astrocytoma cells as well as its effects on astrocytomas cytoskeleton remodeling is not known. In this work we evaluated these aspects in D54 and U251 cells derived from human astrocytomas from the highest degree of malignancy (grade IV, glioblastoma). Our results showed that in scratch-wound assays P4 increased the number of D54 and U251 cells migrating from 3 to 48 h. Both RU486, a P4 receptor (PR) antagonist, and an oligonucleotide antisense against PR significantly blocked P4 effects. Transwell assays showed that P4 significantly increased the number of invasive cells at 24h. As in the case of migration, this effect was blocked by RU486. Finally, by Western blotting, an increase in the cofilin/p-cofilin ratio at 15 and 30 min and a decrease at 30 and 60 min in U251 and D54 cells, respectively, was observed after P4, P4+RU486 and RU486 treatments. These data suggest that P4 increases human astrocytoma cells migration and invasion through its intracellular receptor, and that cofilin activation by P4 is independent of PR action.
Assuntos
Fatores de Despolimerização de Actina/metabolismo , Astrocitoma/metabolismo , Astrocitoma/patologia , Movimento Celular/efeitos dos fármacos , Progesterona/farmacologia , Linhagem Celular Tumoral , Humanos , Mifepristona/farmacologia , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Receptores de Progesterona/metabolismoRESUMO
Stress is an important condition of modern life. The successful wound healing requires the execution of three major overlapping phases: inflammation, proliferation, and remodeling, and stress can disturb this process. Chronic stress impairs wound healing through the activation of the hypothalamic-pituitary-adrenal axis, and the glucocorticoids (GCs) hormones have been shown to delay wound closure. Therefore, the aim of this study was to investigate the effects of a GC receptor antagonist (RU486) treatment on cutaneous healing in chronically stressed mice. Male mice were submitted to rotational stress, whereas control animals were not subjected to stress. Stressed and control animals were treated with RU486. A full-thickness excisional lesion was generated, and seven days later, lesions were recovered. The RU486 treatment improves wound healing since contraction takes place earlier in RU486-treated in comparison to non-treated mice, and the RU486 treatment also improves the angiogenesis in Stress+RU486 mice when compared to stressed animals. The Stress+RU486 group showed a decrease in inflammatory cell infiltration and in hypoxia-inducible factor-1α and inducible nitric oxide synthase expression; meanwhile, there was an increase in myofibroblasts quantity. In conclusion, blockade of GC receptors with RU486 partially ameliorates stress-impaired wound healing, suggesting that stress inhibits healing through more than one functional pathway.
Assuntos
Antagonistas de Hormônios/administração & dosagem , Mifepristona/administração & dosagem , Receptores de Glucocorticoides/antagonistas & inibidores , Pele/lesões , Estresse Fisiológico , Cicatrização , Animais , Masculino , Camundongos , Resultado do TratamentoRESUMO
The control of gonadotropin-releasing hormone (GnRH) secretion depends on the action of ovarian steroids and several substances, including nitric oxide (NO). NO in the medial preoptic area (MPOA) stimulates the proestrus surge of luteinizing hormone (LH). We studied the effect of estrogen (Tamoxifen-TMX) and progesterone (RU-486) antagonists on mRNA and protein expression of NO synthase (NOS), the enzyme that produces NO, as well as its activity within MPOA. Female rats received s.c. injections of TMX (3mg/animal) on first and second days of the estrous cycle (9 am), RU-486 (2mg/animal) on first, second, (8 am and 5 pm) and third days of the estrous cycle (8 am) or oil (controls) and were killed on the third day (5 pm). Real time-PCR and western blotting were performed to study NOS mRNA and protein expressions. The NOS activity was indirectly assessed by measuring the conversion from [(14)C]-L-arginine into [(14)C]-L-citrulline. TMX significantly decreased neuronal NOS (nNOS) mRNA expression (90%), and the activity of NOS, but did not alter nNOS protein expression. Also, TMX significantly decreased LH, FSH, estrogen and progesterone plasma levels. RU-486 nor affected NOS mRNA and protein expressions neither the NOS activity in the MPOA, but reduced FSH levels. The nitrergic system in the MPOA can be stimulated by estrogen whereas TMX decreased NOS activity and mRNA expression. In conclusion, the involvement of the nitrergic system in the MPOA to induce the surge of LH on proestrus depends on the estrogen action to stimulate the mRNA-nNOS expression and the activity of nNOS but it does not seem to depend on progesterone action.
Assuntos
Estradiol/metabolismo , Óxido Nítrico Sintase/metabolismo , Área Pré-Óptica/enzimologia , Progesterona/metabolismo , Animais , Antagonistas de Estrogênios/farmacologia , Ciclo Estral/metabolismo , Feminino , Hormônio Foliculoestimulante/metabolismo , Hormônio Luteinizante/metabolismo , Mifepristona/farmacologia , Área Pré-Óptica/metabolismo , Progesterona/antagonistas & inibidores , Ratos , Ratos Wistar , Tamoxifeno/farmacologiaRESUMO
El uso del mifepriston (RU486), en combinación con análogos de las prostaglandinas, en la inducción del aborto químico requiere una específica reflexión en relación a los principales aspectos farmacológicos y toxicológicos. La actual dialéctica bioética y biopolítica, a menudo ideologizada, impone aún más un tratamiento riguroso basado en evidencias científicas, para aclarar sobre todo los mecanismos de acción y de los eventos adversos. Estos últimos a veces también subvalorados o minimizados. Considerada la iniquidad del aborto voluntario, el artículo se propone también el objetivo de aclarar cómo, a la luz de una reciente bibliografía, el recurso al RU486 representa un significativo riesgo para la salud de las mujeres. Una particular atención está reservada a la aclaración etiopatogenética de las hemorragias y de las sepsis, en las cuales se han evidenciado también distintos decesos. En el artículo están presentes, además, los más actuales desarrollos de la investigación con RU486 sea para el tratamiento experimental de patologías ginecológicas y no como para el uso de la molécula de la contracepción hormonal y la contracepción de emergencias.
The use of mifepristone (RU486), in combination with prostaglandin analogues, in chemical abortion requires a specific reflection on the main aspects in pharmacology and toxicology. The current debate in bioethics and bio-policies, often ideological, imposes a more rigorous treatment based on scientific evidence, especially clarification of the mechanisms of action and severe adverse events. The latter is sometimes underestimated or minimized. Considering the inequity of voluntary abortion, this article aims also to clarify how, in the light of the most recent literature; the use of RU486 represents a significant risk to womens health. Particular attention is given to etiopathogenetic clarification of bleeding and sepsis, which have also involved several deaths. The article reports the latest developments in research with RU486, whether for experimental treatment of pathologies gynaecological and others and for the use of the hormonal contraception molecule and emergency contraception.
Assuntos
Humanos , Feminino , Gravidez , Abortivos , Aborto , Mifepristona , MisoprostolRESUMO
Mifepristone-misoprostol medical abortion promises to revolutionize reproductive health-care. Several simplifications of the standard three clinic visit regimen may be possible, however. Particularly in developing countries, access to the method can be greatly increased by eliminating the longest clinic visit. Indeed, shortly after mifepristone's introduction in Guadeloupe, a semi-developed Caribbean territory administered by France, in 1991, two of the authors conducted a small prospective study of a one treatment-visit regimen. The study regimen was subsequently adopted as the standard of care for medical abortion on the island. Women (n = 92) with amenorrhea of < or = 49 days received 600 mg mifepristone under clinical supervision and were given 400 micrograms oral misoprostol for home administration 2 days later, returning 2 weeks later for follow-up. The success rate (95.4%) is comparable to rates found when both drugs are administered in the clinic and to rates from a similar study conducted recently in the United States. Adverse events were also comparable to protocols requiring in-clinic administration of misoprostol. Protocol adherence appeared to be excellent and loss to follow-up was rare. We suggest that home administration of misoprostol can be safe and effective in most nonindustrialized settings.
PIP: This paper presents a prospective study of home administration and a one-treatment-visit regimen of mifepristone-misoprostol for medical abortion in Guadeloupe. The administration of this contraceptive method usually requires a standard 3-clinic visit regimen, which would sometimes lead to discontinuation of the abortion process. The study consisted of 92 medical abortion cases conducted over a 13-month period. The intervention involved a 1-day treatment visit with patients receiving 600 mg of mifepristone and instructions on ingesting 2 tablets (400 mcg) of misoprostol orally after 2 days and another 200 mcg misoprostol if bleeding had not occurred within 6-12 hours. A follow-up was conducted among these women after 10-15 days of initial clinic visit and contraceptive administration. The total success rate was 95.4% in comparison with those who received a 3-clinic visit regimen and the statistical result of a study conducted in the US. Several adverse effects have been associated with the administration of abortive methods, which include bleeding (19.6% in mifepristone users and 68.2% in misoprostol users) and vomiting. Strict monitoring of mifepristone and misoprostol distribution and patient follow-up was ensured by French legislators. The authors conclude that home administration of misoprostol must be made available to women in developing countries.
Assuntos
Abortivos não Esteroides/administração & dosagem , Abortivos Esteroides/administração & dosagem , Mifepristona/administração & dosagem , Misoprostol/administração & dosagem , Autoadministração , Abortivos não Esteroides/efeitos adversos , Abortivos Esteroides/efeitos adversos , Aborto Induzido , Adulto , Feminino , Idade Gestacional , Guadalupe , Humanos , Mifepristona/efeitos adversos , Misoprostol/efeitos adversos , Cooperação do Paciente , Gravidez , Estudos ProspectivosRESUMO
Low-dose antiprogestin administration has been proposed as a new contraceptive modality to interference with endometrial receptivity without disturbing ovarian function. The effects of 1 mg/day mifepristone for 150 days on the menstrual cycle were assessed in 21 surgically sterilized women. The aim was to study each woman for one control cycle and during months 1, 3 and 5 of treatment. Ovulation, endometrial thickness, serum oestradiol and progesterone, urinary luteinizing hormone, endometrial morphology and cervical mucus were assessed. Luteal phase progesterone concentrations were observed in 36 of the 60 treated months assessed and less frequently as treatment progressed. The bleeding pattern was regular in most biphasic cycles, while prolonged interbleeding intervals or no bleeding were associated with monophasic cycles. Altered endometrial morphology was found in all cases irrespective of the occurrence of luteal activity. Increased endometrial thickness and dilated glands were observed in 25 and 34% respectively of the monophasic cycles. Mifepristone, 1 mg/day, interferes with endometrial development while allowing the occurrence of biphasic ovarian cycles and regular bleeding. However, it also prevents ovarian cyclicity in a high proportion of treated months, and this is associated with increased endometrial growth in some women, which may be of concern.
PIP: Low-dose antiprogestin administration has been proposed as a new contraceptive modality that interferes with endometrial receptivity without disturbing ovarian function. To explore this potential, the effects on the menstrual cycle of 1 mg/day of mifepristone for 150 days were assessed in 21 surgically sterilized women from Santiago, Chile. Control cycles were biphasic in all 21 women and ovulatory in 20 women. Luteal phase progesterone concentrations were observed in 36 of the 60 treatment months (1, 3, and 5) assessed. The proportion of ovulatory cycles was highest during month 1 and decreased progressively with treatment. 40% of treatment cycles were monophasic and bleeding cyclicity was altered in 57%. Prolonged inter-bleeding intervals or no bleeding occurred in monophasic cycles. Endometrial morphology was altered in all cases, regardless of the occurrence of luteal activity. Increased endometrial thickness and dilated glands were recorded in 25% and 34%, respectively, of the monophasic cycles. These findings suggest that 1 mg of mifepristone interferes with endometrial development while allowing biphasic ovarian cycles and regular bleeding. Whether these endometrial alterations are sufficient to prevent implantation remains to be established. The long-term effect of prevention of ovarian cyclicity and the associated increased endometrial growth recorded in some women require further investigation.
Assuntos
Anticoncepcionais Orais Sintéticos/administração & dosagem , Mifepristona/administração & dosagem , Reprodução/efeitos dos fármacos , Adulto , Muco do Colo Uterino/efeitos dos fármacos , Muco do Colo Uterino/fisiologia , Anticoncepcionais Orais Sintéticos/efeitos adversos , Anticoncepcionais Orais Sintéticos/farmacologia , Relação Dose-Resposta a Droga , Endométrio/efeitos dos fármacos , Endométrio/crescimento & desenvolvimento , Feminino , Humanos , Ciclo Menstrual/efeitos dos fármacos , Ciclo Menstrual/fisiologia , Mifepristona/efeitos adversos , Mifepristona/farmacologia , Ovário/efeitos dos fármacos , Ovário/fisiologia , Fatores de TempoRESUMO
The effectiveness of a sequential regimen consisting of mifepristone, 10 mg/day for 15 days, followed by nomegestrol acetate (NOMA), 5 mg/day for the next 13 days, for inhibiting ovulation and maintaining regular bleeding cycles was assessed in 10 surgically sterilized volunteers who were followed for one pretreatment and three treated cycles. Hormonal determinations in blood and urine, ovarian ultrasonography, bleeding records in all cycles and an endometrial biopsy taken on day 22-25 of the third treatment cycle were used to monitor the effects of treatment. During treatment, 24 monophasic (no sustained progesterone rise above 12 nmol/l) and six biphasic cycles were recorded. Nine follicular ruptures were detected echographically in these 30 treated cycles, five of which occurred in monophasic cycles. All follicular ruptures occurred on days 1-7 of NOMA treatment. Echographic and endocrine features of ovulatory cycles were both present in only four treated cycles (13.3%). Development of a secretory endometrium was achieved in all cases, but it was always irregular. Regular withdrawal bleeding occurred in all subjects and no adverse reactions were recorded. The ovarian and endometrial effects of this regimen justify testing its contraceptive effectiveness in phase 2 clinical trials.
PIP: This study investigated the efficacy of mifepristone, 10 mg/day for 15 days, followed by nomegestrol acetate (NOMA), 5 mg/day for the next 13 days, for inhibiting ovulation and maintaining regular bleeding cycles in 10 surgically sterilized volunteers. To monitor the effects of treatment, hormonal determinations in blood and urine, ovarian ultrasonography, bleeding records in all cycles and endometrial biopsy were taken on day 22-25 of the third treatment cycle. About 24 monophasic and 6 biphasic cycles were recorded during treatment. About 9 follicular ruptures were echographically detected in these 30 cycles, 5 of which occurred in monophasic cycle. All follicular ruptures occurred in days 1-7 of NOMA treatment. Echographic and endocrine features of ovulatory cycles were both present in only four treated cycles (13.3%). Development of a secretory endometrium was achieved in all cases, but it was always irregular. Regular withdrawal bleeding occurred in all subjects and no adverse reactions were observed. The ovarian and endometrial effects of this regimen justify testing its contraceptive effectiveness in phase 2 clinical trials.
Assuntos
Anticoncepcionais Orais Combinados/administração & dosagem , Megestrol , Indutores da Menstruação/administração & dosagem , Mifepristona/administração & dosagem , Norpregnadienos/administração & dosagem , Ovulação/efeitos dos fármacos , Adulto , Estradiol/sangue , Feminino , Humanos , Hormônio Luteinizante/urina , Progesterona/sangue , Congêneres da Progesterona/administração & dosagem , Esterilização ReprodutivaRESUMO
Accumulated evidence indicates that the antigestagen mifepristone affects the reproductive axis acting on hypothalamic, pituitary, ovarian, and uterine tissues. The purpose of this study was to further investigate which reproductive functions are impaired by the antagonist, critically compromising the reproductive process, leading to unsuccessful pregnancy. Circulating pituitary and ovarian hormones, sexual receptivity, ovulation, and implantation rates were studied in cycling rats receiving a single dose of mifepristone (1 or 10 mg/kg subcutaneously) at 12:00 proestrus, before luteinizing hormone (LH) stimulation of the ovulatory process. Mifepristone-treated rats had decreased preovulatory surges of LH and prolactin (PRL), and hypersecretion of LH, PRL, and progesterone at estrus. The sexual receptivity was dramatically affected by the antagonist as indicated by the profound decrease in the lordosis response evaluated on the night of proestrus. The number of ovulating animals and the number of oocytes recovered from the oviduct on the morning of estrus were not affected by mifepristone. The low number of rats that succeeded in mating with potent males became pregnant. However, they delivered an average of only two pups at parturition, indicating a failure in the implantation of the fertilized ova, as ovulation was not affected by the antagonist at the dose used. We conclude that a dramatic inhibition of the sexual receptivity and unsuccessful implantation, preceded by a reduction on LH and PRL secretion, are the major components leading to fertility impairment after a single dose of mifepristone administered before the preovulatory surge of LH.
PIP: Mifepristone has been demonstrated to act on hypothalamic, pituitary, ovarian, and uterine tissue. To further investigate impairments in reproductive function triggered by this antagonist, circulating pituitary and ovarian hormones, sexual receptivity, ovulation, and implantation rates were studied in cycling Wistar rats receiving a single dose (1 or 10 mg/kg subcutaneously) of mifepristone at 12:00 proestrus, before luteinizing hormone (LH) stimulation of the ovulatory process. Treated rats had decreased preovulatory LH and prolactin (PRL) surges and hypersecretion of LH, PRL, and progesterone as estrus. A profound decrease in the lordosis response on the night of proestrus indicated a dramatic effect on sexual receptivity. There was no affect on the number of ovulating animals and the number of oocytes recovered from the oviduct on the morning of estrus. The few rats who succeeded in mating with potent males became pregnant, but they delivered an average of only two pups, indicating a failure in the implantation of the fertilized ova. These findings suggest that the dramatic inhibition of sexual receptivity and unsuccessful implantation, preceded by a reduction in LH and PRL secretion, are the major factors producing fertility impairment after a single dose of mifepristone before the preovulatory LH surge. factors such as smoking and parity.
Assuntos
Antagonistas de Hormônios/efeitos adversos , Mifepristona/efeitos adversos , Ovulação/efeitos dos fármacos , Proestro/efeitos dos fármacos , Comportamento Sexual Animal/efeitos dos fármacos , Animais , Estudos de Coortes , Feminino , Antagonistas de Hormônios/administração & dosagem , Injeções Subcutâneas , Hormônio Luteinizante/sangue , Hormônio Luteinizante/efeitos dos fármacos , Masculino , Mifepristona/administração & dosagem , Gravidez , Proestro/sangue , Progesterona/sangue , Prolactina/sangue , Prolactina/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
OBJECTIVE: We investigated safety, efficacy, and acceptability of an oral regimen of medical abortion compared with surgical abortion in three developing countries. STUDY DESIGN: Women (n = 1373) with amenorrhea < or = 56 days chose either surgical abortion (as provided routinely) or 600 mg of mifepristone followed after 48 hours by 400 micrograms of misoprostol. This is the appropriate design for studying safety, efficacy, and acceptability among women selecting medical abortion over available surgical services. RESULTS: The medical regimen had more side effects, particularly bleeding, than did surgical abortion but very few serious side effects. Failure rates for medical abortion, although low, exceeded those for surgical abortion: 8.6% versus 0.4% (China), 16.0% versus 4.0% (Cuba), and 5.2% versus 0% (India). Nearly half of failures among medical clients were not true drug failures, however, but surgical interventions not medically necessary (acceptability failures or misdiagnoses). Women were satisfied with either method, but more preferred medical abortion. CONCLUSION: Medical abortion can be safe, efficacious, and acceptable in developing countries.
PIP: A multi-center comparative study of medical compared to surgical abortion confirmed that medical abortion can be safe, effective, and acceptable in developing countries. A total of 1373 women from medical centers in China, Cuba, and India with pregnancies of 56 days' gestation or less were given the choice of surgical abortion or 600 mg of mifepristone followed after 48 hours by 400 mcg of misoprostol. Since the majority selected medical abortion, researchers in China and Cuba assigned some of these women to the surgical group to equalize the size of the two groups. The surgical abortion failure rates in China, Cuba, and India were 0.4%, 4%, and 0%, respectively, while the failure rates for medical abortion were 8.6%, 16.0%, and 5.2%, respectively. In all sites, both medical failures (an adverse effect resulting in a medically indicated surgical intervention) and acceptability failures (failure to complete the entire regimen) contributed substantially to the gross failure rates for medical abortion. Medical abortion failure rates increased with gestational age. Although cramping, nausea, and vomiting were more frequent among women in the medical abortion group and bleeding was heavier, general assessments of well-being reported at exit interviews did not differ between the two treatment groups at any site. Regardless of abortion method, the majority of women were either satisfied or highly satisfied with the procedure. In all countries, a higher number of medical than surgical abortion patients indicated they would opt again for the same procedure. Neither the bleeding pattern nor the higher failure rate associated with medical abortion justify withholding this option from women in developing countries.
Assuntos
Abortivos , Aborto Induzido/métodos , Países em Desenvolvimento , Mifepristona , Misoprostol , Aceitação pelo Paciente de Cuidados de Saúde , Gestantes , Aborto Induzido/efeitos adversos , Adulto , China , Cuba , Feminino , Humanos , Índia , Participação do Paciente , Gravidez , Projetos de Pesquisa , Medição de Risco , Falha de TratamentoRESUMO
The efficacy of a low dose of mifepristone, 5 mg/day for the first 15 days of the menstrual cycle, followed by medroxy-progesterone acetate (MPA), 10 mg/day for the next 13 days, for inhibiting ovulation was assessed in ten volunteers who were treated for three successive cycles. Hormonal determinations in blood and urine samples, ovarian ultrasonography and an endometrial biopsy taken on day 21-24 of the third treatment cycle were used to monitor the cycles. Ovulation was confirmed in 11 of the 30 treated cycles and, in these 11, the LH peak and follicular rupture occurred during MPA treatment periods. Out of 19 anovulatory cycles, 16 had no increase in progesterone levels and another 3 developed a luteinized unruptured follicle. Progestin administration induced secretory changes in the endometrium, but irregular or delayed development was found. Regular withdrawal bleeding occurred in all subjects. These data indicate that the sequential regimen can suppress ovulation while maintaining regular bleeding but increased efficacy is needed for phase II clinical trials.
PIP: The efficacy of a low dose of mifepristone, 5 mg/day for the first 15 days of the menstrual cycle, followed by medroxyprogesterone acetate (MPA), 10 mg/day for the next 13 days, for inhibiting ovulation was assessed in 10 Chilean volunteers who were treated for 3 successive cycles. They were healthy, surgically sterilized women with a mean age of 36.6 years and mean weight of 58.6 kg. Hormonal determinations in blood and urine samples, ovarian ultrasonography and an endometrial biopsy taken on days 21-24 of the third treatment cycle were used to monitor the cycles. Treatment inhibited ovulation during the 3 treatment cycles in 5 women. The regimen was partially effective in 3 women and totally ineffective in another 2 women. Ovulation was confirmed in 11 of the 30 treated cycles, and, in these 11, the luteinizing (LH) peak and follicular rupture occurred during MPA treatment periods. Out of 19 anovulatory cycles, 16 had no increase in progesterone levels and another 3 developed a luteinized unruptured follicle. Among the anovulatory cycles, 3 cycles presented a biphasic hormonal profile. In these 3 cycles the luteal phase progesterone level were much lower than in baseline cycles and they were associated with unruptured follicles. The other 16 cycles had a monophasic hormonal profile with no increase in progesterone levels in spite of a delayed rise in LH level. Progestin administration induced secretory changes in the endometrium, but irregular or delayed development was found. Only 9 post-treatment cycles were followed and 5 of these were ovulatory, 1 of them without a detectable LH midcycle peak. Regular withdrawal bleeding occurred in all subjects. These data indicate that the sequential regimen can suppress ovulation while maintaining regular bleeding, but increased efficacy is needed for phase II clinical trials.
Assuntos
Endométrio/efeitos dos fármacos , Hormônios/metabolismo , Acetato de Medroxiprogesterona/administração & dosagem , Mifepristona/administração & dosagem , Ovário/efeitos dos fármacos , Adulto , Biópsia , Endométrio/fisiologia , Estradiol/sangue , Feminino , Humanos , Hormônio Luteinizante/sangue , Ciclo Menstrual/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/fisiologia , Ovário/diagnóstico por imagem , Ovário/fisiologia , Ovulação/efeitos dos fármacos , Progesterona/sangue , Fatores de Tempo , UltrassonografiaRESUMO
PIP: As a non-invasive means of early abortion, RU-486 has the potential to increase women's reproductive options; at the same time, the "abortion pill" has stimulated debate about the ethics and safety of new medical technologies. When combined with a prostaglandin (PG), the success rate for RU-486 is 96% for pregnancies of up to 9 weeks' gestation. In France, over 120,000 women have used RU-486/PG to terminate pregnancy, and this regimen is now used in about 25% of abortions. Clinical trials of RU-486 are underway in Cuba, China, India, Singapore, and Zambia. The Program for Appropriate Technology has identified four considerations for introducing RU-486 to developing countries: whether abortion or menstrual regulation is legal; whether women find the method acceptable and can comply with the multiple visit treatment regimen; whether the health infrastructure can support safe method use, including prevention of misuse and provision of appropriate medical backup personnel and facilities; and whether the cost of the regimen is affordable to individuals and/or programs --conditions unlikely to be met in most such countries. Ideal would be development of a medical abortifacient that is single dose and the lowest possible dose of each drug, provokes miscarriage within a more predictable time frame with less acute and prolonged bleeding, is safe and effective beyond two months, has minimal side effects, and maximizes short-term safety and minimizes long-term effects. Technological advances are being undermined, however, by political and religious attacks on the method. Even some feminists have expressed concerns about potential long-term effects of RU-486 use.^ieng
Assuntos
Abortivos , Países em Desenvolvimento , Ética , Estudos de Avaliação como Assunto , Feminismo , Mifepristona , Política , Aborto Induzido , Biologia , Países Desenvolvidos , Sistema Endócrino , Europa (Continente) , Serviços de Planejamento Familiar , França , Antagonistas de Hormônios , Hormônios , FisiologiaRESUMO
PIP: This article was written to counter some of the misinformation contained in the book "RU486: Misconceptions, Myths and Morals." The book concludes that use of RU486 constitutes yet another form of medical violence against women which will have unknown longterm effects. One of the major goals of the women's health movement is to disseminate information about women's health through information networks which also expose abusive reproductive health practices. Critiques about new products and procedures are important because what is considered clinically safe may pose problems for women in practice. While the book on RU486 is important from this viewpoint, it lacks careful scrutiny of its criticisms. Thus, the book suggests that animal testing has been inadequate at 17 months when, in fact, this time frame meets all standards for a single dose drug. The authors also mislabel the exclusion criterion for experimental trials as "contraindications" for use and claim that this incorrectly inflated number of contraindications prohibits the use of RU-486 as a viable alternative to other methods of abortion. In several instances the authors present inaccurate information about the pharmacodynamics and dosages of the drugs involved. The use of prostaglandins is also unjustly criticized by drawing comparisons with other uses of the prostaglandins which involve different doses and delivery periods. The authors act irresponsibly when they suggest that incomplete abortion with Ru-486 may result in uterine cancer or that the simultaneous use of aspirin will result in an almost guaranteed incomplete abortion. Additional ill-founded remarks overemphasize the failure rate, demand unrealistic guarantees about fetal abnormality, and charge that the World Health Organization has "discarded" suction curettage abortion. The book grew out of valid concerns and raises important questions about the best ways to serve women's interests, but these concerns and questions are obfuscated by unsubstantiated and far-flung claims.^ieng
Assuntos
Comunicação , Estudos de Avaliação como Assunto , Feminismo , Mifepristona , Medicina Reprodutiva , Biologia , Sistema Endócrino , Saúde , Antagonistas de Hormônios , Hormônios , FisiologiaRESUMO
PIP: The use of RU-486 to induce abortion represents a new era in reproductive technology and merits ethical attention. The feminists principles of concern for women's well-being, paying attention to the specific needs of women in specific circumstances, and balancing risks and benefits can be applied to an examination of RU-486. RU-486 has invoked the image of women's medical empowerment and has been deemed "the moral property of women." Support for RU-486 has come from major international health and feminist organizations, while the opposition of the anti-choice forces has been matched by that of the Feminist International Network of Resistance to Reproductive and Genetic Engineering. Issues critical to the introduction of RU-486 include 1) access and suitability, 2) whether RU-486 increases women's control over reproduction in a safe manner, and 3) the political problems involved when feminist leaders press for testing and attempt to explain varied and even opposing feminist positions in productive ways.^ieng
Assuntos
Aborto Induzido , Ética , Feminismo , Mifepristona , Filosofia , Política , Biologia , Sistema Endócrino , Serviços de Planejamento Familiar , Antagonistas de Hormônios , Hormônios , FisiologiaRESUMO
PIP: In 1984, in Mexico City, the Reagan administration announced its policy prohibiting USAID from supporting any nongovernmental organization which used its own or US funds for any abortion-related activities. Even though this policy was intended to reduce the incidence of abortion, it had the opposite effect because the cut in funding left some areas of the developing world with no family planning services or information at all. Further, this policy resulted in a loss of $17 million (US) or 25% of the budget of the International Planned Parenthood Federation (IPPF). On January 22, 1993, US President Clinton reversed this policy. IPPF considered President Clinton's action to be a significant event for women's health, human rights, and global development. This reversal will provide family planning services to about 300 million couples who want to practice family planning but could not do so because they did not have access to it. SHortly after President Clinton's announcement, IPPF began writing a proposal to USAID for funds to restore programs that the Mexico City policy eliminated. IPPF hoped the reversal would spark international recognition of the need for safe access to abortion. Other actions President Clinton has taken to promote reproductive health are reversing the Reagan and Bush administrations' rule prohibiting abortion counseling at federally-funded clinics, requesting that the US Food and Drug Administration study the possible marketing of RU-486, removing the ban on abortion in military hospitals, approving regulations allowing fetal tissue research, and appointing an abortion rights advocate as Surgeon General. The Catholic Church opposed all of Clinton's abortion policies. However, many congregations, priests, and Vatican officials are dissatisfied with the Pope's anticontraception position.^ieng