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Objective: Evaluate the efficacy and safety of elagolix, a GnRH antagonist, to treat polycystic ovarian syndrome (PCOS). Design: A phase 2, multicenter, double-blind, randomized, placebo-controlled trial. Setting: Outpatient and academic medical centers. Patients: One hundred fourteen women with PCOS (aged 18-35 years, body mass index 18.5-38 kg/m2). Interventions: Patients were randomized 2:2:2:2:2:3 to elagolix (25 mg twice daily, 50 mg once daily, 75 mg twice daily, 150 mg once daily, and 300 mg twice daily) or placebo. Main Outcome Measures: The primary endpoint was menstrual cycle normalization (defined as 2 menstrual cycles 21-35 days in length during the 4-month treatment period). The secondary endpoint was change from baseline to week 1 in the area under the luteinizing hormone (LH) serum concentration-time curve (AUC). Additional endpoints included change from baseline in serum hormone levels. Results: No significant improvement in restoring normal menstrual cycles was observed in treated subjects; 3 of 114 patients met the primary endpoint. Six patients experienced progesterone elevations indicative of ovulation. The LH levels decreased from baseline to week 16, and LH AUC was significantly reduced from baseline to week 1 in all elagolix treatment groups (P<.1 vs placebo). Follicle-stimulating hormone (FSH) levels generally remained stable through week 16, with no significant differences in FSH AUCs. Serum estradiol and testosterone concentrations were consistently reduced from baseline in all elagolix dose groups compared with placebo. Adverse event rates were similar across treatment groups. Conclusions: Elagolix treatment did not normalize the ovulatory cycle in patients with PCOS. Clinical Trial Registration Number: NCT03951077.
RESUMO
Bone mineral density (BMD) changes during the life span, increasing rapidly during adolescence, plateauing in the third decade of life, and subsequently entering a phase of age-related decline. In women, menopause leads to accelerated bone loss and an increase in fracture risk. Between peak bone mass attainment and menopause, BMD is generally stable and the risk of fracture is typically low. This time period is marked by life events such as pregnancy and lactation, which transiently decrease BMD, yet their long-term effects on fracture risk are less certain. BMD may also be altered by exposure to medications that affect bone metabolism (e.g., contraceptives, glucocorticoids, antidiabetic medications, antiepileptic drugs). Although oral contraceptives are often believed to be neutral with regard to bone health, depot medroxyprogesterone acetate (DMPA) and gonadotropin-releasing hormone (GnRH) agonists have been associated with decreases in BMD. Development of newer medical therapies, principally GnRH antagonists (e.g., ASP1707, elagolix, linzagolix, relugolix), for treatment of endometriosis-associated pelvic pain and heavy menstrual bleeding due to uterine fibroids has renewed interest in the short- and long-term impacts of changes in BMD experienced by premenopausal women. It is important to understand how these drugs influence BMD and put the findings into context with regard to measurement variability and naturally occurring factors that influence bone health. This review summarizes what is known about the effects on bone health pregnancy, lactation, and use of DMPA, GnRH agonists, and GnRH antagonists in premenopausal women and potential consequences later in life. ClinicalTrials.gov identifier: NCT03213457.
Assuntos
Densidade Óssea , Imidazóis , Feminino , Humanos , Lactação , Acetato de Medroxiprogesterona , Gravidez , SulfonasAssuntos
Dilatação e Curetagem/efeitos adversos , Ginatresia/prevenção & controle , Feminino , Fertilidade , Ginatresia/diagnóstico , Ginatresia/etiologia , Ginatresia/fisiopatologia , Humanos , Infertilidade Feminina/etiologia , Infertilidade Feminina/fisiopatologia , Medição de Risco , Fatores de Risco , Aderências Teciduais , Resultado do Tratamento , Doenças Uterinas/patologiaRESUMO
Legal issues affect reproductive medical practice throughout the entire world. The breadth and depth of this interrelationship extend far beyond the scope of one series of articles in Views and Reviews. Given this limitation, we have chosen to present five topics, all different, but illustrative of key concepts that influence our practice of reproductive medicine. Our hope is that this "medical-legal sampler" will both inform and provoke thoughtful consideration of the ways we can best and most responsibly practice and serve our patients.
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Turismo Médico/legislação & jurisprudência , Medicina Reprodutiva/legislação & jurisprudência , Técnicas de Reprodução Assistida/legislação & jurisprudência , Mães Substitutas/legislação & jurisprudência , Feminino , Humanos , Turismo Médico/tendências , Médicos/legislação & jurisprudência , Gravidez , Autonomia Profissional , Medicina Reprodutiva/tendências , Técnicas de Reprodução Assistida/tendênciasRESUMO
BACKGROUND: Uterine fibroids are one of the most common neoplasms found among women globally, with a prevalence of approximately 11 million women in the United States alone. The morbidity of this common disease is significant because it is the leading cause of hysterectomy and causes significant functional impairment for women of reproductive age. Factors including age, body mass index, race, ethnicity, menstrual blood loss, fibroid location, and uterine and fibroid volume influence the incidence of fibroids and severity of symptoms. Elagolix is an oral gonadotropin-releasing hormone receptor antagonist that competitively inhibits pituitary gonadotropin-releasing hormone receptor activity and suppresses the release of gonadotropins from the pituitary gland, resulting in dose-dependent suppression of ovarian sex hormones, follicular growth, and ovulation. In Elaris Uterine Fibroids 1 and Uterine Fibroids 2, 2 replicate multicenter, double-blind, randomized, placebo-controlled, phase 3 studies, treatment of premenopausal women with elagolix with hormonal add-back therapy demonstrated reduction in heavy menstrual bleeding associated with uterine fibroids. OBJECTIVE: This analysis aimed to evaluate the safety and efficacy of elagolix (300 mg twice a day) with add-back therapy (1 mg estradiol/0.5 mg norethindrone acetate once a day) in reducing heavy menstrual bleeding associated with uterine fibroids in various subgroups of women over 6 months of treatment. STUDY DESIGN: Data were pooled from Elaris Uterine Fibroid-1 and Uterine Fibroid-2 studies, which evaluated premenopausal women (18-51 years) with heavy menstrual bleeding (>80 mL menstrual blood loss per cycle, alkaline hematin methodology) and ultrasound-confirmed uterine fibroid diagnosis. Subgroups analyzed included age, body mass index, race, ethnicity, baseline menstrual blood loss, fibroid location, and uterine and primary fibroid volume (largest fibroid identified by ultrasound). The primary endpoint was the proportion of women with <80 mL menstrual blood loss during the final month and ≥50% menstrual blood loss reduction from baseline to final month. Secondary and other efficacy endpoints included mean change in menstrual blood loss from baseline to final month, amenorrhea, symptom severity, and health-related quality of life. Adverse events and other safety endpoints were monitored. RESULTS: The overall pooled Elaris Uterine Fibroid-1 and Uterine Fibroid-2 population was typical of women with fibroids, with a mean age of 42.4 (standard deviation, 5.4) years and a mean body mass index of 33.6 (standard deviation, 7.3) kg/m2 and 67.6% of participants being black or African American women. A wide range of baseline uterine and fibroid volumes and menstrual blood loss were also represented in the overall pooled study population. In all subgroups, the proportion of responders to the primary endpoint, mean change in menstrual blood loss, amenorrhea, reduction in symptom severity, and improvement in health-related quality of life were clinically meaningfully greater for women who received elagolix with add-back therapy than those who received placebo and consistent with the overall pooled study population for the primary endpoint (72.2% vs 9.3%), mean change in menstrual blood loss (-172.5 mL vs -0.8 mL), amenorrhea (50.4% vs 4.5%), symptom severity (-37.1 vs -9.2), and health-related quality of life score (39.9 vs 8.9). Adverse events by subgroup were consistent with the overall pooled study population. CONCLUSION: Elagolix with hormonal add-back therapy was effective in reducing heavy menstrual bleeding associated with uterine fibroids independent of age, body mass index, race, ethnicity, baseline menstrual blood loss, fibroid location, and uterine and primary fibroid volume.
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Endocrinologistas/tendências , Ginecologia/tendências , Internato e Residência/tendências , Obstetrícia/tendências , Papel do Médico , Medicina Reprodutiva/tendências , Competência Clínica , Escolaridade , Endocrinologistas/educação , Ginecologia/educação , Humanos , Obstetrícia/educação , Medicina Reprodutiva/educaçãoRESUMO
OBJECTIVE: To study the development of children conceived from non-IVF infertility treatments consisting of gonadotropins, clomiphene, or letrozole. DESIGN: Prospective cohort study. SETTING: U.S. academic health centers. PATIENT(S): Children of women with polycystic ovary syndrome who conceived with letrozole (LTZ) or clomiphene (CC) in the PPCOS II study or women with unexplained infertility (AMIGOS study) who conceived with LTZ, CC, or gonadotropin (GN). INTERVENTION(S): Longitudinal annual follow-up from birth to age 3. MAIN OUTCOME MEASURE(S): Scores from Ages and Stages Developmental Questionnaire (ASQ), MacArthur-Bates Communicative Development Inventory (MCDI), and annual growth. RESULT(S): One hundred eighty-five children from 160 families participated in at least one follow-up evaluation from the two infertility trials. Most multiple gestations in the follow-up study resulted from GN treatment (n = 14) followed by CC (n = 6) and LTZ (n = 3). There were no significant differences among the three groups at any time point with respect to abnormal scores on the ASQ. On the MCDI Words and Gestures, the LTZ group scored significantly higher than the GN group for most items (phrases, early gestures, later gestures, and total gestures). Children in the CC group scored significantly higher than the GN group for the later gestures and total gestures items. CONCLUSION(S): Differences in growth and cognitive developmental rates among children conceived with first-line infertility therapies, including LTZ, are relatively minor and likely due to differences in multiple pregnancy rates.
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Comportamento Infantil , Desenvolvimento Infantil , Clomifeno/uso terapêutico , Fármacos para a Fertilidade/uso terapêutico , Gonadotropinas/uso terapêutico , Infertilidade Feminina/tratamento farmacológico , Letrozol/uso terapêutico , Indução da Ovulação , Adulto , Fatores Etários , Pré-Escolar , Clomifeno/efeitos adversos , Cognição , Feminino , Fertilidade , Fármacos para a Fertilidade/efeitos adversos , Seguimentos , Gestos , Gonadotropinas/efeitos adversos , Humanos , Lactente , Infertilidade Feminina/epidemiologia , Infertilidade Feminina/fisiopatologia , Letrozol/efeitos adversos , Nascido Vivo , Masculino , Indução da Ovulação/efeitos adversos , Síndrome do Ovário Policístico/epidemiologia , Gravidez , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema de Registros , Resultado do Tratamento , Estados Unidos/epidemiologia , Aumento de PesoRESUMO
OBJECTIVE: To investigate the safety and efficacy of elagolix, an oral gonadotropin-releasing hormone antagonist, with hormonal add-back therapy for up to 12 months in women with heavy menstrual bleeding associated with uterine leiomyomas. METHODS: Elaris UF-EXTEND was a phase 3 extension study that evaluated an additional 6 months (up to 12 months total) of elagolix 300 mg twice daily with hormonal add-back therapy (estradiol 1 mg and norethindrone acetate 0.5 mg once daily) in women who completed an initial 6 months of the same treatment in one of two preceding phase 3 studies. The primary endpoint was the percentage of women with both less than 80 mL menstrual blood loss during final month and a 50% or greater reduction in menstrual blood loss from baseline to final month. Safety evaluations included adverse events and bone mineral density changes. The planned sample size of UF-EXTEND was based on estimated rollover and discontinuation rates in the two preceding studies. RESULTS: From September 2016 to March 2019, 433 women were enrolled in UF-EXTEND. Of these women, 218 received up to 12 months of elagolix with add-back therapy; the mean±SD age of this group was 42.4±5.4 years and 67.3% were black. The percentage of women who met the primary endpoint in this elagolix with add-back group was 87.9% (95% CI [83.4-92.3]). The most frequently reported adverse events with up to 12 months of elagolix plus add-back therapy were hot flush (6.9%), night sweats (3.2%), headache (5.5%), and nausea (4.1%). Mean percent decreases in bone mineral density from baseline to extension month 6 were significantly less with elagolix plus add-back therapy than with elagolix alone {between-group difference in lumbar spine: -3.3 (95% CI [-4.1 to -2.5])}. CONCLUSION: Up to 12 months of elagolix with add-back therapy provided sustained reduction in menstrual blood loss in women with uterine leiomyomas, with the addition of add-back therapy attenuating the hypoestrogenic effects of elagolix alone. No new or unexpected safety concerns were associated with an additional 6 months of elagolix with addback therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02925494. FUNDING SOURCE: AbbVie Inc funded this study.
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Estradiol/administração & dosagem , Hidrocarbonetos Fluorados/administração & dosagem , Leiomioma/tratamento farmacológico , Menorragia/tratamento farmacológico , Noretindrona/administração & dosagem , Pirimidinas/administração & dosagem , Neoplasias Uterinas/tratamento farmacológico , Adulto , Densidade Óssea/efeitos dos fármacos , Método Duplo-Cego , Quimioterapia Combinada , Estradiol/efeitos adversos , Feminino , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Cefaleia/etiologia , Fogachos/etiologia , Humanos , Hidrocarbonetos Fluorados/efeitos adversos , Leiomioma/complicações , Leiomioma/patologia , Menorragia/sangue , Menorragia/etiologia , Pessoa de Meia-Idade , Náusea/etiologia , Noretindrona/efeitos adversos , Pirimidinas/efeitos adversos , Qualidade de Vida , Neoplasias Uterinas/complicações , Neoplasias Uterinas/patologiaAssuntos
Esterilização Tubária , Adulto , Anastomose Cirúrgica , Tubas Uterinas , Feminino , Fertilidade , Fertilização in vitro , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Uterine fibroids are hormone-responsive neoplasms that are associated with heavy menstrual bleeding. Elagolix, an oral gonadotropin-releasing hormone antagonist resulting in rapid, reversible suppression of ovarian sex hormones, may reduce fibroid-associated bleeding. METHODS: We conducted two identical, double-blind, randomized, placebo-controlled, 6-month phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to evaluate the efficacy and safety of elagolix at a dose of 300 mg twice daily with hormonal "add-back" therapy (to replace reduced levels of endogenous hormones; in this case, estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) in women with fibroid-associated bleeding. An elagolix-alone group was included to assess the impact of add-back therapy on the hypoestrogenic effects of elagolix. The primary end point was menstrual blood loss of less than 80 ml during the final month of treatment and at least a 50% reduction in menstrual blood loss from baseline to the final month; missing data were imputed with the use of multiple imputation. RESULTS: A total of 412 women in UF-1 and 378 women in UF-2 underwent randomization, received elagolix or placebo, and were included in the analyses. Criteria for the primary end point were met in 68.5% of 206 women in UF-1 and in 76.5% of 189 women in UF-2 who received elagolix plus add-back therapy, as compared with 8.7% of 102 women and 10% of 94 women, respectively, who received placebo (P<0.001 for both trials). Among the women who received elagolix alone, the primary end point was met in 84.1% of 104 women in UF-1 and in 77% of 95 women in UF-2. Hot flushes (in both trials) and metrorrhagia (in UF-1) occurred significantly more commonly with elagolix plus add-back therapy than with placebo. Hypoestrogenic effects of elagolix, especially decreases in bone mineral density, were attenuated with add-back therapy. CONCLUSIONS: Elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. (Funded by AbbVie; Elaris UF-1 and Elaris UF-2 ClinicalTrials.gov numbers, NCT02654054 and NCT02691494.).
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Estradiol/uso terapêutico , Estrogênios/uso terapêutico , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Hidrocarbonetos Fluorados/uso terapêutico , Leiomioma/complicações , Menorragia/tratamento farmacológico , Pirimidinas/uso terapêutico , Adulto , Densidade Óssea/efeitos dos fármacos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Fogachos/induzido quimicamente , Humanos , Hidrocarbonetos Fluorados/efeitos adversos , Menorragia/etiologia , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Qualidade de Vida , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
Osteoporosis continues to be a major public health challenge in both women and men. There are more than 2 million low-impact fractures in the United States every year, 39% of which occur in men. The mortality rate in the first year after hip fracture is estimated at 20% to 25% in women and is even higher in men. The goal of this Views and Reviews is to provide an update regarding bone metabolism and contemporary approaches to prevention and treatment of osteoporosis.