RESUMEN

Objective: To evaluate the effect of follicular phase length (FPL) on pregnancy outcomes and endometrial thickness (ET) among women with unexplained infertility undergoing ovarian stimulation with intrauterine insemination (OS-IUI) with clomiphene citrate, letrozole, or gonadotropins. Design: Cohort analysis of the Reproductive Medicine Network's Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation randomized controlled trial. Setting: Multicenter randomized controlled trial. Patients: A total of 869 couples with unexplained infertility who underwent OS-IUI treatment cycles as part of the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation study. Interventions: FPL was evaluated as a categorical variable defined by quintiles (q1: ≤11 days, q2: 12 days, q3: 13 days, q4: 14-15 days, and q5: ≥16 days). Main outcome measures: Clinical pregnancy, live birth rates, and ET. Results: Decreasing FPL quintiles did not reduce clinical pregnancy or live birth rates in unadjusted or adjusted models with all treatment groups combined or when stratified by the ovarian stimulation medication. All FPL categories had significantly thinner ET compared with the 5th quintile (≥16 days) among women treated with clomiphene citrate or letrozole. Similar but diminished associations were observed among women who underwent ovarian stimulation with gonadotropins, but the observed differences were limited to those with FPL of 12 days or shorter when compared with FPL ≥16 days. Conclusions: Although shorter FPL was associated with reduced ET, it was not associated with the outcomes of clinical pregnancy or live birth in women with unexplained infertility undergoing OS-IUI in all treatment groups combined. Similar patterns existed when analyses of clinical pregnancy and live birth rates were stratified by treatment. Clinical trial registration: NCT01044862.

RESUMEN

Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor of GDP-bound KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular signaling and demonstrates selective antiproliferative activity in KRASG12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRASG12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with inhibitors of SHP2, MEK, or CDK4/6. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRASG12C-mutated tumors. SIGNIFICANCE: JDQ443 is a structurally novel covalent KRASG12C inhibitor with a unique binding mode that demonstrates potent and selective antitumor activity in cell lines and in vivo models. In preclinical models and patients with KRASG12C-mutated malignancies, JDQ443 shows potent antitumor activity as monotherapy and in combination with the SHP2 inhibitor TNO155. This article is highlighted in the In This Issue feature, p. 1397.

Asunto(s)

Inhibidores Enzimáticos , Indazoles , Neoplasias , Proteínas Proto-Oncogénicas p21(ras) , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Indazoles/química , Indazoles/farmacología , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/genética , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo

RESUMEN

We evaluated endometrial pattern, defined as the relative echogenicity of the endometrium on a longitudinal uterine ultrasonic section, as a surrogate for endometrial receptivity in an attempt to evaluate the association between endometrial pattern and pregnancy outcome in women who underwent ART treatment. The primary outcome was live birth and secondary outcomes were clinical intrauterine pregnancy and miscarriage. Potential associations were evaluated using cluster-weighted generalized estimating equations to account for within-couple correlation among repeated ART cycles while adjusting for potentially confounding variables. There were 1034 ART cycles with embryo transfer (778 fresh, 256 frozen) among 695 women (median age: 31.0 (6.0) years). The average number of embryos transferred per cycle was 2.1. The clinical intrauterine pregnancy rate per transfer was 56.0% for fresh and 54.3% for frozen cycles. The overall live birth rate per embryo transfer was 48.4%. Live birth rates were unchanged when the endometrium was semi-trilinear (RR:0.91 CI:0.74,1.12) or unilinear (RR:1.15 CI:0.89,1.49) in comparison to trilinear endometrium after controlling for potentially confounding variables. Results were similar when analysed separately for fresh and frozen cycles and when evaluating associations with clinical intrauterine pregnancy and miscarriage rates. It appears that endometrial pattern does not significantly affect live birth in ART and our data do not support cancelling an ART cycle if the endometrium is less than trilinear.

Asunto(s)

Nacimiento Vivo , Resultado del Embarazo , Adulto , Endometrio/diagnóstico por imagen , Femenino , Humanos , Embarazo , Índice de Embarazo , Técnicas Reproductivas Asistidas , Estudios Retrospectivos , Ultrasonografía

RESUMEN

PURPOSE: We have recently demonstrated that gonadotrophin-releasing hormone receptor-activating autoantibodies (GnRHR-AAb) are associated with polycystic ovary syndrome (PCOS). The aim of this study was to map the antigenic epitopes of GnRHR-AAb from PCOS patients, and develop retro-inverso peptide inhibitors that specifically target GnRHR-AAb. METHODS: Serum samples from ten GnRHR-AAb-positive PCOS patients and ten GnRHR-AAb-negative healthy controls were tested. Epitope mapping for GnRHR-AAb was performed using a set of 11 overlapping octapeptides spanning the second extracellular loop of GnRHR. Antibody-blocking effect of the designed retro-inverso peptide inhibitors was evaluated in a cell-based bioassay. RESULTS: Two peptide sequences, FSQCVTHC and HCSFSQWW, were found to react with all PCOS sera, but not with control sera. Two retro-inverso peptides that mimic the identified epitopes, d-CHTVCQSF and d-WWQSFSCH, significantly inhibited PCOS serum IgG-induced GnRHR activation. One of these two peptide inhibitors, d-CHTVCQSF, largely suppressed autoantibody-induced GnRHR activation, suggesting that the epitope sequence FSQCVTHC may be a major functional target of GnRHR-AAb. CONCLUSION: We have identified a dominant functional epitope for GnRHR-AAb associated with PCOS, and demonstrated effective blocking of GnRHR-AAb activity with epitope-mimicking retro-inverso peptide inhibitors. These proteolytically stable decoy peptides may have important therapeutic implications in subjects who harbor these autoantibodies.

Asunto(s)

Síndrome del Ovario Poliquístico , Autoanticuerpos , Epítopos , Femenino , Humanos , Péptidos , Receptores LHRH

RESUMEN

OBJECTIVE: To evaluate the relationship between semen regurgitation and intrauterine insemination (IUI) outcomes. We hypothesized that clinical pregnancy rates and live birth rates would be reduced when regurgitation occurred. DESIGN: Retrospective cohort study. SETTING: A university-based reproductive endocrinology and infertility clinic. PATIENT(S): Retrospective review of 1,957 IUI cycles performed on 660 patients between July 2007 and May 2012. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was live birth. Secondary outcomes were positive serum pregnancy result and clinical pregnancy. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a cluster-weighted generalized estimating equations method to estimate modified Poisson regression models with robust standard errors to account for multiple IUI cycles in the same patient. RESULT(S): Live birth rates were similar in IUI cycles with and without regurgitation (6.3% vs. 6.8%, respectively, RR = 0.82, 95% CI [0.53-1.26]). Clinical pregnancy rates in the presence or absence of regurgitation were 10.5% vs. 10.0% (RR = 0.99, 95% CI [0.73-1.35]). Positive serum pregnancy tests after IUI did not differ by regurgitation status (15.0% vs. 15.4%, RR = 0.97, 95% CI [0.75-1.24]). Results were unchanged when adjusted for covariates (age, race and ethnicity, body mass index, duration of infertility, medication, infertility diagnosis, total motile count, and method of sperm preparation). CONCLUSION(S): The presence of regurgitation during the IUI procedure is not related to pregnancy outcome.

Asunto(s)

Inseminación Artificial/métodos , Inseminación Artificial/tendencias , Índice de Embarazo/tendencias , Semen/fisiología , Adulto , Estudios de Cohortes , Femenino , Fertilización In Vitro/métodos , Fertilización In Vitro/tendencias , Humanos , Nacimiento Vivo/epidemiología , Embarazo , Estudios Retrospectivos

RESUMEN

OBJECTIVE: To report 2 very rare cases of young women who presented with severe dysmenorrhea and a large cystic lesion in the myometrium, which presented a diagnostic dilemma because they were confused with a Müllerian anomaly. DESIGN: Case reports and a literature review. SETTING: A university-based reproductive endocrinology and infertility clinic in the United States. PATIENTS: An 18- and a 16-year-old nulliparous girl presented with worsening of their longstanding pelvic pain, and imaging study results were suggestive of a Müllerian anomaly. INTERVENTIONS: Abdominal and pelvic computed tomography, transvaginal ultrasonography, pelvic magnetic resonance imaging, operative laparoscopy, and excision of a juvenile cystic adenomyoma (JCA). MAIN OUTCOME MEASURES: Resolution of the pelvic pain and restoration of normal uterine anatomy after appropriate intervention. RESULTS: Restoration of normal uterine anatomy, which was confirmed by 3-dimensional ultrasonography for case 1; however, case 2 still had a small remnant of JCA postoperatively. CONCLUSIONS: Clinical and radiologic examinations may not be useful in differentiating a Müllerian anomaly from other rare abnormalities like JCA. When in doubt, laparoscopy can assist in diagnosing and treating the condition.

RESUMEN

PURPOSE: The recently identified agonistic autoantibodies (AAb) to the gonadotropin-releasing hormone receptor (GnRHR) are a novel investigative and therapeutic target for polycystic ovary syndrome (PCOS). In this study, we used a new cell-based fluorescence resonance energy transfer (FRET) bioassay to analyze serum GnRHR-AAb activity and examine its relationship with testosterone and proinflammatory cytokines in patients with PCOS. METHODS: Serum samples from 33 PCOS patients, 39 non-PCOS ovulatory infertile controls and 30 normal controls were tested for GnRHR-AAb activity and proinflammatory cytokines in a FRET-based bioassay and multiplex bead-based immunoassay, respectively. Correlation was analyzed using the Spearman's correlation test. RESULTS: Serum GnRHR-AAb activity was significantly higher in the PCOS patients than for the ovulatory infertile (p < 0.05) and normal (p < 0.01) controls. GnRHR-AAb were positive in 39% of PCOS patients, 10% of ovulatory infertile controls, and 0% of normal controls. PCOS IgG-induced GnRHR activation was specifically blocked by the GnRHR antagonist cetrorelix. Serum levels of proinflammatory cytokines interleukin-2, interleukin-6, interferon-γ, and tumor necrosis factor-α were significantly increased in PCOS patients compared with ovulatory infertile and normal controls (p < 0.01). Correlation analysis demonstrated positive correlations of GnRHR-AAb activity with testosterone and proinflammatory cytokine levels in the PCOS group. CONCLUSIONS: Elevated GnRHR-AAb activity, as assessed by a new FRET assay, is associated with increased testosterone and proinflammatory cytokines in PCOS, suggesting autoimmune activation of GnRHR may contribute to the pathogenesis of this common disorder.

Asunto(s)

Síndrome del Ovario Poliquístico , Autoanticuerpos , Bioensayo , Citocinas , Femenino , Transferencia Resonante de Energía de Fluorescencia , Humanos , Receptores LHRH , Testosterona

RESUMEN

Three limonoid natural products with selective anti-proliferative activity against BRAF(V600E) and NRAS(Q61K)-mutation-dependent melanoma cell lines were identified. Differential transcriptome analysis revealed dependency of compound activity on expression of the mitochondrial cytochrome P450 oxidase CYP27A1, a transcriptional target of melanogenesis-associated transcription factor (MITF). We determined that CYP27A1 activity is necessary for the generation of a reactive metabolite that proceeds to inhibit cellular proliferation. A genome-wide small interfering RNA screen in combination with chemical proteomics experiments revealed gene-drug functional epistasis, suggesting that these compounds target mitochondrial biogenesis and inhibit tumor bioenergetics through a covalent mechanism. Our work suggests a strategy for melanoma-specific targeting by exploiting the expression of MITF target gene CYP27A1 and inhibiting mitochondrial oxidative phosphorylation in BRAF mutant melanomas.

Asunto(s)

Colestanotriol 26-Monooxigenasa/metabolismo , Limoninas/farmacología , Mitocondrias/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Productos Biológicos/química , Productos Biológicos/metabolismo , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colestanotriol 26-Monooxigenasa/antagonistas & inhibidores , Colestanotriol 26-Monooxigenasa/genética , Humanos , Limoninas/química , Limoninas/metabolismo , Limoninas/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/patología , Factor de Transcripción Asociado a Microftalmía/genética , Factor de Transcripción Asociado a Microftalmía/metabolismo , Mitocondrias/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Regiones Promotoras Genéticas , Unión Proteica , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo

RESUMEN

OBJECTIVE: Is polycystic ovary syndrome (PCOS) associated with activating autoantibodies (AAb) to the second extracellular loop (ECL2) of gonadotropin-releasing hormone receptor (GnRHR)? DESIGN AND METHODS: We retrospectively screened sera from 40 patients with PCOS and 14 normal controls (NCs) with regular menses using enzyme-linked immunosorbent assay (ELISA) for the presence of GnRHR-ECL2-AAb. We obtained similar data from 40 non-PCOS ovulatory but infertile patients as a control group (OIC) of interest. We analyzed GnRHR-ECL2-AAb activity in purified immunoglobulin (Ig)G using a cell-based GnRHR bioassay. RESULTS: The mean ELISA value in the PCOS group was markedly higher than the NC (P = .000036) and the OIC (P = .0028) groups. IgG from a sample of 5 PCOS subjects, in contrast to a sample of 5 OIC subjects, demonstrated a dose-dependent increase in GnRHR-stimulating activity qualitatively similar to the acute action of the natural ligand GnRH and the synthetic agonist leuprolide. The GnRHR antagonist cetrorelix significantly suppressed (P < .01) the elevated GnRHR activity induced by IgG from 7 PCOS patients while the IgG activity level from 7 OIC subjects was unchanged. Five other OIC subjects had relatively high ELISA values at or above the 95% confidence limits. On further study, 3 had normal or low activity while 2 had elevated IgG-induced GnRHR activity. One suppressed with cetrorelix while the other did not. The copresence of PCOS IgG increased the responsiveness to GnRH and shifted the dosage response curve to the left (P < .01). CONCLUSIONS: GnRHR-ECL2-AAb are significantly elevated in patients with PCOS compared with NCs. Their presence raises important etiological, diagnostic, and therapeutic implications.

Asunto(s)

Histerosalpingografía , Infertilidad , Medios de Contraste/efectos adversos , Aceite Etiodizado , Femenino , Humanos , Agua

RESUMEN

OBJECTIVES: 1) To confirm the correlation of GnRH receptor (GnRHR) activating autoantibody (AAb) activity with polycystic ovary syndrome (PCOS) diagnosis in large well defined cohorts; and 2) to evaluate suppression of AAb activity with GnRH antagonist medication in transfected GnRHR cells exposed to serum of PCOS patients. DESIGN: Cross-sectional matched case-control study. SETTING: University-based research facility. PATIENTS: Sera from 200 patients with PCOS from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial and from 200 race, parity-, age-, and body mass index (BMI)-matched ovulatory unexplained infertile control patients from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) trial were obtained and used for this study. INTERVENTIONS: GnRHR AAb activity was determined with the use of the GeneBlazer cell-based fluorescence resonance energy transfer assay with and without cetrorelix, a GnRH antagonist. MAIN OUTCOME MEASURES: 1) GnRHR AAb activity in PCOS patients compared with control subjects; and 2) effectiveness of GnRH antagonist in suppressing GnRHR AAb activity. RESULTS: GnRHR AAb activity levels in the PCOS group were significantly higher than in the control group. With cetrorelix, GnRHR AAb activity was largely suppressed in the PCOS group but not in the control group. These differences remained significant after adjusting for within-pair differences in age, BMI, and antimüllerian hormone (AMH) levels. CONCLUSIONS: We confirmed higher GnRHR AAb activity levels in the sera of a large cohort of PCOS patients compared with unexplained infertile control subjects. Addition of cetrorelix resulted in significant suppression of AAb activity levels in PCOS patients as a group whereas control subjects were unaffected. GnRHR AAb, along with patient age and AMH level, may provide a promising future diagnostic test for PCOS.

RESUMEN

The obstetrician/gynecologist frequently serves as the primary care physician for women. Specialty-specific guidelines vary in screening recommendations for lipid disorders; women's health practitioners often follow recommendations to screen at age 45 in the absence of other risk factors. However, 2013 American College of Cardiology/American Heart Association cholesterol guidelines recommend screening at age 21 to capture those at risk of cardiovascular disease and allow for early intervention with lifestyle and, in the most severe cases, evidence-based statins. We discuss the care of women who primarily benefit from screening: those with familial hypercholesterolemia (FH), those with the metabolic syndrome (MetS) or polycystic ovary syndrome, and those with hypertriglyceridemia. Those with FH have elevated low-density lipoprotein cholesterol from birth and a propensity for premature coronary heart disease. Early recognition of FH can allow risk-reducing interventions, as well as identification of additional affected relatives. Early detection of metabolic variables, such as in the MetS and hypertriglyceridemia, can lead to an enhanced focus on physical activity and heart-healthy diet. Finally, we discuss a practical approach to lipid management and review concerns regarding drug safety. Our objective is to provide a current overview of cardiovascular risk factor optimization that women's health practitioners can use in identifying and/or treating patients at risk for cardiovascular disease and diabetes.

Asunto(s)

Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipidemias/diagnóstico , Hiperlipidemias/tratamiento farmacológico , Lípidos/sangre , Adulto , Anciano , Enfermedades de las Arterias Carótidas/prevención & control , Colesterol/sangre , Femenino , Humanos , Hipolipemiantes/uso terapéutico , Tamizaje Masivo , Síndrome Metabólico/terapia , Persona de Mediana Edad , Factores de Riesgo , Conducta de Reducción del Riesgo

RESUMEN

OBJECTIVE: To determine whether there is an increased risk of ovarian cancer in women undergoing radical cystectomy (RC) for bladder cancer using a large population-based data source. Current American Urologic Association guidelines suggest removal of ovaries during RC in women with bladder cancer, presumably to mitigate the risk ovarian cancer. However, recent data have demonstrated an increased risk of all-cause mortality, cardiovascular disease, osteoporosis, cognitive impairment, and diminished sexual function in some populations of women after oophorectomy. METHODS: We queried the surveillance, epidemiology and end results (SEER) database for all women with a diagnosis of primary bladder cancer who underwent RC between 1998 and 2010. Patients with concurrent or subsequent primary ovarian cancer were then identified using the SEER multiple primaries dataset. Multiple primary standardized incidence ratio was calculated as an estimate of the relative risk of a concurrent or subsequent ovarian malignancy using SEER*Stat software. RESULTS: A total of 1851 women met inclusion criteria for analysis. Of this population, 221 (11.9%) women developed a subsequent nonbladder malignancy, of which 2 (0.11%) women developed subsequent ovarian cancer during the observation period. Multiple primary standardized incidence ratio for development of an ovarian malignancy was 2/4 (0.50). CONCLUSION: The risk of concurrent or subsequent ovarian malignancy in women undergoing RC for bladder cancer is very low. Therefore, oophorectomy at the time of RC may be obviated in order to mitigate the undue risk of cardiovascular disease, osteoporosis, cognitive impairment, and diminished sexual function.

Asunto(s)

Cistectomía , Neoplasias Primarias Múltiples/epidemiología , Neoplasias Ováricas/epidemiología , Neoplasias de la Vejiga Urinaria/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Cistectomía/métodos , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Primarias Múltiples/prevención & control , Neoplasias Ováricas/prevención & control , Ovariectomía , Procedimientos Quirúrgicos Profilácticos , Medición de Riesgo , Adulto Joven

RESUMEN

In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.

Asunto(s)

Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Receptor alfa de Estrógeno/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Tiofenos/síntesis química , Tiofenos/farmacología , Animales , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Diseño de Fármacos , Descubrimiento de Drogas , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Moduladores Selectivos de los Receptores de Estrógeno/farmacocinética , Tiofenos/química , Tiofenos/farmacocinética , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Providing reasonable expectations to patients with diminished ovarian reserve prior to attempting pregnancy through in vitro fertilization (IVF) is one of the most challenging aspects of fertility care. In some instances, advice from the clinician to pursue more effective treatment, such as donor oocytes, may not be acceptable to the patient. In this case report, a patient is presented who represents a poor prognosis candidate for IVF treatment. She was 43 years old with six prior failed IVF cycles and repetitive basal FSH values above 30 mIU/mL. Presented are the challenges in patient counseling and decision making. In her seventh IVF cycle, which she was strongly counseled against pursuing, the patient experienced the desired outcome of live birth. Increasing reports are emerging of live birth using autologous oocytes among women of advanced reproductive age. These instances, as well as the case of our patient, raise issues commonly encountered in patient counseling in poor prognosis patients. This discussion should include an emphasis on patient goals as well as an acknowledgement that no test for ovarian reserve has a 100% positive predictive value.

Asunto(s)

Fertilización In Vitro/psicología , Hormona Folículo Estimulante/sangre , Oocitos/patología , Pronóstico , Adulto , Consejo , Femenino , Humanos , Nacimiento Vivo/psicología , Oocitos/trasplante , Reserva Ovárica , Embarazo , Resultado del Embarazo , Resultado del Tratamiento

RESUMEN

Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.

Asunto(s)

Antineoplásicos/química , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Mama/efectos de los fármacos , Receptor alfa de Estrógeno/antagonistas & inhibidores , Tetrahidroisoquinolinas/química , Tetrahidroisoquinolinas/uso terapéutico , Acrilatos/química , Acrilatos/farmacocinética , Acrilatos/farmacología , Acrilatos/uso terapéutico , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Mama/metabolismo , Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Perros , Descubrimiento de Drogas , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Células MCF-7 , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Proteolisis/efectos de los fármacos , Tetrahidroisoquinolinas/farmacocinética , Tetrahidroisoquinolinas/farmacología

RESUMEN

BACKGROUND: Age-adjusted rates of obesity are reported to be 35.8 % among US adult women and 49 % in some race/ethnicity, underserved populations. (1). Underserved populations often have less access to weight-loss intervention options and are at high risk for obesity related problems including anovulation, infertility, pregnancy-related complications and adverse long-term health outcomes. (2). The purpose of this study was to evaluate a home exercise plan using a pedometer on weight loss, ovulation induction and pregnancy rates in our overweight and obese underserved clinic population. METHODS: Twenty one overweight (BMI ≥ 25-29.9) and obese I-II (BMI ≥ 30-39.9) 18-42 years old were recruited. Participants received an exercise/nutrition questionnaire at the initiation and completion and called weekly for 4 weeks. Ten participants were randomly assigned to the home exercise program (PedGp). PedGp received a pedometer, daily step-count goal, and were called to increase goal by 50 % weekly. All participants then underwent clomiphene stair-step ovulation induction. All study participants were referred to the University Wellness Clinic for diet and exercise counseling. RESULTS: There were high percentages of women with co-morbidities in both groups including fatty liver, low vitamin D, hyperlipidemia, hypothyroidism, prediabetes and diabetes.1. Those completing the 4-week home program increased baseline steps by 21.2 % weekly. Only 3/10 women reached at least one weekly goal of 50 % increase. Although the goal was rarely met, participants who completed study had increased number of daily steps.2. Greater number in PedGp lost weight or stayed the same (5/10 vs. 2/11).3. Greater number in PedGp spontaneously ovulated (4/10 vs. 1/11) or became pregnant (4/10 vs. 3/11). (not statistically significant due to small sample size). CONCLUSION: There are high percentages of comorbidities in this population. Although the goal was rarely met, participants who completed study had increased number of daily steps. A greater number in PedGp lost weight or stayed the same. A greater number in PedGp spontaneously ovulated or became pregnant (not statistically significant due to small sample size). Importantly, 40 % of women who lost weight became pregnant. This is highly encouraging and suggests that the development of pedometer interventions may prove a cost effective option. Weight loss programs for this population hold promise and efficient hospital or community-based programs may prove beneficial.

RESUMEN

PURPOSE: In fresh IVF cycles, embryos reaching the eight-cell stage on day 3 of development are thought to have a higher chance of implantation than those reaching this stage on day 4. To determine whether this difference persists after cryopreservation, we compared pregnancy and implantation rates between frozen embryo transfer (FET) cycles using delayed cleavage-stage embryos (cryopreserved day 4) and normal cleavage-stage embryos (cryopreserved day 3). METHODS: Participants underwent FET between 2008 and 2012 using embryos cryopreserved on either day 3 (n = 76) or day 4 (n = 48), depending on the length of time needed to achieve the eight-cell stage. All embryos, regardless of day of cryopreservation, were thawed and transferred on the 4th day of vaginal progesterone following endometrial preparation with oral estradiol. Chi-square and Mann-Whitney U tests were used to compare patient demographics and cycle outcomes. RESULTS: More women in the day 4 group had diminished ovarian reserve (44 vs 16 %, p = 0.003). Pregnancy outcomes in preceding fresh cycles were not different between the two groups. Pregnancy, implantation, and live birth rates following FET did not differ between the day 3 and day 4 groups. CONCLUSIONS: This is the first study to address outcomes using day 3 versus day 4 cryopreserved embryos. Despite a higher prevalence of diminished ovarian reserve (DOR) in the day 4 group, delayed cleavage-stage embryos utilized in FET cycles performed as well as embryos growing at the normal rate, suggesting delayed embryo development does not affect embryo implantation as long as endometrial synchrony is maintained.

Asunto(s)

Blastocisto/fisiología , Criopreservación/métodos , Implantación del Embrión/fisiología , Transferencia de Embrión/métodos , Administración Intravaginal , Adulto , Fase de Segmentación del Huevo/fisiología , Estudios de Cohortes , Femenino , Humanos , Nacimiento Vivo , Persona de Mediana Edad , Embarazo , Índice de Embarazo , Progesterona/administración & dosificación , Estudios Retrospectivos , Resultado del Tratamiento