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J Endocr Soc ; 3(11): 2123-2134, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31687639


Müllerian-inhibiting substance (MIS), also known as anti-Müllerian hormone, is thought to be a negative regulator of primordial follicle activation. We have previously reported that treatment with exogenous MIS can induce complete ovarian suppression within 5 weeks of treatment in mice. To investigate the kinetics of the return of folliculogenesis following the reversal of suppression, we treated animals with recombinant human MIS (rhMIS) protein for 40 days in adult female Nu/Nu mice and monitored the recovery of each follicle type over time. Following cessation of MIS therapy, secondary, and antral follicles returned within 30 days, along with the normalization of reproductive hormones, including LH, FSH, MIS, and Inhibin B. Furthermore, 30 days following MIS pretreatment, the number of antral follicles were significantly higher than controls, and superovulation with timed pregnant mare serum gonadotropin and human chorionic gonadotropin stimulation at this time point resulted in an approximately threefold increased yield of eggs. Use of the combined rhMIS-gonadotropin superovulation regimen in a diminished ovarian reserve (DOR) mouse model, created by 4-vinylcyclohexene dioxide treatment, also resulted in a twofold improvement in the yield of eggs. In conclusion, treatment with rhMIS can induce a reversible ovarian suppression, following which a rapid and synchronized large initial wave of growing follicles can be harnessed to enhance the response to superovulation. Therapies modulating MIS signaling may therefore augment the response to current ovarian stimulation protocols and could be particularly useful to women with DOR or poor responders to controlled ovarian hyperstimulation during in vitro fertilization.

J Clin Endocrinol Metab ; 103(11): 4187-4196, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30239805


Context: There is increasing evidence for Müllerian-inhibiting substance (MIS)/anti-Müllerian hormone (AMH) physiologic activity in the human uterus, so it is relevant to study how MIS/AMH levels impact pregnancy. Objective: To investigate the association of MIS/AMH levels with the risk of adverse obstetric outcomes. Design: Retrospective cohort study. Setting: Academic fertility center. Patients: Women who became pregnant through in vitro fertilization between January 2012 and October 2016. Exclusion criteria were: oocyte donation, gestational carrier, multiple gestations, miscarriage before 20 weeks, or medically indicated preterm deliveries. Interventions: None. Main Outcome Measures: There were two primary outcomes, preterm birth and cesarean delivery for arrest of labor. Because MIS/AMH level is highly skewed by certain infertility diagnoses, the preterm birth analysis was stratified by polycystic ovary syndrome (PCOS) diagnosis, and the cesarean delivery for arrest of labor analysis was stratified by diminished ovarian reserve diagnosis. χ2, Mann-Whitney, and t tests were used as appropriate. A P value of <0.05 was considered statistically significant. Results: Among women with PCOS, those who delivered prematurely had substantially higher MIS/AMH levels (18 vs 6.4 ng/mL, P = 0.003) than did those who delivered at term. At the highest MIS/AMH values, preterm deliveries predominated; above the 90th percentile in women with PCOS, all deliveries were premature. No effect of MIS/AMH level was observed in women without PCOS. We found no association between MIS/AMH values and cesarean delivery for labor arrest. Conclusion: In women with PCOS, substantially elevated MIS/AMH levels are significantly associated with preterm birth, suggesting closer follow-up and further studies to elucidate the underlying mechanisms.

Hormônio Antimülleriano/sangue , Cesárea/estatística & dados numéricos , Distocia/diagnóstico , Síndrome do Ovário Policístico/sangue , Nascimento Prematuro/diagnóstico , Adulto , Distocia/sangue , Distocia/etiologia , Distocia/cirurgia , Feminino , Humanos , Recém-Nascido , Síndrome do Ovário Policístico/complicações , Gravidez , Nascimento Prematuro/etiologia , Prognóstico , Estudos Retrospectivos , Inércia Uterina
Am J Obstet Gynecol ; 217(1): 49.e1-49.e10, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28288792


BACKGROUND: Ectopic pregnancy is common among young women. Treatment can consist of either surgery with salpingectomy or salpingostomy or medical management with methotrexate. In addition to acute complications, treatment of ectopic pregnancy can result in long-term sequelae that include decreased fertility. Little is known about the patterns of care and predictors of treatment in women with ectopic pregnancy. Similarly, data on outcomes for various treatments are limited. OBJECTIVE: We examined the patterns of care and outcomes for women with ectopic pregnancy. Specifically, we examined predictors of medical (vs surgical) management of ectopic pregnancy and tubal conservation (salpingostomy vs salpingectomy) among women who underwent surgery. STUDY DESIGN: The Perspective database was used to identify women with a diagnosis of tubal ectopic pregnancy treated from 2006-2015. Perspective is an all-payer database that collects data on patients at hospitals from throughout the United States. Women were classified as having undergone medical treatment, if they received methotrexate, and surgical treatment, if treatment consisted of salpingostomy or salpingectomy. Multivariable models were developed to examine predictors of medical treatment and of tubal conserving salpingostomy among women who were treated surgically. RESULTS: Among the 62,588 women, 49,090 women (78.4%) were treated surgically, and 13,498 women (21.6%) received methotrexate. Use of methotrexate increased from 14.5% in 2006 to 27.3% by 2015 (P<.001). Among women who underwent surgery, salpingostomy decreased over time from 13.0% in 2006 to 6.0% in 2015 (P<.001). Treatment in more recent years, at a teaching hospital and at higher volume centers, were associated with the increased use of methotrexate (P<.05 for all). In contrast, Medicaid recipients (adjusted risk ratio, 0.92; 95% confidence interval, 0.87-0.98) and uninsured women (adjusted risk ratio, 0.87; 95% confidence interval, 0.82-0.93) were less likely to receive methotrexate than commercially insured patients. Among those who underwent surgery, black (adjusted risk ratio, 0.76; 95% confidence interval, 0.69-0.85) and Hispanic (adjusted risk ratio, 0.80; 95% confidence interval, 0.66-0.96) patients were less likely to undergo tubal conserving surgery than white women and Medicaid recipients (adjusted risk ratio, 0.69; 95% confidence interval, 0.64-0.75); uninsured women (adjusted risk ratio, 0.60; 95% confidence interval, 0.55-0.66) less frequently underwent salpingostomy than commercially insured patients. CONCLUSION: There is substantial variation in the management of ectopic pregnancy. There are significant race- and insurance-related disparities associated with treatment.

Disparidades em Assistência à Saúde/estatística & dados numéricos , Gravidez Ectópica/tratamento farmacológico , Gravidez Ectópica/cirurgia , Resultado do Tratamento , Abortivos não Esteroides , Adulto , Grupo com Ancestrais do Continente Africano , Grupo com Ancestrais do Continente Europeu , Feminino , Hispano-Americanos , Humanos , Infertilidade Feminina/epidemiologia , Medicaid , Pessoas sem Cobertura de Seguro de Saúde , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Gravidez , Gravidez Tubária/tratamento farmacológico , Gravidez Tubária/cirurgia , Salpingectomia/efeitos adversos , Salpingectomia/estatística & dados numéricos , Salpingostomia/efeitos adversos , Salpingostomia/estatística & dados numéricos , Estados Unidos , Adulto Jovem
Gynecol Endocrinol ; 33(4): 301-305, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28010150


No significant differences in outcomes have been found between protocols of endometrial preparation for frozen embryo transfer (FET), though gonadotropin releasing hormone (GnRH) antagonists may have detrimental effects on the endometrium. We conducted a retrospective cohort noninferiority study at a single academic center of women receiving multiple doses of mid-cycle GnRH antagonist (GAnt) to those receiving GnRH agonist (GAg) to determine if there are detrimental effects of GnRH antagonists. 1047 FET cycles were identified, detailed data was available in 840 cycles: 610 GAg and 230 GAnt cycles. Patients undergoing GAnt cycles were older (40 ± 6.6 versus 37 ± 5.1 years, p < 0.0001), more often used donor oocyte (36% versus 18.6%, p < 0.0001), and more often exhibited diminished ovarian reserve (49.1% versus 36.2%, p = 0.0009). Clinical pregnancy rates (CPRs) per transfer and implantation rates (IRs) were similar for GAnt and GAg cycles. There was a trend for higher pregnancy and IRs with GAg cycles in younger women (CPR 38.8% versus 26.7%, p = 0.16; IR 36% versus 23.3%, p = 0.07). Stratifying by diagnosis, CPR and IR were similar in GAnt and GAg cycles. A GAnt protocol of endometrial preparation for FET is not inferior to a GAg protocol regardless of patient age, use of donor oocyte, or infertility diagnosis.

Transferência Embrionária/métodos , Fármacos para a Fertilidade Feminina/uso terapêutico , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Antagonistas de Hormônios/uso terapêutico , Leuprolida/uso terapêutico , Adulto , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Estradiol/sangue , Estradiol/uso terapêutico , Feminino , Fármacos para a Fertilidade Feminina/administração & dosagem , Fertilização In Vitro/métodos , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/uso terapêutico , Antagonistas de Hormônios/administração & dosagem , Humanos , Leuprolida/administração & dosagem , Indução da Ovulação/métodos , Gravidez , Resultado da Gravidez , Taxa de Gravidez , Estudos Retrospectivos
Int J Gynecol Cancer ; 22(5): 732-41, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22635025


OBJECTIVE: To identify obesity-related cancer genes in endometrial and adipose tissue depots of body mass index-matched morbidly obese women with and without endometrial cancer. METHODS: Eight women undergoing hysterectomy (4 women with and 4 women without endometrial cancer) were matched by age (52.6 years) and body mass index (44.5 kg/m). Endometrium, visceral adipose tissue, and subcutaneous adipose tissue were collected and subjected to microarray analysis using Affymetrix Human Genome U133 Plus 2.0 Arrays. Gene set enrichment analysis used to extract biological information from the gene expression data and t test metric ranked and compared genes in the expression data set. Protein expression was measured in the endometrial samples, and serum was collected for hormone/metabolite assays. RESULTS: No significant differences were detected in hormone/metabolite levels between groups. Gene set enrichment analysis comparisons demonstrated that endometrial, visceral adipose and subcutaneous adipose tissues displayed 40, 47, and 38 alternatively regulated gene set pathways when comparing patients with and without cancer. Nineteen gene sets were alternately regulated in both visceral and subcutaneous adipose tissues; however, eighteen of these were regulated in the opposite direction. Five pathways were significantly and alternately regulated in all 3 tissue types and included glycolysis/gluconeogenesis, ribosome, peroxisome proliferator activated receptor signaling, pathogenic Escherichia coli infection, and natural killer-mediated cytotoxicity. In the malignant endometrium, liver kinase B1 underexpression was observed in all patients with cancer. Liver kinase B1 underexpression decreased adenosine monophosphate-activated protein kinase activity toward acetyl-CoA carboxylase and implied enhanced lipid biosynthesis in obesity-induced endometrial cancer. CONCLUSIONS: Subcutaneous and visceral adipose tissue depots have opposite patterns of gene expression in obese patients with and without endometrial cancer. The altered de novo lipogenesis and individual gene targets identified provide new potential targets for cancer treatment and prevention for at-risk obese women.

Adiposidade/genética , Biomarcadores Tumorais/genética , Neoplasias do Endométrio/etiologia , Endométrio/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/genética , Gordura Subcutânea/metabolismo , Adulto , Western Blotting , Índice de Massa Corporal , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Endométrio/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Gordura Intra-Abdominal/patologia , Pessoa de Meia-Idade , Obesidade/complicações , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Gordura Subcutânea/patologia