RESUMEN
CONTEXT: Polycystic ovary syndrome (PCOS), the most common endocrinopathy of reproductive-aged women, is characterized by ovulatory dysfunction and hyperandrogenism. OBJECTIVE: The aim was to compare gene expression between endometrial samples of normal fertile controls and women with PCOS. DESIGN AND SETTING: We conducted a case control study at university teaching hospitals. PATIENTS: Normal fertile controls and women with PCOS participated in the study. INTERVENTIONS: Endometrial samples were obtained from normal fertile controls and from women with PCOS, either induced to ovulate with clomiphene citrate or from a modeled secretory phase using daily administration of progesterone. MAIN OUTCOME MEASURE: Total RNA was isolated from samples and processed for array hybridization with Affymetrix HG U133 Plus 2 arrays. Data were analyzed using GeneSpring GX11 and Ingenuity Pathways Analysis. Selected gene expression differences were validated using RT-PCR and/or immunohistochemistry in separately obtained PCOS and normal endometrium. RESULTS: ANOVA analysis revealed 5160 significantly different genes among the three conditions. Of these, 466 were differentially regulated between fertile controls and PCOS. Progesterone-regulated genes, including mitogen-inducible gene 6 (MIG6), leukemia inhibitory factor (LIF), GRB2-associated binding protein 1 (GAB1), S100P, and claudin-4 were significantly lower in PCOS endometrium; whereas cell proliferation genes, such as Anillin and cyclin B1, were up-regulated. CONCLUSIONS: Differences in gene expression provide evidence of progesterone resistance in midsecretory PCOS endometrium, independent of clomiphene citrate and corresponding to the observed phenotypes of hyperplasia, cancer, and poor reproductive outcomes in this group of women.
Asunto(s)
Clomifeno/uso terapéutico , Endometrio/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Progesterona/uso terapéutico , Análisis de Varianza , Estudios de Casos y Controles , Clomifeno/farmacología , Endometrio/efectos de los fármacos , Femenino , Expresión Génica/efectos de los fármacos , Expresión Génica/fisiología , Humanos , Inmunohistoquímica , Análisis de Secuencia por Matrices de Oligonucleótidos , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/genética , Análisis de Componente Principal , Progesterona/farmacologíaRESUMEN
Eighteen normal women underwent pituitary down-regulation with leuprolide, followed by a 10-day treatment with 0.2 mg/d transdermal estradiol (E(2)) with subsequent allocation to one of two 10-day estradiol regimens plus 40 mg daily intramuscular P: supraphysiologic (0.2 mg/d transdermal E(2) mg/d vaginal micronized E(2)) or subphysiologic (no exogenous E(2) treatment). Average E(2) and P in the supraphysiologic, physiologic, and subphysiologic groups were 1,175.9 pg/mL and 17.5 ng/mL, 136.9 pg/mL and 21.2 pg/mL, and 23.8 ng/mL and 22.0 ng/mL, respectively, and there were no differences between groups in endometrial histology or expression of biomarkers of receptivity.
Asunto(s)
Endometrio/metabolismo , Estradiol/sangre , Fármacos para la Fertilidad Femenina/administración & dosificación , Leuprolida/administración & dosificación , Fase Luteínica/efectos de los fármacos , Adolescente , Adulto , Endometrio/efectos de los fármacos , Femenino , Humanos , Integrina beta3/metabolismo , Osteopontina/metabolismo , Adulto JovenRESUMEN
CONTEXT: It is generally assumed that delayed endometrial development observed in luteal phase deficiency (LPD) is the result of abnormally low progesterone (P) levels. This hypothesis has never been tested by direct experiment. OBJECTIVE: Our objective was to evaluate the effects of P concentrations on human endometrium. DESIGN AND SETTING: A randomized trial was conducted at an academic medical center. SUBJECTS: Twenty-nine healthy, ovulatory 18- to 35-yr-old women participated. INTERVENTION: Endometrial samples were obtained from women in natural cycles and two groups of experimentally modeled cycles. Women undergoing modeled cycles were treated with GnRH agonist and a fixed physiological dose of transdermal estradiol, followed by randomization to 10 or 40 mg daily im P administration to achieve either normal circulating luteal P or 4-fold lower P concentrations, the latter representing an experimental model of LPD. MAIN OUTCOME MEASURES: Tissue specimens, obtained after 10 days of P exposure, were analyzed by histological dating, immunohistochemistry, immunoblot, and real-time quantitative RT-PCR (qRT-PCR). RESULTS: Histological dating of endometrium, immunohistochemistry for endometrial integrins, and qRT-PCR analysis for nine putative functional markers showed no differences between the three groups. Preliminary data from Western analysis suggest that some proteins may be affected by low serum P concentrations. CONCLUSIONS: Histological endometrial dating does not reflect circulating P concentrations and cannot serve as a reliable bioassay of the quality of luteal function. Assessment of selected functional markers by either immunohistochemistry or qRT-PCR is similarly insensitive to decreased circulating P. Preliminary evidence suggests that abnormally low luteal phase serum P concentrations may have important functional consequences not otherwise detected.
Asunto(s)
Endometrio/crecimiento & desarrollo , Endometrio/fisiología , Leuprolida/farmacología , Fase Luteínica/fisiología , Enfermedades Uterinas/inducido químicamente , Enfermedades Uterinas/fisiopatología , Administración Cutánea , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Endometrio/efectos de los fármacos , Endometrio/patología , Estradiol/administración & dosificación , Femenino , Fármacos para la Fertilidad Femenina/administración & dosificación , Fármacos para la Fertilidad Femenina/farmacología , Humanos , Leuprolida/administración & dosificación , Fase Luteínica/sangre , Fase Luteínica/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Progesterona/administración & dosificación , Progesterona/sangre , Progesterona/farmacología , Enfermedades Uterinas/sangre , Enfermedades Uterinas/patologíaRESUMEN
To illustrate the recommended approach to questions concerning prognosis and the formulation of clinical recommendations, the principles of evidence-based medicine were applied to questions regarding the cardiovascular health risks associated with polycystic ovary syndrome (PCOS) and the effects of treatment on risk. A critical examination of the published literature reveals that the clinical diagnosis of PCOS does not, by itself, increase the risk of developing coronary heart disease (CHD) or adversely affect the prognosis in women with CHD. Rather, any increased risks can be attributed to other known risk factors (obesity, hypertension, diabetes, dyslipidemia) commonly observed in women with the disorder. Treatment strategies that decrease the probability of developing such co-morbid conditions (diet, exercise) or are effective in their management (antihypertensives, statins, insulin-sinsitizing agents) may be expected to reduce risk or improve prognosis, but available evidence is insufficient to warrant a general recommendation for metformin treatment as a CHD risk reduction strategy in all women with PCOS.