RESUMEN
OBJECTIVE: To evaluate the adequacy of the insulin dose prescribed at hospital discharge in a high-risk population and assess patient characteristics that influence insulin dose requirement in the immediate postdischarge period. METHODS: This was a retrospective study conducted at Parkland Health System. We included all patients admitted to a medical floor who received an insulin prescription at discharge and had at least one follow-up visit within 6 months of discharge. All data were extracted by a detailed manual review of each electronic medical record. RESULTS: At the postdischarge follow-up (N = 797, median 33 days from discharge), 60% of patients required an insulin dose adjustment; 47% of the patients required a dose decrease. Significant predictors of a decrease insulin requirement postdischarge included (multiple regression beta coefficient [95% confidence interval]): newly diagnosed diabetes, -12.7 (-17.7, -7.7); ketosis-prone diabetes, -8.4 (-15, -1.8); glycated hemoglobin A1c (HbA1c), <10% (86 mmol/mol) -7.0 (-11.4, -2.6); discharge insulin total daily dose, -5.3 (-9.3, -1.3); and metformin prescription, -4.9 (-8.4, -1.3). CONCLUSION: An insulin dose adjustment (most commonly a decrease) was necessary shortly after discharge in more than half of our patients. A better model to estimate insulin dose at discharge is needed along with short-term follow-up after discharge for insulin titration. A pre-emptive insulin dose reduction at discharge should be considered for patients with newly diagnosed diabetes, ketosis-prone diabetes, metformin prescription, and those with HbA1c <10% at presentation. ABBREVIATIONS: DKA = diabetic ketoacidosis; HbA1c = glycated hemoglobin A1c; KPDM = ketosis-prone diabetes mellitus; TDD = total daily dose.
Asunto(s)
Diabetes Mellitus Tipo 2 , Cetoacidosis Diabética , Insulina/uso terapéutico , Glucemia , Hemoglobina Glucada , Humanos , Hipoglucemiantes , Alta del Paciente , Estudios RetrospectivosRESUMEN
Depending on the estrous/menstrual cycle stage in females, ovarian-derived estradiol (E(2)) exerts either a negative or a positive effect on the hypothalamic-pituitary axis to regulate the synthesis and secretion of pituitary gonadotropins, LH, and FSH. To study the role of estrogen receptor-alpha (ERalpha) mediating these effects, we assessed the relevant parameters in adult wild-type (WT) and ERalpha-null (alphaERKO) female mice in vivo and in primary pituitary cell cultures. The alphaERKO mice exhibited significantly higher plasma and pituitary LH levels relative to WT females despite possessing markedly high levels of circulating E(2). In contrast, hypothalamic GnRH content and circulating FSH levels were comparable between genotypes. Ovariectomy led to increased plasma LH in WT females but no further increase in alphaERKO females, while plasma FSH levels increased in both genotypes. E(2) treatment suppressed the high plasma LH and pituitary Lhb mRNA expression in ovariectomized WT females but had no effect in alphaERKO. In contrast, E(2) treatments only partially suppressed plasma FSH in ovariectomized WT females, but this too was lacking in alphaERKO females. Therefore, negative feedback on FSH is partially E(2)/ERalpha mediated but more dependent on ovarian-derived inhibin, which was increased threefold above normal in alphaERKO females. Together, these data indicate that E(2)-mediated negative feedback is dependent on functional ERalpha and acts to primarily regulate LH synthesis and secretion. Studies in primary cultures of pituitary cells from WT females revealed that E(2) did not suppress basal or GnRH-induced LH secretion but instead enhanced the latter response, indicating that the positive influence of E(2) on gonadotropin secretion may occur at the level of the pituitary. Once again this effect was lacking in alphaERKO gonadotropes in culture. These data indicate that the aspects of negative and positive effects of E(2) on gonadotropin secretion are ERalpha dependent and occur at the level of the hypothalamus and pituitary respectively.
Asunto(s)
Estradiol/farmacología , Receptor alfa de Estrógeno/metabolismo , Gonadotropinas Hipofisarias/biosíntesis , Hipotálamo/metabolismo , Hipófisis/metabolismo , Animales , Northern Blotting/métodos , Células Cultivadas , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Femenino , Hormona Folículo Estimulante/biosíntesis , Hormona Folículo Estimulante/metabolismo , Hormona Liberadora de Gonadotropina/farmacología , Gonadotropinas Hipofisarias/metabolismo , Hormona Luteinizante/biosíntesis , Hormona Luteinizante/genética , Hormona Luteinizante/metabolismo , Hormona Luteinizante de Subunidad beta/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ovariectomía , Hipófisis/química , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The predisposition of the testis and ovary to primarily synthesize testosterone (T) and estradiol (E2), respectively, is due to gonadal-specific cell types that differentially express the various hydroxysteroid (17beta) dehydrogenase (HSD17B) isoforms. In testes, Leydig cells rely on LH stimulation to maintain expression of the type 3 (HSD17B3) isoform, which specifically converts androstenedione to T. In ovaries, thecal interstitial (TI) cells also rely on LH to induce androgen synthesis but lack HSD17B3 and therefore secrete androgens of low biological activity. Therefore, thecal cells may possess a mechanism to repress the Leydig cell phenotype and HSD17B3 expression. E2 is known to inhibit experimentally Leydig cell function and proliferation. In the current study, we provide evidence that E2 prevents the development of functional Leydig-like cells in the murine ovary and that this action is mediated by estrogen receptor (ER) alpha. ERalpha-null (alphaERKO) female mice exhibit testis-like levels of Hsd17b3 expression in the ovaries and male-like levels of plasma T. Herein, we demonstrate that: 1) Hsd17b3 expression in alphaERKO ovaries is a primary effect of the loss of intraovarian ERalpha actions; 2) alphaERKO ovarian cells produce substantial levels of T in vitro, and this is blocked by a HSD17B3-specific inhibitor; 3) Hsd17b3 expression in alphaERKO ovaries is LH regulated and localized to the secondary interstitial (SI)/TI cells; and 4) alphaERKO SI/TI cells possess Leydig-like ultrastructural features. These data indicate that intraovarian ERalpha actions are required to repress Hsd17b3 expression in the ovary and may be important to maintaining a female phenotype in SI/TI cells.
Asunto(s)
Receptor alfa de Estrógeno/metabolismo , Células Intersticiales del Testículo/ultraestructura , Ovario/citología , Ovario/fisiología , 17-Hidroxiesteroide Deshidrogenasas/genética , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Animales , Diferenciación Celular/fisiología , Receptor alfa de Estrógeno/genética , Femenino , Regulación del Desarrollo de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Hormona Luteinizante/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Electrónica de Transmisión , Ovario/crecimiento & desarrollo , Fenotipo , Testículo/citología , Testículo/fisiología , Testosterona/biosíntesis , Testosterona/sangreRESUMEN
The process of granulosa cell differentiation that occurs in preovulatory follicles is dependent on FSH but requires augmentation by estradiol. To determine which estrogen receptor (ER) form mediates the effects of estradiol during gonadotropin-induced follicle growth, differentiation, and rupture, we characterized the response of ERalpha- and ERbeta-null mice to gonadotropin-induced ovulation. Immature mice were treated with an ovulatory regimen of exogenous gonadotropins and tissues were collected at distinct time points for morphological, biochemical, gene expression, and immunohistochemical analyses. Granulosa cells of ERbeta knockout (ERKO) preovulatory follicles exhibited an attenuated response to FSH-induced differentiation, as evident by reduced aromatase activity and estradiol synthesis, and insufficient expression of LH receptor. As a result, betaERKO ovaries were unable to fully respond to an ovulatory bolus of gonadotropin, leading to a reduced rate of follicle rupture; insufficient induction of prostaglandin-synthase 2 and progesterone receptor; an aberrant increase in aromatase activity and plasma estradiol; and incomplete expansion of the cumulus-oocyte complex. Parallel characterization of alphaERKO females indicated a minimal role for ERalpha in granulosa cell differentiation, ovulation, and the concomitant changes in gene expression, although some abnormalities were revealed. These studies demonstrate that ERbeta-mediated estradiol actions are vital to FSH-induced granulosa cell differentiation; and in the absence of ERbeta, preovulatory follicles are deficient in the necessary cellular organization (i.e. antrum and cumulus oocyte complex), enzymatic activity (i.e. capacity to convert androgen precursor to estradiol), and receptor signaling pathways (i.e. LH receptor) to respond to a gonadotropin surge and expel a healthy oocyte.
Asunto(s)
Receptor alfa de Estrógeno/fisiología , Receptor beta de Estrógeno/fisiología , Células de la Granulosa/citología , Ovulación/fisiología , Animales , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Estradiol/sangre , Receptor beta de Estrógeno/deficiencia , Receptor beta de Estrógeno/genética , Femenino , Hormona Folículo Estimulante/farmacología , Regulación de la Expresión Génica , Células de la Granulosa/efectos de los fármacos , Ratones , Ratones Noqueados , Ovulación/efectos de los fármacos , Progesterona/sangre , ARN/genética , ARN/aislamiento & purificación , Receptores de HL/efectos de los fármacos , Receptores de HL/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Both estrogen receptor (ER) alpha and beta are expressed within the ovary and lack of either of these receptors affects ovarian function. In this study, the role of ERalpha and ERbeta in folliculogenesis and ovulation was further analyzed. Evaluation of ovarian follicle populations in wild-type and ERbeta knockout (betaERKO) ovaries revealed reduced late antral growth and ovulatory capacity of betaERKO follicles, indicated by reduced numbers of large antral follicles and corpora lutea and increased atresia of large antral follicles. An in vitro culture system was used to study growth, rupture, and luteinization of wild-type, ERalpha knockout (alphaERKO) and betaERKO ovarian follicles. alphaERKO follicles exhibited wild-type-like growth and ovulation rates but an increased capacity to synthesize estradiol. In contrast, betaERKO follicles showed a significant lack of progression from early antral to large antral stage, decreased estradiol production, and reduced ovulation. Expression patterns of several genes involved in follicle maturation and ovulation were analyzed in follicles grown in vitro. Ar, Pgr, and Has2 mRNA expression levels were the same among the three genotypes. However, betaERKO follicles showed reduced expression of Cyp19 mRNA during follicle maturation and reduced Lhcgr and Ptgs2 mRNA expression after human chorionic gonadotropin stimulus. Luteinization occurs normally in alphaERKO and betaERKO follicles, shown by increased progesterone secretion and increased cdkn1b mRNA expression after human chorionic gonadotropin. Collectively, these data indicate that ERbeta, but not ERalpha, plays a direct role in folliculogenesis. ERbeta appears to facilitate follicle maturation from the early antral to the preovulatory stage.
Asunto(s)
Receptor alfa de Estrógeno/fisiología , Receptor beta de Estrógeno/fisiología , Folículo Ovárico/crecimiento & desarrollo , Folículo Ovárico/fisiología , Ovulación/fisiología , Animales , Gonadotropina Coriónica/farmacología , Cuerpo Lúteo/efectos de los fármacos , Cuerpo Lúteo/crecimiento & desarrollo , Cuerpo Lúteo/fisiología , Dinoprostona/farmacología , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Femenino , Fase Folicular/efectos de los fármacos , Fase Folicular/fisiología , Técnicas In Vitro , Ratones , Ratones Noqueados , Folículo Ovárico/efectos de los fármacos , Ovulación/efectos de los fármacosRESUMEN
Stringent regulation of LH secretion from the pituitary is vital to ovarian function in mammals. Two rodent models of LH hypersecretion are the transgenic LHbeta-C-terminal peptide (LHbetaCTP) and estrogen receptor-alpha (ERalpha)-null (alphaERKO) mice. Both exhibit ovarian phenotypes of chronic anovulation, cystic and hemorrhagic follicles, lack of corpora lutea, interstitial/stromal hyperplasia, and elevated plasma estradiol and testosterone. Because ERbeta is highly expressed in granulosa cells of the ovary, we hypothesized the intraovarian actions of ERbeta may be necessary for full manifestation of phenotypes associated with LH hyperstimulation. To address this question, we generated female mice that possess elevated LH, but lack ERbeta, by breeding the LHbetaCTP and ERbeta-null (betaERKO) mice. A comparison of LHbetaCTP, alphaERKO, and betaERKO(LHCTP) females has allowed us to elucidate the contribution of each ER form to the pathologies and endocrinopathies that occur during chronic LH stimulation of the ovary. alphaERKO ovaries respond to elevated LH by exhibiting an amplified steroidogenic pathway characteristic of the follicular stage of the ovarian cycle, whereas wild-type(LHCTP) and betaERKO(LHCTP) females exhibit a steroidogenic profile more characteristic of the luteal stage. In addition, the hemorrhagic and cystic follicles of the LHbetaCTP and alphaERKO ovaries require the intraovarian actions of ERbeta for manifestation, because they were lacking in the betaERKO(LHCTP) ovary. In turn, ectopic expression of the Leydig cell-specific enzyme, Hsd17b3, and male-like testosterone synthesis in the alphaERKO ovary are unique to this genotype and are therefore the culmination of elevated LH and the loss of functional ERalpha within the ovary.
Asunto(s)
Hormona Luteinizante/metabolismo , Quistes Ováricos/etiología , Quistes Ováricos/metabolismo , Folículo Ovárico , Receptores de Estrógenos/metabolismo , Animales , Receptor beta de Estrógeno , Femenino , Expresión Génica , Hormonas/sangre , Hormona Luteinizante/sangre , Ratones , Ratones Noqueados , Ratones Transgénicos , Quistes Ováricos/sangre , Quistes Ováricos/patología , Folículo Ovárico/metabolismo , Folículo Ovárico/patología , Ovario/patología , Receptores de Estrógenos/deficiencia , Receptores de Estrógenos/genéticaRESUMEN
Targeted disruption of the different ER genes has generated experimental animal models that are very useful in evaluating the distinct and cooperative roles of the two estrogen receptors, ERalpha and ERbeta, in reproductive but also non-reproductive tissues of both sexes. Phenotypic analysis has provided definitive experimental findings for estrogen receptor mediated physiological actions, involving ERalpha in uterine, mammary gland and neuroendocrine sites. ERbeta is involved most dramatically in the ovary as is ERalpha. More detailed studies in combination with tissue specific or inducible ER knock outs will be important for future research.
Asunto(s)
Receptores de Estrógenos/fisiología , Animales , Femenino , Infertilidad Masculina/genética , Infertilidad Masculina/metabolismo , Masculino , Glándulas Mamarias Animales/metabolismo , Modelos Animales , Ovario/metabolismo , Fenotipo , Reproducción/genética , Útero/metabolismoRESUMEN
To determine the role of each estrogen receptor (ER) form (ERalpha, ERbeta) in mediating the estrogen actions necessary to maintain proper function of the hypothalamic-pituitary-gonadal axis, we have characterized the hypothalamic-pituitary-gonadal axis in female ER knockout (ERKO) mice. Evaluation of pituitary function included gene expression assays for Gnrhr, Cga, Lhb, Fshb, and Prl. Evaluation of ovarian steroidogenic capacity included gene expression assays for the components necessary for estradiol synthesis: i.e. Star, Cyp11a, Cyp17, Cyp19, Hsd3b1, and Hsd17b1. These data were corroborated by assessing plasma levels of the respective peptide and steroid hormones. alphaERKO and alphabetaERKO females exhibited increased pituitary Cga and Lhb expression and increased plasma LH levels, whereas both were normal in betaERKO. Pituitary Fshb expression and plasma FSH were normal in all three ERKOs. In the ovary, all three ERKOs exhibited normal expression of Star, Cyp11a, and Hsd3b1. In contrast, Cyp17 and Cyp19 expression were elevated in alphaERKO but normal in betaERKO and alphabetaERKO. Plasma steroid levels in each ERKO mirrored the steroidogenic enzyme expression, with only the alphaERKO exhibiting elevated androstenedione and estradiol. Elevated plasma testosterone in alphaERKO and alphabetaERKO females was attributable to aberrant expression of Hsd17b3 in the ovary, representing a form of endocrine sex reversal, as this enzyme is unique to the testes. Enhanced steroidogenic capacity in alphaERKO ovaries was erased by treatment with a GnRH antagonist, indicating these phenotypes to be the indirect result of excess LH stimulation that follows the loss of ERalpha in the hypothalamic-pituitary axis. Overall, these findings indicate that ERalpha, but not ERbeta, is indispensable to the negative-feedback effects of estradiol that maintain proper LH secretion from the pituitary. The subsequent hypergonadism is illustrated as increased Cyp17, Cyp19, Hsd17b1, and ectopic Hsd17b3 expression in the ovary.