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1.
Hum Mol Genet ; 2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620954

RESUMO

Dysfunction of the gonadotropin-releasing hormone (GnRH) axis causes a range of reproductive phenotypes resulting from defects in the specification, migration and/or function of GnRH neurons. To identify additional molecular components of this system, we initiated a systematic genetic interrogation of families with isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD). Here we report thirteen families (twelve autosomal dominant, and one autosomal recessive) with an anosmic form of IGD (Kallmann syndrome; KS) with loss-of-function mutations in TCF12, a locus also known to cause syndromic and non-syndromic craniosynostosis. We show that loss of tcf12 in zebrafish larvae perturbs GnRH neuronal patterning with concomitant attenuation of the orthologous expression of tcf3a/b, encoding a binding partner of TCF12; and stub1, a gene that is both mutated in other syndromic forms of IGD and maps to a TCF12 affinity network. Finally, we report that restored STUB1 mRNA rescues loss of tcf12 in vivo. Our data extend the mutational landscape of IGD; highlight the genetic links between craniofacial patterning and GnRH dysfunction; and begin to assemble the functional network that regulates the development of the GnRH axis.

2.
NeuroRehabilitation ; 46(3): 355-368, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32250330

RESUMO

BACKGROUND: Endocrinopathy, including hypogonadism, is common following traumatic brain injury (TBI). Prior evidence suggests hypogonadism is associated with poorer function. OBJECTIVE: Determine the feasibility, safety, and efficacy of testosterone (T) therapy in hypogonadal men following TBI in acute rehabilitation. DESIGN: Randomized, double blind, placebo-controlled pilot trial. SETTING: Inpatient rehabilitation brain injury unit. PARTICIPANTS: Men ages 18 -65, post moderate to severe TBI receiving inpatient rehabilitation. INTERVENTIONS: Transdermal T gel or placebo. MAIN OUTCOME MEASURES: Revised FIM™ score, strength, adverse events. RESULTS: Of 498 screened, 70 participants were enrolled, and 22 meeting all criteria were randomized into placebo (n = 10) or physiologic T therapy (n = 12). There was no significant difference between groups in rate of improvement on the FIM™ (intercepts t = -0.31, p = 0.7593, or slopes t = 0.61, p = 0.5472). The Treatment group demonstrated the greatest absolute improvement in FIM™ scores and grip strength compared to Placebo or Normal T groups. There was no difference in adverse events between groups. Percentage of time with agitation or aggression was highest in the Placebo group. CONCLUSIONS: Although there were no significant differences in rates of recovery, treatment group subjects showed greater absolute functional and strength improvement compared to the Placebo or Normal T groups.

3.
Curr Opin Endocrinol Diabetes Obes ; 27(3): 170-176, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32304391

RESUMO

PURPOSE OF REVIEW: The aim of this review is to summarize recent advances on development of in vivo preclinical models of adrenocortical carcinoma (ACC). RECENT FINDINGS: Significant progress has been achieved in the underlying molecular mechanisms of adrenocortical tumorigenesis over the last decade, and recent comprehensive profiling analysis of ACC tumors identified several genetic and molecular drivers of this disease. Therapeutic breakthroughs, however, have been limited because of the lack of preclinical models recapitulating the molecular features and heterogeneity of the tumors. Recent publications on genetically engineered mouse models and development of patient-derived ACC xenografts in both nude mice and humanized mice now provide researchers with novel tools to explore therapeutic targets in the context of heterogeneity and tumor microenvironment in human ACC. SUMMARY: We review current in-vivo models of ACC and discuss potential therapeutic opportunities that have emerged from these studies.

4.
Cell Death Dis ; 11(3): 192, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32184394

RESUMO

Conditions of impaired adrenal function and tissue destruction, such as in Addison's disease, and treatment resistance of adrenocortical carcinoma (ACC) necessitate improved understanding of the pathophysiology of adrenal cell death. Due to relevant oxidative processes in the adrenal cortex, our study investigated the role of ferroptosis, an iron-dependent cell death mechanism and found high adrenocortical expression of glutathione peroxidase 4 (GPX4) and long-chain-fatty-acid CoA ligase 4 (ACSL4) genes, key factors in the initiation of ferroptosis. By applying MALDI mass spectrometry imaging to normal and neoplastic adrenocortical tissue, we detected high abundance of arachidonic and adrenic acid, two long chain polyunsaturated fatty acids which undergo peroxidation during ferroptosis. In three available adrenal cortex cell models (H295R, CU-ACC1 and CU-ACC-2) a high susceptibility to GPX4 inhibition with RSL3 was documented with EC50 values of 5.7 × 10-8, 8.1 × 10-7 and 2.1 × 10-8 M, respectively, while all non-steroidogenic cells were significantly less sensitive. Complete block of GPX4 activity by RSL3 led to ferroptosis which was completely reversed in adrenal cortex cells by inhibition of steroidogenesis with ketoconazole but not by blocking the final step of cortisol synthesis with metyrapone. Mitotane, the only approved drug for ACC did not induce ferroptosis, despite strong induction of lipid peroxidation in ACC cells. Together, this report is the first to demonstrate extraordinary sensitivity of adrenal cortex cells to ferroptosis dependent on their active steroid synthetic pathways. Mitotane does not induce this form of cell death in ACC cells.

5.
J Clin Endocrinol Metab ; 105(1)2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31513709

RESUMO

CONTEXT: Although the development of immune checkpoint inhibitors has transformed treatment strategies of several human malignancies, research models to study immunotherapy in adrenocortical carcinoma (ACC) are lacking. OBJECTIVE: To explore the effect of anti-PD1 immunotherapy on the alteration of the immune milieu in ACC in a newly generated preclinical model and correlate with the response of the matched patient. DESIGN, SETTING, AND INTERVENTION: To characterize the CU-ACC2-M2B patient-derived xenograft in a humanized mouse model, evaluate the effect of a PD-1 inhibitor therapy, and compare it with the CU-ACC2 patient with metastatic disease. RESULTS: Characterization of the CU-ACC2-humanized cord blood-BALB/c-Rag2nullIl2rγnullSirpaNOD model confirmed ACC origin and match with the original human tumor. Treatment of the mice with pembrolizumab demonstrated significant tumor growth inhibition (60%) compared with controls, which correlated with increased tumor infiltrating lymphocyte activity, with an increase of human CD8+ T cells (P < 0.05), HLA-DR+ T cells (P < 0.05) as well as Granzyme B+ CD8+ T cells (<0.001). In parallel, treatment of the CU-ACC2 patient, who had progressive disease, demonstrated a partial response with 79% to 100% reduction in the size of target lesions, and no new sites of metastasis. Pretreatment analysis of the patient's metastatic liver lesion demonstrated abundant intratumoral CD8+ T cells by immunohistochemistry. CONCLUSIONS: Our study reports the first humanized ACC patient-derived xenograft mouse model, which may be useful to define mechanisms and biomarkers of response and resistance to immune-based therapies, to ultimately provide more personalized care for patients with ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Modelos Animais de Doenças , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral/imunologia , Neoplasias do Córtex Suprarrenal/imunologia , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/imunologia , Carcinoma Adrenocortical/patologia , Animais , Antineoplásicos Imunológicos/farmacologia , Apoptose , Proliferação de Células , Feminino , Humanos , Imunoterapia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptor de Morte Celular Programada 1/imunologia , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Endocr Soc ; 3(12): 2295-2304, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31745526

RESUMO

Adrenocortical carcinoma (ACC) is a rare orphan disease with a dismal prognosis. Surgery remains the first-line treatment, but most patients eventually develop metastatic disease. Mitotane is often used with chemotherapy with modest success. Little information is available concerning the efficacy of immunotherapy in combination with mitotane. We conducted a retrospective review of our initial six patients with metastatic ACC, for whom mitotane alone or with chemotherapy failed, and who were subsequently treated with a combination of pembrolizumab and mitotane, between July 2016 and March 2019. Imaging was analyzed per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Two patients had a partial response and four patients had stable disease (8 to 19 months). One patient had grade 3 hepatitis and pembrolizumab was discontinued after 8 months. She died with disease progression 16 months after initiating pembrolizumab. One patient developed brain metastasis after 19 months of treatment and was transitioned to hospice. One patient had focal pneumonitis after 18 months of treatment, and pembrolizumab was discontinued. Three remaining patients continue pembrolizumab plus mitotane at the time of this writing. The current standard of care for ACC is a combination of etoposide, doxorubicin, cisplatin, and mitotane with an overall survival of 14.8 months. All six patients lived for at least 16 months after starting pembrolizumab added to mitotane therapy. The therapy appeared to be effective in both microsatellite instability-high and microsatellite stable tumors, suggesting some synergistic effect with mitotane. Combined immunotherapy and mitotane should be considered in future clinical trials in patients with ACC.

7.
J Clin Endocrinol Metab ; 104(10): 4660-4666, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31498871

RESUMO

This Position Statement has been endorsed by the International Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The International Society for Sexual Medicine, The International Society for the Study of Women's Sexual Health, The North American Menopause Society, The Federacion Latinoamericana de Sociedades de Climaterio y Menopausia, The Royal College of Obstetricians and Gynecologists, The International Society of Endocrinology, The Endocrine Society of Australia, and The Royal Australian and New Zealand College of Obstetricians and Gynecologists.

8.
J Sex Med ; 16(9): 1331-1337, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31488288

RESUMO

This Statement is being simultaneously published in the journals Climacteric, Maturitas, Journal of Sexual Medicine, and Journal of Clinical Endocrinology and Metabolism on behalf of the International Menopause Society, The European Menopause and Andropause Society, The International Society for Sexual Medicine, and The Endocrine Society, respectively. This Position Statement has been endorsed by the International Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The International Society for Sexual Medicine, The International Society for the Study of Women's Sexual Health, The North American Menopause Society, The Federacion Latinoamericana de Sociedades de Climaterio y Menopausia, The Royal College of Obstetricians and Gynaecologists, The International Society of Endocrinology, The Endocrine Society of Australia, and The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

11.
J Steroid Biochem Mol Biol ; 193: 105422, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31265901

RESUMO

The adrenal cortex governs fundamental metabolic processes though synthesis of glucocorticoid, mineralocorticoids and androgens. Studies in rodents have demonstrated that the cortex undergoes a self-renewal process and that capsular/subcapsular stem/progenitor cell pools differentiate towards functional steroidogenic cells supporting the dynamic centripetal streaming of adrenocortical cells throughout life. We previously demonstrated that the Notch atypical ligand Delta-like homologue 1 (DLK1)/preadipocyte factor 1 (PREF1) is expressed in subcapsular Sf1 and Shh-positive, CYP11B1-negative and CYP11B2-partially positive cortical progenitor cells in rat adrenals, and that secreted DLK1 can modulate GLI1 expression in H295R cells. Here we show that the human adrenal cortex remodels with age to generate clusters of relatively undifferentiated cells expressing DLK1. These clusters (named DLK1-expressing cell clusters or DCCs) increased with age in size and were found to be different entities to aldosterone-producing cell clusters, another well-characterized and age-dependent cluster structure. DLK1 was markedly overexpressed in adrenocortical carcinomas but not in aldosterone-producing adenomas. Thus, this data identifies a novel cell population in the human adrenal cortex and might suggest a yet-to be identified role of DLK1 in the pathogenesis of adrenocortical carcinoma in humans.


Assuntos
Córtex Suprarrenal/citologia , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Membrana/metabolismo , Córtex Suprarrenal/metabolismo , Aldosterona/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos
12.
Endocr Relat Cancer ; 26(10): 765-778, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325906

RESUMO

Adrenocortical carcinoma (ACC) is an aggressive orphan malignancy with less than 35% 5-year survival and 75% recurrence. Surgery remains the primary therapy and mitotane, an adrenolytic, is the only FDA-approved drug with wide-range toxicities and poor tolerability. There are no targeted agents available to date. For the last three decades, H295R cell line and its xenograft were the only available preclinical models. We recently developed two new ACC patient-derived xenograft mouse models and corresponding cell lines (CU-ACC1 and CU-ACC2) to advance research in the field. Here, we have utilized these novel models along with H295R cells to establish the mitotic PDZ-binding kinase (PBK) as a promising therapeutic target. PBK is overexpressed in ACC samples and correlates with poor survival. We show that PBK is regulated by FOXM1 and targeting PBK via shRNA decreased cell proliferation, clonogenicity and anchorage-independent growth in ACC cell lines. PBK silencing inhibited pAkt, pp38MAPK and pHistone H3 altering the cell cycle. Therapeutically, targeting PBK with the small-molecule inhibitor HITOPK032 phenocopied PBK-specific modulation of pAkt and pHistone H3, but also induced apoptosis via activation of JNK. Consistent with in vitro findings, treatment of CU-ACC1 PDXs with HITOPK032 significantly reduced tumor growth by 5-fold (P < 0.01). Treated tumor tissues demonstrated increased rates of apoptosis and JNK activation, with decreased pAkt and Histone H3 phosphorylation, consistent with effects observed in ACC cell lines. Together these studies elucidate the mechanism of PBK in ACC tumorigenesis and establish the potential therapeutic potential of HITOPK032 in ACC patients.

14.
Endocr Rev ; 40(2): 417-446, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30500887

RESUMO

The liver and the reproductive system interact in a multifaceted bidirectional fashion. Sex steroid signaling influences hepatic endobiotic and xenobiotic metabolism and contributes to the pathogenesis of functional and structural disorders of the liver. In turn, liver function affects the reproductive axis via modulating sex steroid metabolism and transport to tissues via sex hormone-binding globulin (SHBG). The liver senses the body's metabolic status and adapts its energy homeostasis in a sex-dependent fashion, a dimorphism signaled by the sex steroid milieu and possibly related to the metabolic costs of reproduction. Sex steroids impact the pathogenesis of nonalcoholic fatty liver disease, including development of hepatic steatosis, fibrosis, and carcinogenesis. Preclinical studies in male rodents demonstrate that androgens protect against hepatic steatosis and insulin resistance both via androgen receptor signaling and, following aromatization to estradiol, estrogen receptor signaling, through regulating genes involved in hepatic lipogenesis and glucose metabolism. In female rodents in contrast to males, androgens promote hepatic steatosis and dysglycemia, whereas estradiol is similarly protective against liver disease. In men, hepatic steatosis is associated with modest reductions in circulating testosterone, in part consequent to a reduction in circulating SHBG. Testosterone treatment has not been demonstrated to improve hepatic steatosis in randomized controlled clinical trials. Consistent with sex-dimorphic preclinical findings, androgens promote hepatic steatosis and dysglycemia in women, whereas endogenous estradiol appears protective in both men and women. In both sexes, androgens promote hepatic fibrosis and the development of hepatocellular carcinoma, whereas estradiol is protective.


Assuntos
Androgênios/metabolismo , Estradiol/metabolismo , Transtornos do Metabolismo de Glucose/metabolismo , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Caracteres Sexuais , Globulina de Ligação a Hormônio Sexual/metabolismo , Animais , Feminino , Humanos , Masculino
15.
Endocrine ; 62(2): 333-339, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29961198

RESUMO

PURPOSE: Disorders of water balance, particularly hyponatremia from altered antidiuretic hormone (ADH) secretion, are a common post-operative complication of transsphenoidal surgery (TSS). We present our results from implementation of a 2-week 1.5 liter/daily fluid restriction on readmission rates for hyponatremia. METHODS: A retrospective chart review was performed on 295 patients that underwent TSS for pituitary adenomas at the University of Colorado, between March 2014 and March 2017. Groups were divided into those before and after the implementation of a two-week, 1.5 liter daily fluid restriction and measurement of a serum sodium level 7 days (+/- 2 days) after discharge. A standard-of-care approach for variable degrees of hyponatremia was also utilized to guide hyponatremia management. Patient demographics, hospital course, post-operative complication rates, and rates of hospital admissions for hyponatremia were then evaluated. RESULTS: Readmissions for symptomatic hyponatremia within 30 days of TSS occurred in 9 of 118 (7.6%) of patients prior to fluid restriction implementation and in four of 169 (2.4%) of patients in the post-implementation, fluid-restricted group (p-value = 0.04): a 70% reduction in hospitalizations. The two groups were similarly matched for pituitary tumor sub-type, age and gender. None of these factors were predictive for hyponatremia. Importantly, the mild fluid restriction did not result in any hospital readmissions for hypernatremia. CONCLUSIONS: Mild fluid restriction (to 1.5 liters daily), in addition to a single post-operative serum sodium level, is an effective approach to preventing readmission for hyponatremia after TSS for pituitary adenomas.


Assuntos
Adenoma/cirurgia , Hiponatremia , Procedimentos Neurocirúrgicos/métodos , Readmissão do Paciente , Neoplasias Hipofisárias/cirurgia , Seio Esfenoidal/cirurgia , Adenoma/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hiponatremia/epidemiologia , Hiponatremia/etiologia , Hiponatremia/prevenção & controle , Hiponatremia/terapia , Síndrome de Secreção Inadequada de HAD/complicações , Síndrome de Secreção Inadequada de HAD/epidemiologia , Síndrome de Secreção Inadequada de HAD/prevenção & controle , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/efeitos adversos , Readmissão do Paciente/estatística & dados numéricos , Neoplasias Hipofisárias/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/terapia , Estudos Retrospectivos , Adulto Jovem
16.
Endocrinology ; 159(6): 2421-2434, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29726995

RESUMO

Prolactin-secreting adenomas, or prolactinomas, cause hypogonadism, osteoporosis, and infertility. Although dopamine agonists (DAs) are used clinically to treat prolactinoma and reduce prolactin secretion via cAMP inhibition, the precise mechanism by which DAs inhibit lactotrope proliferation has not been defined. In this study, we report that phosphatidylinositol 3-kinase (PI3K) signals through AKT and mTOR to drive proliferation of pituitary somatolactotrope GH4T2 cells. We demonstrate that the DA cabergoline reduces activity of the mTOR effector s6K and diminishes GH4T2 cell proliferation primarily via activation of the long isoform of the dopamine D2 receptor (D2R). Dysfunctional D2R-mediated signaling and/or downregulated D2R expression is thought be the primary mechanism of DA resistance, which is observed in 10% to 20% of prolactinoma tumors. Dopamine-mediated D2R activation results in ERK stimulation and PI3K inhibition, suggesting that these two pathways act in an inverse manner to maintain lactotrope homeostasis. In this study, we found that ERK1/2-mediated prolactin transcription is inhibited by PI3K/CDK4-driven cell cycle progression, emphasizing that the ERK and PI3K signaling pathways oppose one another in lactotrope cells under homeostatic conditions. Lastly, we show that both ERK1/2 and AKT are activated in prolactinoma, demonstrating that the balance of ERK and AKT is dysregulated in human prolactinoma. Our findings reveal a potential use for dual pharmacological inhibitors of ERK and AKT as an alternative treatment strategy for DA-resistant prolactinomas.


Assuntos
Dopamina/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Neoplasias Hipofisárias/metabolismo , Prolactinoma/metabolismo , Animais , Cabergolina/farmacologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Células HEK293 , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Sistema de Sinalização das MAP Quinases/genética , Fosfatidilinositol 3-Quinase/genética , Inibidores de Fosfoinositídeo-3 Quinase , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Prolactinoma/genética , Prolactinoma/patologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
17.
Endocrinology ; 159(7): 2532-2544, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29790920

RESUMO

Adrenocortical carcinoma (ACC) is an aggressive cancer with a 5-year survival rate <35%. Mortality remains high due to lack of targeted therapies. Using bioinformatic analyses, we identified maternal embryonic leucine zipper kinase (MELK) as 4.1-fold overexpressed in ACC compared with normal adrenal samples. High MELK expression in human tumors correlated with shorter survival and with increased expression of genes involved in cell division and growth. We investigated the functional effects of MELK inhibition using newly developed ACC cell lines with variable MELK expression, CU-ACC1 and CU-ACC2, compared with H295R cells. In vitro treatment with the MELK inhibitor, OTSSP167, resulted in a dose-dependent decrease in rates of cell proliferation, colony formation, and cell survival, with relative sensitivity of each ACC cell line based upon the level of MELK overexpression. To confirm a MELK-specific antitumorigenic effect, MELK was inhibited in H295R cells via multiple short hairpin RNAs. MELK silencing resulted in 1.9-fold decrease in proliferation, and 3- to 10-fold decrease in colony formation in soft agar and clonogenicity assays, respectively. In addition, although MELK silencing had no effect on survival in normoxia, exposure to a hypoxia resulted in a sixfold and eightfold increase in apoptosis as assessed by caspase-3 activation and TUNEL, respectively. Together these data suggest that MELK is a modulator of tumor cell growth and survival in a hypoxic microenvironment in adrenal cancer cells and support future investigation of its role as a therapeutic kinase target in patients with ACC.


Assuntos
Carcinoma Adrenocortical/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Carcinoma Adrenocortical/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Humanos , Immunoblotting , Imuno-Histoquímica , Lamina Tipo B/genética , Lamina Tipo B/metabolismo , Quinases Relacionadas a NIMA/genética , Quinases Relacionadas a NIMA/metabolismo , Naftiridinas/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
18.
Am J Physiol Endocrinol Metab ; 315(2): E316-E325, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29631362

RESUMO

Sex hormones appear to play a role in the regulation of hypothalamic-pituitary-adrenal (HPA) axis activity. The objective was to isolate the effects of estradiol (E2) on central activation of the HPA axis. We hypothesized that the HPA axis response to corticotropin-releasing hormone (CRH) under dexamethasone (Dex) suppression would be exaggerated in response to chronic ovarian hormone suppression and that physiologic E2 add-back would mitigate this response. Thirty premenopausal women underwent 20 wk of gonadotropin-releasing hormone agonist therapy (GnRHAG) and transdermal E2 (0.075 mg per day, GnRHAG + E2, n = 15) or placebo (PL) patch (GnRHAG + PL, n = 15). Women in the GnRHAG + PL and GnRHAG + E2 groups were of similar age (38 (SD 5) yr vs. 36 (SD 7) yr) and body mass index (27 (SD 6) kg/m2 vs. 27 (SD 6) kg/m2). Serum E2 changed differently between the groups ( P = 0.01); it decreased in response to GnRHAG + PL (77.9 ± 17.4 to 23.2 ± 2.6 pg/ml; P = 0.008) and did not change in response to GnRHAG + E2 (70.6 ± 12.4 to 105 ± 30.4 pg/ml; P = 0.36). The incremental area under the curve (AUCINC) responses to CRH were different between the groups for total cortisol ( P = 0.03) and cortisone ( P = 0.04) but not serum adrenocorticotropic hormone (ACTH) ( P = 0.28). When examining within-group changes, GnRHAG + PL did not alter the HPA axis response to Dex/CRH, but GnRHAG + E2 decreased the AUCINC for ACTH (AUCINC, 1,623 ± 257 to 1,211 ± 236 pg/ml·min, P = 0.004), cortisone (1,795 ± 367 to 1,090 ± 281 ng/ml·min, P = 0.009), and total cortisol (7,008 ± 1,387 to 3,893 ± 1,090 ng/ml·min, P = 0.02). Suppression of ovarian hormones by GnRHAG therapy for 20 wk did not exaggerate the HPA axis response to CRH, but physiologic E2 add-back reduced HPA axis activity compared with preintervention levels.


Assuntos
Hormônio Liberador da Corticotropina/farmacologia , Hormônio Liberador de Gonadotropina/agonistas , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Pré-Menopausa/fisiologia , Adiposidade/efeitos dos fármacos , Hormônio Adrenocorticotrópico/sangue , Adulto , Composição Corporal/efeitos dos fármacos , Cortisona/análise , Cortisona/metabolismo , Dexametasona/farmacologia , Método Duplo-Cego , Estradiol/farmacologia , Feminino , Humanos , Hidrocortisona/análise , Hidrocortisona/metabolismo , Pessoa de Meia-Idade
19.
Med Sci Sports Exerc ; 50(8): 1704-1709, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29509642

RESUMO

PURPOSE: This study aimed to determine the effects of 5 months of ovarian hormone suppression in premenopausal women on objectively measured physical activity (PA). METHODS: Participants (age, 35 ± 8 yr; body mass index, 27 ± 6 kg·m) received monthly intramuscular injections of gonadotropin-releasing hormone agonist (GnRHAG) therapy, which suppresses pituitary gonadotropins and results in suppression of ovarian sex hormones. Women were randomized to receive concurrent transdermal E2 (GnRHAG + E2; n = 30) or placebo (GnRHAG + PL, n = 31). PA was assessed for 1 wk before and during each month of the 5-month intervention using a hip-worn accelerometer (Actical, Mini Mitter Co., Inc., Bend, OR). Estimates of time spent in sedentary, light, and moderate-to-vigorous PA (MVPA) were derived using a previously published equation. Subsets of participants in each group were also randomized to a supervised progressive resistance exercise training program. RESULTS: Total MVPA tended toward being higher (P = 0.08) in the GnRHAG + E2 group at month 4. There were no significant effects of intervention or time in sedentary or light PA. In the subset of women who did not participate in structured exercise training for which Actical data were obtained (n = 16 in each group), total MVPA was higher at month 4 (P = 0.01). CONCLUSIONS: PA levels seem to be maintained at a higher level in women undergoing pharmacological suppression of ovarian function with E2 add-back when compared with women treated with placebo. These data provide proof-of-concept data that E2 contributes to the regulation of PA in humans. However, given the exploratory nature of this study, future confirmatory investigations will be necessary.


Assuntos
Estradiol/fisiologia , Exercício Físico/fisiologia , Ovário/fisiologia , Pré-Menopausa/fisiologia , Adulto , Método Duplo-Cego , Feminino , Hormônio Liberador de Gonadotropina/agonistas , Humanos , Pessoa de Meia-Idade , Ovário/efeitos dos fármacos , Estudo de Prova de Conceito , Treinamento de Resistência
20.
Endocr Relat Cancer ; 25(4): 437-451, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29371329

RESUMO

Adrenocortical cancer (ACC) is an orphan malignancy that results in heterogeneous clinical phenotypes and molecular genotypes. There are no curative treatments for this deadly cancer with 35% survival at five years. Our understanding of the underlying pathobiology and our ability to test novel therapeutic targets has been limited due to the lack of preclinical models. Here, we report the establishment of two new ACC cell lines and corresponding patient-derived xenograft (PDX) models. CU-ACC1 cell line and PDX were derived from a perinephric metastasis in a patient whose primary tumor secreted aldosterone. CU-ACC2 cell line and PDX were derived from a liver metastasis in a patient with Lynch syndrome. Short tandem repeat profiling confirmed consistent matches between human samples and models. Both exomic and RNA sequencing profiling were performed on the patient samples and the models, and hormonal secretion was evaluated in the new cell lines. RNA sequencing and immunohistochemistry confirmed the expression of adrenal cortex markers in the PDXs and human tumors. The new cell lines replicate two of the known genetic models of ACC. CU-ACC1 cells had a mutation in CTNNB1 and secreted cortisol but not aldosterone. CU-ACC2 cells had a TP53 mutation and loss of MSH2 consistent with the patient's known germline mutation causing Lynch syndrome. Both cell lines can be transfected and transduced with similar growth rates. These new preclinical models of ACC significantly advance the field by allowing investigation of underlying molecular mechanisms of ACC and the ability to test patient-specific therapeutic targets.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/metabolismo , Aldosterona/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Mutação em Linhagem Germinativa , Humanos
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