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Taija Saloniemi Päivi Järvensivu Pasi Koskimies Heli Jokela Tarja Lamminen Sadaf Ghaem-Maghami Roberto Dina Pauliina Damdimopoulou Sari Mäkelä Antti Perheentupa Harry Kujari Jan Brosens Matti Poutanen 《The American journal of pathology》2010,176(3):1443-1451
Local estrogen production plays a key role in proliferative endometrial disorders, such as endometrial hyperplasia and cancer. Hydroxysteroid (17β) dehydrogenase 1 (HSD17B1) is an enzyme that catalyzes with high efficiency the conversion of weakly active estrone into highly potent estradiol. Here we report that female transgenic mice expressing human HSD17B1 invariably develop endometrial hyperplasia in adulthood. These mice also fail to ovulate and have enhanced peripheral conversion of estrone into estradiol in a variety of target tissues, including the uterus. As in humans, endometrial hyperplasia in HSD17B1 transgenic female mice was reversible on ovulation induction, which triggers a rise in circulating progesterone levels, and in response to exogenous progestins. Strikingly, a treatment with an HSD17B1 inhibitor failed to restore ovulation yet completely reversed the hyperplastic morphology of epithelial cells in the glandular compartment, although less so in the luminal epithelium. The data indicate that human HSD17B1 expression enhances endometrial estrogen production, and consequently, estrogen-dependent proliferation. Therefore, HSD17B1 is a promising new therapeutic target in the management of estrogen-dependent endometrial diseases.Estrogen-dependent uterine disorders, such as endometriosis, endometrial hyperplasia, and cancer, are very prevalent during reproductive years. For example endometriosis affects up to 10% of women and is a major cause of pelvic pain and infertility.1,2 Endometrial carcinoma is the most common invasive cancer of the female genital tract and ranks as the fourth most common malignancy in women in Western Europe and in the United States.3–5 Estrogen-dependent endometrial carcinoma (endometrial carcinoma type I, hereafter referred to as endometrial carcinoma) generally arises from atypical endometrial hyperplasia, whereas hyperplasia without atypia is less likely to become malignant.5,6 Patients with typical hyperplasia are usually managed conservatively with progestins, but hysterectomy remains the treatment of choice for atypical hyperplasia and endometrial carcinoma.3,6 Obesity and anovulation, often associated with polycystic ovary syndrome, are major risk factors for endometrial hyperplasia during reproductive years, as is unopposed estrogen replacement therapy in postmenopausal women.7–10Hydroxysteroid (17β) dehydrogenases (HSD17Bs) catalyze the conversion of low active 17-ketosteroids and the highly active 17β-hydroxysteroids.11–13 Most of HSD17Bs belong to the ketosteroid reductase family of enzymes, which are also known as short-chain alcohol dehydrogenases/reductases.14 We have previously shown that human HSD17B1 catalyzes the reduction of estrone (E1), which has low biological activity, to highly potent estradiol (E2) in cultured cells and in vivo.15–18 Besides estrogens, androgens are also, albeit less efficient, substrates for human HSD17B1 in vivo.17,19 These studies are in line with the essential role of the enzyme in ovarian E2 biosynthesis. Notably, human HSD17B1 has a wider tissue-distribution than the murine ortholog, which is mainly expressed in the ovaries. We, thus, hypothesized that human HSD17B1 expression enhances estrogen action at target tissues by increasing the E2/E1-ratio, and providing increased concentration of highly active ligand for estrogen receptors (ESR1 and ESR2). In humans, HSD17B1 has been detected in various sex steroid-responsive tissues and linked to various estrogen-dependent diseases, such as breast cancer16,20,21 and endometriosis.2,22 However, HSD17B1 expression in cycling endometrium or in other endometrial disorders, like endometrial cancer, is still controversial with some studies reporting HSD17B1 expression and/or activity,2,4,23–29 whereas others found no evidence of expression at mRNA or protein level.30–32 The human endometrium also reportedly expresses several other HSD17Bs, including types 2, 4, 5, 7, and 12.4,26,33–36 Thus the availability of E2 at a tissue or cellular level is likely to be tightly regulated by the relative activities of various enzymes with opposing functions (activation or inactivation of estrogens). HSD17B2 in particular opposes the activity of HSD17B1, while the role of the other HSD17Bs in regulating local estrogen metabolism remains poorly understood.Because of its putative role in E2 biosynthesis in ovaries and peripheral target tissues, HSD17B1 is considered a promising drug target for estrogen-dependent diseases. Several preclinical studies indicate that HSD17B1 inhibitors are indeed capable of modulating estrogen responses in vitro and in vivo.16,18,37–39 In the present study, we report that expression of human HSD17B1 in a transgenic mouse model (HSD17B1TG mice)17 not only induces anovulation, but also estrogen-dependent endometrial hyperplasia. Moreover, we demonstrate that this endometrial phenotype can be reversed using novel HSD17B1 inhibitors. 相似文献
606.
Farooqi IS Volders K Stanhope R Heuschkel R White A Lank E Keogh J O'Rahilly S Creemers JW 《The Journal of clinical endocrinology and metabolism》2007,92(9):3369-3373
CONTEXT: Congenital deficiency of the neuroendocrine-specific enzyme prohormone convertase (PC) 1/3 leads to a syndrome characterized by obesity, small intestinal dysfunction, and dysregulation of glucose homeostasis in humans. To date, only two unrelated subjects with this disorder have been reported. Research DESIGN AND METHODS: We now report a third proband, a 6-yr-old boy, offspring of a consanguineous union of parents of North African origin, who was homozygous for a novel missense mutation Ser307Leu. We characterized the functional properties of the mutant PC1/3 and characterized the clinical phenotype of the patient. RESULTS: In vitro this mutation markedly impairs the catalytic activity of the convertase. However, in contrast to other previously described naturally occurring mutations, intracellular trafficking of this mutant enzyme appeared normal. The Ser307Leu mutant retained some autocatalytic activity, even though it was completely inactive on other substrates. As with the previous two patients, this child had obesity and persistent diarrhea, however, there was no history of reactive hypoglycemia. The patient showed markedly increased food intake at an ad libitum test meal, confirming that hyperphagia makes a major contribution to the obesity seen in this syndrome. CONCLUSION: This case extends the clinical and molecular spectrum of human congenital PC1/3 deficiency. 相似文献
607.
ObjectivesTo compare ion exchange and boronate affinity chromatography for HbA1c estimation in patients with type I and II diabetes having hemoglobin D.Design and methodsSystems based on ion exchange and boronate affinity chromatography were evaluated and compared for their performance for HbA1c estimation in patients with homozygous and heterozygous D disease.ResultsBoronate affinity chromatography shows least interference by HbD in heterozygous as well as homozygous diabetic patients for HbA1c estimation.ConclusionsThe use of boronate affinity chromatography was found to be helpful in evaluating glycemic control in diabetic subjects with HbD. 相似文献
608.
Donovan KA Taliaferro LA Brock CW Bazargan S 《Journal of pain and symptom management》2008,36(2):167-172
Few studies have evaluated sex differences in the adequacy of pain management in cancer. Existing studies have been marked by methodological limitations and results have been mixed. The present study sought to determine whether sex was associated with pain severity and pain management in cancer patients newly referred by their primary oncology team to a multidisciplinary cancer pain clinic. One hundred thirty-one cancer patients completed the Brief Pain Inventory-Short Form and medical chart review was conducted to obtain patients' clinical characteristics and pain treatment data. There were no differences between males and females in ratings of worst pain in the last week. Females were significantly less likely to have been prescribed high potency opioids by their primary oncology team and significantly more likely to report inadequate pain management as measured by Pain Management Index scores. These results suggest a sex bias in the treatment of cancer pain and support the routine examination of the effect of sex in cancer pain research. 相似文献
609.
INTRODUCTION: Hypervolemia and hyponatremia are common features in heart failure and have been associated with increased morbidity and mortality. Stimulation of arginine vasopressin (AVP) plays an important role in the development of both hypervolemia and hyponatremia. Lixivaptan is a selective vasopressin type 2 (V(2)) receptor antagonist that has been demonstrated to have the ability to induce aquaresis, the electrolyte sparing excretion of water, resulting in fluid removal as well as correction of hyponatremia. AREAS COVERED: This article describes the prevalence, pathophysiology and current treatment limitations of hyponatremia, highlights the importance of arginine vasopressin and the potential role of arginine vasopressin antagonists and reviews all available literature on lixivaptan, a selective V(2) receptor antagonist. EXPERT OPINION: The available experience of lixivaptan in heart failure, although limited, is encouraging. Its aquaretic effect provides the basis for its use to correct hypervolemia and hyponatremia in patients with heart failure, and the absence of neurhormonal stimulation provides positive signal for the exploration of its potential in improving outcomes. 相似文献
610.
Due to the molecular complexity of cancer, combination therapy is becoming increasingly important for better long-term prognosis with fewer side effects. To further increase the therapeutic effects, advanced drug delivery systems (DDSs), capable of simultaneously delivering multiple drugs to the site of action with specific time-programmed release profiles, are important requirements. Nanocarriers for the simultaneous co-delivery of multiple chemical drugs in combination therapy have been extensively reviewed. Here we focus on the nanotechnology enabled DDSs for the simultaneous co-delivery of therapeutic genes and chemical drugs for cancer treatment. The opportunities for this combination strategy and their challenges will be discussed. 相似文献