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  1. Article ; Online: Development of the Pituitary Gland.

    Alatzoglou, Kyriaki S / Gregory, Louise C / Dattani, Mehul T

    Comprehensive Physiology

    2020  Volume 10, Issue 2, Page(s) 389–413

    Abstract: The development of the anterior pituitary gland occurs in distinct sequential developmental steps, leading to the formation of a complex organ containing five different cell types secreting six different hormones. During this process, the temporal and ... ...

    Abstract The development of the anterior pituitary gland occurs in distinct sequential developmental steps, leading to the formation of a complex organ containing five different cell types secreting six different hormones. During this process, the temporal and spatial expression of a cascade of signaling molecules and transcription factors plays a crucial role in organ commitment, cell proliferation, patterning, and terminal differentiation. The morphogenesis of the gland and the emergence of distinct cell types from a common primordium are governed by complex regulatory networks involving transcription factors and signaling molecules that may be either intrinsic to the developing pituitary or extrinsic, originating from the ventral diencephalon, the oral ectoderm, and the surrounding mesenchyme. Endocrine cells of the pituitary gland are organized into structural and functional networks that contribute to the coordinated response of endocrine cells to stimuli; these cellular networks are formed during embryonic development and are maintained or may be modified in adulthood, contributing to the plasticity of the gland. Abnormalities in any of the steps of pituitary development may lead to congenital hypopituitarism that includes a spectrum of disorders from isolated to combined hormone deficiencies including syndromic disorders such as septo-optic dysplasia. Over the past decade, the acceleration of next-generation sequencing has allowed for rapid analysis of the patient genome to identify novel mutations and novel candidate genes associated with hypothalmo-pituitary development. Subsequent functional analysis using patient fibroblast cells, and the generation of stem cells derived from patient cells, is fast replacing the need for animal models while providing a more physiologically relevant characterization of novel mutations. Furthermore, CRISPR-Cas9 as the method for gene editing is replacing previous laborious and time-consuming gene editing methods that were commonly used, thus yielding knockout cell lines in a fraction of the time. © 2020 American Physiological Society. Compr Physiol 10:389-413, 2020.
    MeSH term(s) Animals ; Humans ; Morphogenesis ; Pituitary Diseases/genetics ; Pituitary Diseases/metabolism ; Pituitary Diseases/pathology ; Pituitary Gland/cytology ; Pituitary Gland/embryology ; Pituitary Gland/growth & development ; Pituitary Gland/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism
    Chemical Substances Transcription Factors
    Language English
    Publishing date 2020-03-12
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2040-4603
    ISSN (online) 2040-4603
    DOI 10.1002/cphy.c150043
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  2. Article: Autosomal Dominant Growth Hormone Deficiency (Type II).

    Alatzoglou, Kyriaki S / Kular, Dalvir / Dattani, Mehul T

    Pediatric endocrinology reviews : PER

    2015  Volume 12, Issue 4, Page(s) 347–355

    Abstract: Isolated growth hormone deficiency (IGHD) is the commonest pituitary hormone deficiency resulting from congenital or acquired causes, although for most patients its etiology remains unknown. Among the known factors, heterozygous mutations in the growth ... ...

    Abstract Isolated growth hormone deficiency (IGHD) is the commonest pituitary hormone deficiency resulting from congenital or acquired causes, although for most patients its etiology remains unknown. Among the known factors, heterozygous mutations in the growth hormone gene (GH1) lead to the autosomal dominant form of GHD, also known as type II GHD. In many cohorts this is the commonest form of congenital isolated GHD and is mainly caused by mutations that affect the correct splicing of GH-1. These mutations cause skipping of the third exon and lead to the production of a 17.5-kDa GH isoform that exerts a dominant negative effect on the secretion of the wild type GH. The identification of these mutations has clinical implications for the management of patients, as there is a well-documented correlation between the severity of the phenotype and the increased expression of the 17.5-kDa isoform. Patients with type II GHD have a variable height deficit and severity of GHD and may develop additional pituitary hormone defiencies over time, including ACTH, TSH and gonadotropin deficiencies. Therefore, their lifelong follow-up is recommended. Detailed studies on the effect of heterozygous GH1 mutations on the trafficking, secretion and action of growth hormone can elucidate their mechanism on a cellular level and may influence future treatment options for GHD type II.
    MeSH term(s) Body Height ; Chromosomes, Human, Pair 17 ; Dwarfism, Pituitary/genetics ; Dwarfism, Pituitary/physiopathology ; Dwarfism, Pituitary/therapy ; Genetic Therapy ; Heterozygote ; Humans ; Mutation ; Mutation, Missense ; Phenotype ; RNA Splicing/genetics
    Language English
    Publishing date 2015-06
    Publishing country Israel
    Document type Journal Article ; Review
    ZDB-ID 2434390-0
    ISSN 1565-4753
    ISSN 1565-4753
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  3. Article ; Online: Phenotype-genotype correlations in congenital isolated growth hormone deficiency (IGHD).

    Alatzoglou, Kyriaki S / Dattani, Mehul T

    Indian journal of pediatrics

    2011  Volume 79, Issue 1, Page(s) 99–106

    Abstract: Isolated growth hormone deficiency (IGHD) may be congenital, often due to genetic mutations, or acquired as a result of other factors such as cranial irradiation. The commonest genes implicated in its genetic etiology are those encoding growth hormone ( ... ...

    Abstract Isolated growth hormone deficiency (IGHD) may be congenital, often due to genetic mutations, or acquired as a result of other factors such as cranial irradiation. The commonest genes implicated in its genetic etiology are those encoding growth hormone (GH1) and the receptor for GH-releasing hormone (GHRHR). Rarely, IGHD may be caused by mutations in transcription factors (HESX1, SOX3, OTX2) or be the first presentation before the development of other pituitary hormone deficiencies. IGHD has been classified in four genetic forms (type IA, IB, II and III). Despite the increasing number of genes implicated in the etiology of IGHD, mutations in known genes account only for a small percentage of cases; therefore, other as yet unidentified factors may be implicated in its etiology. Although there is no strict genotype/phenotype correlation in patients with IGHD, there are some emerging patterns that may guide us towards a genetic diagnosis of the condition. There is increasing understanding that the phenotype of patients with IGHD is highly variable and sometimes even evolving, dictating the need for long term follow-up in these cases.
    MeSH term(s) Dwarfism, Pituitary/genetics ; Genetic Association Studies ; Human Growth Hormone/deficiency ; Human Growth Hormone/genetics ; Humans ; Mutation ; Receptors, Neuropeptide/genetics ; Receptors, Pituitary Hormone-Regulating Hormone/genetics
    Chemical Substances Receptors, Neuropeptide ; Receptors, Pituitary Hormone-Regulating Hormone ; somatocrinin receptor ; Human Growth Hormone (12629-01-5)
    Language English
    Publishing date 2011-12-03
    Publishing country India
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 218231-2
    ISSN 0973-7693 ; 0019-5456
    ISSN (online) 0973-7693
    ISSN 0019-5456
    DOI 10.1007/s12098-011-0614-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Genetic causes and treatment of isolated growth hormone deficiency-an update.

    Alatzoglou, Kyriaki S / Dattani, Mehul T

    Nature reviews. Endocrinology

    2010  Volume 6, Issue 10, Page(s) 562–576

    Abstract: Isolated growth hormone deficiency is the most common pituitary hormone deficiency and can result from congenital or acquired causes, although the majority of cases are idiopathic with no identifiable etiology. Known genes involved in the genetic ... ...

    Abstract Isolated growth hormone deficiency is the most common pituitary hormone deficiency and can result from congenital or acquired causes, although the majority of cases are idiopathic with no identifiable etiology. Known genes involved in the genetic etiology of isolated growth hormone deficiency include those that encode growth hormone (GH1), growth-hormone-releasing hormone receptor (GHRHR) and transcription factor SOX3. However, mutations are identified in a relatively small percentage of patients, which suggests that other, yet unidentified, genetic factors are involved. Among the known factors, heterozygous mutations in GH1 remain the most frequent cause of isolated growth hormone deficiency. The identification of mutations has clinical implications for the management of patients with this condition, as individuals with heterozygous GH1 mutations vary in phenotype and can, in some cases, develop additional pituitary hormone deficiencies. Lifelong follow-up of these patients is, therefore, recommended. Further studies in the genetic etiology of isolated growth hormone deficiency will help to elucidate mechanisms implicated in the control of growth and may influence future treatment options. Advances in pharmacogenomics will also optimize the treatment of isolated growth hormone deficiency and other conditions associated with short stature, for which recombinant human growth hormone is a licensed therapy.
    MeSH term(s) Dwarfism, Pituitary/genetics ; Human Growth Hormone/genetics ; Humans ; Mutation ; Receptors, Neuropeptide/genetics ; Receptors, Pituitary Hormone-Regulating Hormone/genetics
    Chemical Substances Receptors, Neuropeptide ; Receptors, Pituitary Hormone-Regulating Hormone ; Human Growth Hormone (12629-01-5) ; somatotropin releasing hormone receptor (F8L0ODC9D7)
    Language English
    Publishing date 2010-09-13
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2489381-X
    ISSN 1759-5037 ; 1759-5029
    ISSN (online) 1759-5037
    ISSN 1759-5029
    DOI 10.1038/nrendo.2010.147
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  5. Article ; Online: Recent advances in central congenital hypothyroidism.

    Schoenmakers, Nadia / Alatzoglou, Kyriaki S / Chatterjee, V Krishna / Dattani, Mehul T

    The Journal of endocrinology

    2015  Volume 227, Issue 3, Page(s) R51–71

    Abstract: Central congenital hypothyroidism (CCH) may occur in isolation, or more frequently in combination with additional pituitary hormone deficits with or without associated extrapituitary abnormalities. Although uncommon, it may be more prevalent than ... ...

    Abstract Central congenital hypothyroidism (CCH) may occur in isolation, or more frequently in combination with additional pituitary hormone deficits with or without associated extrapituitary abnormalities. Although uncommon, it may be more prevalent than previously thought, affecting up to 1:16 000 neonates in the Netherlands. Since TSH is not elevated, CCH will evade diagnosis in primary, TSH-based, CH screening programs and delayed detection may result in neurodevelopmental delay due to untreated neonatal hypothyroidism. Alternatively, coexisting growth hormones or ACTH deficiency may pose additional risks, such as life threatening hypoglycaemia. Genetic ascertainment is possible in a minority of cases and reveals mutations in genes controlling the TSH biosynthetic pathway (TSHB, TRHR, IGSF1) in isolated TSH deficiency, or early (HESX1, LHX3, LHX4, SOX3, OTX2) or late (PROP1, POU1F1) pituitary transcription factors in combined hormone deficits. Since TSH cannot be used as an indicator of euthyroidism, adequacy of treatment can be difficult to monitor due to a paucity of alternative biomarkers. This review will summarize the normal physiology of pituitary development and the hypothalamic-pituitary-thyroid axis, then describe known genetic causes of isolated central hypothyroidism and combined pituitary hormone deficits associated with TSH deficiency. Difficulties in diagnosis and management of these conditions will then be discussed.
    MeSH term(s) Congenital Hypothyroidism/diagnosis ; Congenital Hypothyroidism/etiology ; Congenital Hypothyroidism/physiopathology ; Humans ; Infant, Newborn ; Pituitary Gland/physiopathology ; Pituitary Hormones/physiology
    Chemical Substances Pituitary Hormones
    Language English
    Publishing date 2015-09-28
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 3028-4
    ISSN 1479-6805 ; 0022-0795
    ISSN (online) 1479-6805
    ISSN 0022-0795
    DOI 10.1530/JOE-15-0341
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  6. Article ; Online: Genetic forms of hypopituitarism and their manifestation in the neonatal period.

    Alatzoglou, Kyriaki S / Dattani, Mehul T

    Early human development

    2009  Volume 85, Issue 11, Page(s) 705–712

    Abstract: The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis. The development of the pituitary gland depends on the sequential temporal and spatial expression of transcription factors and signalling molecules. Naturally ... ...

    Abstract The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis. The development of the pituitary gland depends on the sequential temporal and spatial expression of transcription factors and signalling molecules. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of congenital hypopituitarism. These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, PITX1, PITX2, OTX2, SOX2 and SOX3. Mutations in any of the genes involved in pituitary development may result in congenital hypopituitarism, which manifests as the deficiency in one or more pituitary hormones. The phenotype can be highly variable and may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia (SOD) and holoprosencephaly. Neonates with congenital hypopituitarism may present with non-specific symptoms, with or without associated developmental defects such as ocular, midline and genital abnormalities. Alternatively, they may be initially asymptomatic but at risk of developing pituitary hormone deficiencies over time. The overall incidence of mutations in known transcription factors in patients with hypopituitarism is low, indicating that many genes remain to be identified. Their characterization will further elucidate the pathogenesis of this complex condition and will shed light on normal pituitary development.
    MeSH term(s) Genes, Developmental/physiology ; Genetic Diseases, Inborn/complications ; Genetic Diseases, Inborn/genetics ; Humans ; Hypopituitarism/complications ; Hypopituitarism/congenital ; Hypopituitarism/diagnosis ; Hypopituitarism/genetics ; Infant, Newborn ; Models, Biological ; Neonatal Screening ; Pituitary Gland/embryology ; Pituitary Gland/growth & development ; Pituitary Hormones/deficiency ; Syndrome
    Chemical Substances Pituitary Hormones
    Language English
    Publishing date 2009-11
    Publishing country Ireland
    Document type Journal Article ; Review
    ZDB-ID 752532-1
    ISSN 1872-6232 ; 0378-3782
    ISSN (online) 1872-6232
    ISSN 0378-3782
    DOI 10.1016/j.earlhumdev.2009.08.057
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  7. Article ; Online: Isolated growth hormone deficiency (GHD) in childhood and adolescence: recent advances.

    Alatzoglou, Kyriaki S / Webb, Emma Alice / Le Tissier, Paul / Dattani, Mehul T

    Endocrine reviews

    2014  Volume 35, Issue 3, Page(s) 376–432

    Abstract: The diagnosis of GH deficiency (GHD) in childhood is a multistep process involving clinical history, examination with detailed auxology, biochemical testing, and pituitary imaging, with an increasing contribution from genetics in patients with congenital ...

    Abstract The diagnosis of GH deficiency (GHD) in childhood is a multistep process involving clinical history, examination with detailed auxology, biochemical testing, and pituitary imaging, with an increasing contribution from genetics in patients with congenital GHD. Our increasing understanding of the factors involved in the development of somatotropes and the dynamic function of the somatotrope network may explain, at least in part, the development and progression of childhood GHD in different age groups. With respect to the genetic etiology of isolated GHD (IGHD), mutations in known genes such as those encoding GH (GH1), GHRH receptor (GHRHR), or transcription factors involved in pituitary development, are identified in a relatively small percentage of patients suggesting the involvement of other, yet unidentified, factors. Genome-wide association studies point toward an increasing number of genes involved in the control of growth, but their role in the etiology of IGHD remains unknown. Despite the many years of research in the area of GHD, there are still controversies on the etiology, diagnosis, and management of IGHD in children. Recent data suggest that childhood IGHD may have a wider impact on the health and neurodevelopment of children, but it is yet unknown to what extent treatment with recombinant human GH can reverse this effect. Finally, the safety of recombinant human GH is currently the subject of much debate and research, and it is clear that long-term controlled studies are needed to clarify the consequences of childhood IGHD and the long-term safety of its treatment.
    MeSH term(s) Adolescent ; Animals ; Child ; Dwarfism, Pituitary/diagnosis ; Dwarfism, Pituitary/drug therapy ; Dwarfism, Pituitary/etiology ; Dwarfism, Pituitary/genetics ; Human Growth Hormone/adverse effects ; Human Growth Hormone/genetics ; Human Growth Hormone/pharmacology ; Humans
    Chemical Substances Human Growth Hormone (12629-01-5)
    Language English
    Publishing date 2014-06
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 603096-8
    ISSN 1945-7189 ; 0163-769X
    ISSN (online) 1945-7189
    ISSN 0163-769X
    DOI 10.1210/er.2013-1067
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  8. Article ; Online: Septo-optic dysplasia and other midline defects: the role of transcription factors: HESX1 and beyond.

    McCabe, Mark James / Alatzoglou, Kyriaki S / Dattani, Mehul T

    Best practice & research. Clinical endocrinology & metabolism

    2011  Volume 25, Issue 1, Page(s) 115–124

    Abstract: Septo-optic dysplasia (SOD) is a highly heterogeneous condition comprising variable phenotypes including midline and forebrain abnormalities, optic nerve and pituitary hypoplasia. Most instances of SOD are sporadic and several aetiologies including drug ... ...

    Abstract Septo-optic dysplasia (SOD) is a highly heterogeneous condition comprising variable phenotypes including midline and forebrain abnormalities, optic nerve and pituitary hypoplasia. Most instances of SOD are sporadic and several aetiologies including drug and alcohol abuse have been suggested to account for the pathogenesis of the condition. However, a number of familial cases have been described with an increasing number of mutations in developmental transcription factors including HESX1, SOX2, SOX3 and OTX2 being implicated in its aetiology. These factors are essential for normal forebrain/pituitary development, and disruptions to these genes could account for the features observed in SOD and other midline disorders. The variable phenotypes observed within the condition are most likely due to the varying contributions of genetic and environmental factors. This review will discuss the current knowledge about SOD. Further study of these and other novel factors may shed light on the complex aetiology of this condition.
    MeSH term(s) Animals ; Environmental Exposure ; Female ; Homeodomain Proteins/genetics ; Humans ; Male ; Mice ; Otx Transcription Factors/genetics ; Phenotype ; Pituitary Gland/abnormalities ; Pituitary Gland/embryology ; Prosencephalon/embryology ; SOXB1 Transcription Factors/genetics ; Septo-Optic Dysplasia/genetics ; Septo-Optic Dysplasia/pathology
    Chemical Substances HESX1 protein, human ; Homeodomain Proteins ; OTX2 protein, human ; Otx Transcription Factors ; SOX2 protein, human ; SOX3 protein, human ; SOXB1 Transcription Factors
    Language English
    Publishing date 2011-02
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 2052339-7
    ISSN 1878-1594 ; 1532-1908 ; 1521-690X
    ISSN (online) 1878-1594 ; 1532-1908
    ISSN 1521-690X
    DOI 10.1016/j.beem.2010.06.008
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  9. Article ; Online: The role of SOX proteins in normal pituitary development.

    Alatzoglou, Kyriaki S / Kelberman, Daniel / Dattani, Mehul T

    The Journal of endocrinology

    2008  Volume 200, Issue 3, Page(s) 245–258

    Abstract: Pituitary development is a complex process that depends on the co-ordinated spatial and temporal expression of transcription factors and signalling molecules that culminates in the formation of a complex organ that secretes six hormones from five ... ...

    Abstract Pituitary development is a complex process that depends on the co-ordinated spatial and temporal expression of transcription factors and signalling molecules that culminates in the formation of a complex organ that secretes six hormones from five different cell types. Given the fact that all distinct hormone producing cells arise from a common ectodermal primordium, the patterning, architecture and plasticity of the gland is impressive. Among the transcription factors involved in the early steps of pituitary organogenesis are SOX2 and SOX3, members of the SOX family that are emerging as key players in many developmental processes. Studies in vitro and in vivo in transgenic animal models have helped to elucidate their expression patterns and roles in the developing hypothalamo-pituitary region. It has been demonstrated that they may be involved in pituitary development either directly, through shaping of Rathke's pouch, or indirectly affecting signalling from the diencephalon. Their role has been further underlined by the pleiotropic effects of their mutations in humans that range from isolated hormone deficiencies to panhypopituitarism and developmental abnormalities affecting many organ systems. However, the exact mechanism of action of SOX proteins, their downstream targets and their interplay within the extensive network that regulates pituitary development is still the subject of a growing number of studies. The elucidation of their role is crucial for the understanding of a number of processes that range from developmental mechanisms to disease phenotypes and tumorigenesis.
    MeSH term(s) Animals ; Gene Expression Regulation, Developmental/physiology ; Humans ; Mice ; Pituitary Gland/growth & development ; SOX Transcription Factors/genetics ; SOX Transcription Factors/metabolism
    Chemical Substances SOX Transcription Factors
    Language English
    Publishing date 2008-12-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 3028-4
    ISSN 1479-6805 ; 0022-0795
    ISSN (online) 1479-6805
    ISSN 0022-0795
    DOI 10.1677/JOE-08-0447
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  10. Article ; Online: Two cases of myomectomy complicated by intravascular hemolysis and renal failure: disseminated intravascular coagulation or hemolytic uremic syndrome?

    Tsimpanakos, Ioannis / Connolly, John / Alatzoglou, Kyriaki S / Rowan, Camilla / Magos, Adam

    Fertility and sterility

    2010  Volume 93, Issue 6, Page(s) 2075.e11–5

    Abstract: ... Minimally Invasive Therapy Unit, University Department of Obstetrics and Gynecology.: Patient(s): Two ... premenopausal patients with uterine fibroids.: Intervention(s): Both patients underwent otherwise ... ovarian vessels being used to control intraoperative bleeding.: Main outcome measure(s): Renal function ...

    Abstract Objective: To present two cases of myomectomy complicated by intravascular hemolysis leading to acute renal failure and discuss the differential diagnosis and possible mechanism.
    Design: Case report.
    Setting: Minimally Invasive Therapy Unit, University Department of Obstetrics and Gynecology.
    Patient(s): Two premenopausal patients with uterine fibroids.
    Intervention(s): Both patients underwent otherwise uncomplicated myomectomies, one by laparotomy and one by laparoscopy, with tourniquets around the uterine and ovarian vessels being used to control intraoperative bleeding.
    Main outcome measure(s): Renal function in the postoperative period.
    Result(s): Both patients developed a very rare complication after surgery of severe thrombocytopenia with microangiopathic hemolytic anemia leading to acute renal failure. One patient made a full recovery within weeks but the other still has reduced renal function almost 2 years after the surgery. The differential diagnosis consisted of disseminated intravascular coagulation or hemolytic uremic syndrome.
    Conclusion(s): The etiology of thrombotic microangiopathy in these patients was unclear, but disruption and manipulation of fibroids during surgery may have led to the dissemination of pro-coagulant tissue factor containing particles leading to disseminated intravascular coagulation or hemolytic uremic syndrome, perhaps aggravated by utero-ovarian ischemia caused by the tourniquets.
    MeSH term(s) Adult ; Diagnosis, Differential ; Disseminated Intravascular Coagulation/complications ; Disseminated Intravascular Coagulation/diagnosis ; Female ; Gynecologic Surgical Procedures/adverse effects ; Hemolysis/physiology ; Hemolytic-Uremic Syndrome/complications ; Hemolytic-Uremic Syndrome/diagnosis ; Humans ; Leiomyoma/surgery ; Middle Aged ; Postoperative Complications/diagnosis ; Postoperative Complications/etiology ; Renal Insufficiency/complications ; Renal Insufficiency/diagnosis ; Uterine Neoplasms/surgery
    Language English
    Publishing date 2010-04
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 80133-1
    ISSN 1556-5653 ; 0015-0282
    ISSN (online) 1556-5653
    ISSN 0015-0282
    DOI 10.1016/j.fertnstert.2009.11.023
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