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Cesare Carani - One of the best experts on this subject based on the ideXlab platform.
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complete Aromatase Deficiency in four adult men detection of a novel mutation and two known mutations in the cyp19a1 gene
The 95th Annual Meeting of the Endocrine Society ENDO2013, 2013Co-Authors: Elisa Pignatti, Cesare Carani, Manuela Simoni, Kursad Unluhizarci, Ermine Kartal, Kamel Ajlouni, Nahla Khawaja, Marco Marino, Eleonora Vighi, Vincenzo RochiraAbstract:1Department of Biomedical, Metabolic and Neural Sciences, University of Modena & Reggio Emilia, Modena Italy; 2Integrated Department of Medicine, Endocrinology and Metabolism, Geriatrics, Azienda USL of Modena, Italy; 3Department of Endocrinology, Erciyes University Medical School, Kayseri, Turkey, 4Ege University, Department of Endocrinology and Metabolisim Disease, Ýzmir, Turkey, 5Molecular Genetics Laboratory, National Center for Diabetes, Endocrinology and Genetics (NCDEG), Amman, Jordan. COMPLETE Aromatase Deficiency IN FOUR ADULT MEN: DETECTION OF A NOVEL MUTATION AND TWO KNOWN MUTATIONS IN THE CYP19A1 GENE P640
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tall stature without growth hormone four male patients with Aromatase Deficiency
The Journal of Clinical Endocrinology and Metabolism, 2010Co-Authors: Vincenzo Rochira, Cesare Carani, Laura Maffei, Lucia Zirilli, Valeria Premrou, Claudio Aranda, Matteo Baldi, Ezio Ghigo, Gianluca Aimaretti, Fabio LanfrancoAbstract:Context: From preliminary observations, GH-IGF-I seems to be compromised in men with Aromatase Deficiency. The GH Deficiency (GHD) coexists paradoxically with tall stature, raising the question whether or not a true GHD is part of this rare syndrome. Objective: To evaluate the GH secretion in Aromatase-deficient men, their GH response to the GHRH plus arginine (GHRH-ARG) test was compared with that of normal subjects. The effect of estrogen replacement treatment on the GH-IGF-I axis in Aromatase-deficient men was evaluated before and during therapy. Design and Setting: A case-control study was conducted. Patients: Four adult men with Aromatase Deficiency were compared with 12 normal subjects. Main Outcome Measures: We measured the GH response to GHRH-ARG in Aromatase-deficient men (at baseline and during estrogen treatment) and in normal subjects. Basal serum IGF-I was measured in both patients and controls. Results: The response of GH to GHRH-ARG was severely impaired in men with Aromatase Deficiency and...
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the effects of long term raloxifene and estradiol treatments on bone in a patient with congenital Aromatase Deficiency
Bone, 2009Co-Authors: Lucia Zirilli, Cesare Carani, Laura Maffei, Pj Meunier, P Chavassieux, Vincenzo RochiraAbstract:Abstract Introduction In adult Aromatase-deficient men, estrogen treatment has always resulted in a rapid skeletal maturation with epiphyseal closure and improved BMD. Raloxifene is a SERM with proven estrogen agonist action on bone that leads to an improvement in BMD and a reduction in bone turnover. The present study reports the effects of raloxifene and transdermal estradiol treatment, respectively, on epiphyseal closure and BMD in an Aromatase-deficient man, over a 24-month follow-up, with the aim of obtaining further insight into the role of estrogens in the male skeletal homeostasis. Materials and methods A 25-year-old Caucasian man with Aromatase Deficiency, a bone age of 15.3 years, unfused epiphyses and an impaired BMD was initially administered raloxifene (60 mg/day per os) for 12 months, while transdermal estradiol (25 μg twice weekly) was administered for the subsequent 12 months. During the follow-up, the effects of the two treatments on epiphyseal closure, BMD and bone turnover markers were investigated. An iliac crest bone biopsy was performed only before and after the raloxifene treatment, but it was not repeated after transdermal estradiol treatment. Results No changes in bone age were observed after raloxifene therapy, whereas a complete epiphyseal closure was achieved with transdermal estradiol treatment. Compared with baseline values, raloxifene treatment led to improved BMD both at the ultradistal forearm and 33% radius; the transdermal estradiol treatment resulted in a further slight increase in BMD at the 33% radius, but not at the ultradistal forearm. The baseline bone biopsy showed elevated bone remodelling in trabecular bone, while the second biopsy following raloxifene treatment revealed a decrease in remodelling. Discussion This study shows that the management of Aromatase Deficiency in the male cannot consider raloxifene as a first choice treatment, but should be still based on estrogen replacement treatment since in this patient the completion of bone maturation has only been obtained once estradiol substitution was performed. The present case also demonstrates that raloxifene is able to improve BMD in Aromatase-deficient men.
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Aromatase Deficiency in men a clinical perspective
Nature Reviews Endocrinology, 2009Co-Authors: Vincenzo Rochira, Cesare CaraniAbstract:Human Aromatase Deficiency is a very rare syndrome characterized by congenital estrogen deprivation that is caused by loss-of-function mutations in CYP19A1, which encodes Aromatase. Here, we review the presentation, diagnosis and treatment of Aromatase Deficiency in men to provide useful advice for clinical management of the condition. At presentation, all men with Aromatase Deficiency have tall stature, delayed bone maturation, osteopenia or osteoporosis and eunuchoid skeletal proportions. Diagnosis of the condition is supported by the presence of unfused epiphyses and undetectable serum estradiol levels; the condition can be further substantiated by genetic sequencing of CYP19A1. Transdermal estradiol treatment at a daily dose of about 25 microg might be adequate for lifelong replacement therapy. BMD and levels of serum estradiol, luteinizing hormone and testosterone should be monitored carefully and considered powerful biochemical markers of adequate estrogen substitution in clinical practice. Early diagnosis is important to initiate estrogen therapy as soon after puberty as possible to avoid the skeletal complications that are associated with this condition.
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a novel mutation in the human Aromatase gene insights on the relationship among serum estradiol longitudinal growth and bone mineral density in an adult man under estrogen replacement treatment
Bone, 2008Co-Authors: Fabio Lanfranco, Cesare Carani, Lucia Zirilli, Matteo Baldi, Ezio Ghigo, Gianluca Aimaretti, Elisa Pignatti, G Corneli, Vincenzo RochiraAbstract:Abstract Objective Here we report on a new case of human Aromatase Deficiency in a man of 26 years of age and present the results of five year follow-up during trandermal estradiol (tE 2 ) substitution, focusing on bone growth and mineralization. The lack of patient's compliance to tE 2 treatment, resulting in low but detectable serum estradiol levels, provides helpful information about the physiological estradiol needed in serum to guarantee a complete bone maturation and mineralization. Design Clinical case report study. Methods Genetic, biochemical and hormonal evaluations and the study of bone health were performed before and during estrogen treatment. Results Eunuchoid body proportions, unfused epiphyses, tall stature, osteopenia, increase fasting insulin, mild astenozoospermia and a history of right cryptorchidism were present. Baseline serum FSH was slightly above the normal range and estradiol was undetectable. Genetic analysis revealed a pattern of compound heterozygosity due to 23 bp deletion in exon IV and a point mutation in the first nucleotide of intron IX of the CYP19A1 gene, respectively. The closure of epiphyseal cartilage, the normalization of bone BMD and bone turnover markers, and the improvement of insulin levels were reached during tE 2 only when serum estradiol raised above 73 pmol/L. Sperm parameters and overweight did not improve with substitutive therapy. Conclusions This new case of Aromatase Deficiency underlines the role of estrogen on skeletal maturation, BMD, metabolic abnormalities and gonadal axis. It provides evidence on the need not only of a continuous estrogen replacement, but also of ensuring adequate estradiol levels in serum in order to ensure a complete bone maturation and mineralization and to prevent the worsening of body skeletal proportions. The comprehension of this physiological aspect has relevant clinical significance especially for the development of new therapeutic strategies useful to treat growth disorders by targeting serum estradiol in men.
Vincenzo Rochira - One of the best experts on this subject based on the ideXlab platform.
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complete Aromatase Deficiency in four adult men detection of a novel mutation and two known mutations in the cyp19a1 gene
The 95th Annual Meeting of the Endocrine Society ENDO2013, 2013Co-Authors: Elisa Pignatti, Cesare Carani, Manuela Simoni, Kursad Unluhizarci, Ermine Kartal, Kamel Ajlouni, Nahla Khawaja, Marco Marino, Eleonora Vighi, Vincenzo RochiraAbstract:1Department of Biomedical, Metabolic and Neural Sciences, University of Modena & Reggio Emilia, Modena Italy; 2Integrated Department of Medicine, Endocrinology and Metabolism, Geriatrics, Azienda USL of Modena, Italy; 3Department of Endocrinology, Erciyes University Medical School, Kayseri, Turkey, 4Ege University, Department of Endocrinology and Metabolisim Disease, Ýzmir, Turkey, 5Molecular Genetics Laboratory, National Center for Diabetes, Endocrinology and Genetics (NCDEG), Amman, Jordan. COMPLETE Aromatase Deficiency IN FOUR ADULT MEN: DETECTION OF A NOVEL MUTATION AND TWO KNOWN MUTATIONS IN THE CYP19A1 GENE P640
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tall stature without growth hormone four male patients with Aromatase Deficiency
The Journal of Clinical Endocrinology and Metabolism, 2010Co-Authors: Vincenzo Rochira, Cesare Carani, Laura Maffei, Lucia Zirilli, Valeria Premrou, Claudio Aranda, Matteo Baldi, Ezio Ghigo, Gianluca Aimaretti, Fabio LanfrancoAbstract:Context: From preliminary observations, GH-IGF-I seems to be compromised in men with Aromatase Deficiency. The GH Deficiency (GHD) coexists paradoxically with tall stature, raising the question whether or not a true GHD is part of this rare syndrome. Objective: To evaluate the GH secretion in Aromatase-deficient men, their GH response to the GHRH plus arginine (GHRH-ARG) test was compared with that of normal subjects. The effect of estrogen replacement treatment on the GH-IGF-I axis in Aromatase-deficient men was evaluated before and during therapy. Design and Setting: A case-control study was conducted. Patients: Four adult men with Aromatase Deficiency were compared with 12 normal subjects. Main Outcome Measures: We measured the GH response to GHRH-ARG in Aromatase-deficient men (at baseline and during estrogen treatment) and in normal subjects. Basal serum IGF-I was measured in both patients and controls. Results: The response of GH to GHRH-ARG was severely impaired in men with Aromatase Deficiency and...
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the effects of long term raloxifene and estradiol treatments on bone in a patient with congenital Aromatase Deficiency
Bone, 2009Co-Authors: Lucia Zirilli, Cesare Carani, Laura Maffei, Pj Meunier, P Chavassieux, Vincenzo RochiraAbstract:Abstract Introduction In adult Aromatase-deficient men, estrogen treatment has always resulted in a rapid skeletal maturation with epiphyseal closure and improved BMD. Raloxifene is a SERM with proven estrogen agonist action on bone that leads to an improvement in BMD and a reduction in bone turnover. The present study reports the effects of raloxifene and transdermal estradiol treatment, respectively, on epiphyseal closure and BMD in an Aromatase-deficient man, over a 24-month follow-up, with the aim of obtaining further insight into the role of estrogens in the male skeletal homeostasis. Materials and methods A 25-year-old Caucasian man with Aromatase Deficiency, a bone age of 15.3 years, unfused epiphyses and an impaired BMD was initially administered raloxifene (60 mg/day per os) for 12 months, while transdermal estradiol (25 μg twice weekly) was administered for the subsequent 12 months. During the follow-up, the effects of the two treatments on epiphyseal closure, BMD and bone turnover markers were investigated. An iliac crest bone biopsy was performed only before and after the raloxifene treatment, but it was not repeated after transdermal estradiol treatment. Results No changes in bone age were observed after raloxifene therapy, whereas a complete epiphyseal closure was achieved with transdermal estradiol treatment. Compared with baseline values, raloxifene treatment led to improved BMD both at the ultradistal forearm and 33% radius; the transdermal estradiol treatment resulted in a further slight increase in BMD at the 33% radius, but not at the ultradistal forearm. The baseline bone biopsy showed elevated bone remodelling in trabecular bone, while the second biopsy following raloxifene treatment revealed a decrease in remodelling. Discussion This study shows that the management of Aromatase Deficiency in the male cannot consider raloxifene as a first choice treatment, but should be still based on estrogen replacement treatment since in this patient the completion of bone maturation has only been obtained once estradiol substitution was performed. The present case also demonstrates that raloxifene is able to improve BMD in Aromatase-deficient men.
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Aromatase Deficiency in men a clinical perspective
Nature Reviews Endocrinology, 2009Co-Authors: Vincenzo Rochira, Cesare CaraniAbstract:Human Aromatase Deficiency is a very rare syndrome characterized by congenital estrogen deprivation that is caused by loss-of-function mutations in CYP19A1, which encodes Aromatase. Here, we review the presentation, diagnosis and treatment of Aromatase Deficiency in men to provide useful advice for clinical management of the condition. At presentation, all men with Aromatase Deficiency have tall stature, delayed bone maturation, osteopenia or osteoporosis and eunuchoid skeletal proportions. Diagnosis of the condition is supported by the presence of unfused epiphyses and undetectable serum estradiol levels; the condition can be further substantiated by genetic sequencing of CYP19A1. Transdermal estradiol treatment at a daily dose of about 25 microg might be adequate for lifelong replacement therapy. BMD and levels of serum estradiol, luteinizing hormone and testosterone should be monitored carefully and considered powerful biochemical markers of adequate estrogen substitution in clinical practice. Early diagnosis is important to initiate estrogen therapy as soon after puberty as possible to avoid the skeletal complications that are associated with this condition.
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a novel mutation in the human Aromatase gene insights on the relationship among serum estradiol longitudinal growth and bone mineral density in an adult man under estrogen replacement treatment
Bone, 2008Co-Authors: Fabio Lanfranco, Cesare Carani, Lucia Zirilli, Matteo Baldi, Ezio Ghigo, Gianluca Aimaretti, Elisa Pignatti, G Corneli, Vincenzo RochiraAbstract:Abstract Objective Here we report on a new case of human Aromatase Deficiency in a man of 26 years of age and present the results of five year follow-up during trandermal estradiol (tE 2 ) substitution, focusing on bone growth and mineralization. The lack of patient's compliance to tE 2 treatment, resulting in low but detectable serum estradiol levels, provides helpful information about the physiological estradiol needed in serum to guarantee a complete bone maturation and mineralization. Design Clinical case report study. Methods Genetic, biochemical and hormonal evaluations and the study of bone health were performed before and during estrogen treatment. Results Eunuchoid body proportions, unfused epiphyses, tall stature, osteopenia, increase fasting insulin, mild astenozoospermia and a history of right cryptorchidism were present. Baseline serum FSH was slightly above the normal range and estradiol was undetectable. Genetic analysis revealed a pattern of compound heterozygosity due to 23 bp deletion in exon IV and a point mutation in the first nucleotide of intron IX of the CYP19A1 gene, respectively. The closure of epiphyseal cartilage, the normalization of bone BMD and bone turnover markers, and the improvement of insulin levels were reached during tE 2 only when serum estradiol raised above 73 pmol/L. Sperm parameters and overweight did not improve with substitutive therapy. Conclusions This new case of Aromatase Deficiency underlines the role of estrogen on skeletal maturation, BMD, metabolic abnormalities and gonadal axis. It provides evidence on the need not only of a continuous estrogen replacement, but also of ensuring adequate estradiol levels in serum in order to ensure a complete bone maturation and mineralization and to prevent the worsening of body skeletal proportions. The comprehension of this physiological aspect has relevant clinical significance especially for the development of new therapeutic strategies useful to treat growth disorders by targeting serum estradiol in men.
Evan R Simpson - One of the best experts on this subject based on the ideXlab platform.
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Aromatase Deficiency confers paradoxical postischemic cardioprotection
Endocrinology, 2011Co-Authors: Jimmy D Bell, Evan R Simpson, Kimberley M Mellor, Amanda C Wollermann, Melissa E Reichelt, Sarah J Meachem, Leanne M D DelbridgeAbstract:The conventional view is that estrogen confers female cardioprotection. Estrogen synthesis depends on androgen availability, with Aromatase regulating conversion of testosterone to estradiol. Extragonadal Aromatase expression mediates estrogen production in some tissues, but a role for local steroid conversion has not yet been demonstrated in the heart. This study's goal was to investigate how Aromatase Deficiency influences myocardial function and ischemic resilience. RT-PCR analysis of C57Bl/6 mouse hearts confirmed cardiac-specific Aromatase expression in adult females. Functional performance of isolated hearts from female Aromatase knockout (ArKO) and Aromatase wild-type mice were compared. Left ventricular developed pressures were similar in aerobic perfusion, but the maximal rate of rise of ventricular pressure was modestly reduced in ArKO hearts (3725 ± 144 vs. 4272 ± 154 mm Hg/sec, P < 0.05). After 25 min of ischemia, the recovery of left ventricular developed pressure was substantially improved in ArKO (percentage of basal at 60 min of reperfusion, 62 ± 8 vs. 30 ± 6%; P < 0.05). Hypercontracture was attenuated (end diastolic pressure, 25 ± 5 vs. 51 ± 1 mm Hg; P < 0.05), and lactate dehydrogenase content of coronary effluent was reduced throughout reperfusion in ArKO hearts. This was associated with a hyperphosphorylation of phospholamban and a reduction in phosphorylated Akt. Immediately after reperfusion, ArKO hearts exhibited increased incidence of ventricular premature beats (194 ± 70 vs. 46 ± 6, P < 0.05). These observations indicate more robust functional recovery, reduced cellular injury, and modified cardiomyocyte Ca(2+) handling in Aromatase-deficient hearts. Our findings indicate that androgen-to-estrogen conversion may be of pathophysiologic importance to the heart and challenge the notion that estrogen Deficiency is deleterious. These studies suggest the possibility that Aromatase suppression may offer inotropic benefit in the acute ischemia/reperfusion setting with appropriate arrhythmia management.
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Aromatase Deficiency inhibits the permeability transition in mouse liver mitochondria
Endocrinology, 2010Co-Authors: J Ford, Evan R Simpson, Loredana Moro, Arnaldo A Arbini, Jer Tsong Hsieh, Asghar HajibeigiAbstract:Lack of estrogens affects male physiology in a number of ways, including severe changes in liver metabolism that result in lipid accumulation and massive hepatic steatosis. Here we investigated whether estrogen Deficiency may alter the functionality and permeability properties of liver mitochondria using, as an experimental model, Aromatase knockout (ArKO) male mice, which cannot synthesize endogenous estrogens due to a disruption of the Cyp19 gene. Liver mitochondria isolated from ArKO mice displayed increased activity of the mitochondrial respiratory complex IV compared with wild-type mice and were less prone to undergo cyclosporin A-sensitive mitochondrial permeability transition (MPT) induced by calcium loading. The altered permeability properties of the mitochondrial membranes were not due to changes in reactive oxygen species, ATP levels, or mitochondrial membrane potential but were associated with increased content of the phospholipid cardiolipin, structural component of the mitochondrial membranes...
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bone has a sexually dimorphic response to Aromatase Deficiency
Journal of Bone and Mineral Research, 2010Co-Authors: Joseph E Zerwekh, Carolyn R. Fisher, Kathy H Graves, Lydia Nanu, Rita Millsaps, Evan R SimpsonAbstract:Aromatase synthesizes estrogen from androgen precursors. To better understand the role of estrogen in skeletal metabolism and growth, we have assessed long bone growth and histomorphometry in Aromatase-deficient (ArKO) mice. The age range for the animals was 5-7 months. At this age mice have already achieved peak bone density but continue slow bone growth. Femur length, an index of long bone growth, showed decreased growth in ArKO males compared with wild-type (wt) littermates but no significant difference in females. Radiographically, compared with age- and sex- matched littermates both ArKO males and females showed osteopenia in the lumbar spine. Histologically, both ArKO males and females showed an osteoporotic-type picture, characterized by significant decreases in trabecular bone volume and trabecular thickness. However, compared with wt littermates female ArKO animals showed a bone remodeling picture consistent with increased bone turnover, much like early postmenopausal osteoporosis in humans. On the other hand, male ArKO animals showed decreases in both osteoblastic and osteoclastic surfaces compared with wt littermates, similar to age-related osteopenia. These findings suggest that osteoporosis seen in Aromatase-deficient mice may arise from different bone remodeling activities between males and females. These results also show that the ArKO model exhibits the expected results of estrogen Deficiency and may be a good model for investigating sex-specific responses to estrogen Deficiency. Furthermore, they imply that estrogen is important for attaining peak bone mass in male as well as in female mice.
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estrogen and adiposity utilizing models of Aromatase Deficiency to explore the relationship
The Journal of Steroid Biochemistry and Molecular Biology, 2007Co-Authors: Margaret E E Jones, Wah Chin Boon, Kerry J Mcinnes, Evan R SimpsonAbstract:Estrogen has an important role to play in energy homeostasis in both men and mice. Lack of estrogen results in the development of a metabolic syndrome in humans and rodents, including excess adiposity, hepatic steatosis (in male but not female Aromatase knockout (ArKO) mice) and insulin resistance. Estrogen replacement results in a prompt reversal of the energy imbalance symptoms associated with estrogen Deficiency. A corollary to the perturbed energy balance observed in the ArKO mouse is the death by apoptosis of dopaminergic neurons in the hypothalamic arcuate nucleus of male ArKO mice, an area of the brain pivotal to the regulation of energy uptake, storage, and mobilisation. An extension of our work exploring the relationship between estrogen and adiposity has been to examine the role played by androgens in energy balance. We have demonstrated that an increased androgen to estrogen ratio can promote visceral fat accumulation in the rodent by inhibiting AMPK activation and stimulating lipogenesis. Therefore, understanding the regulation of energy homeostasis is becoming an increasingly fascinating challenge, as the number of contributors, their communications, and the complexity of their interactions, involved in the preservation of this equilibrium continues to increase. Models of Aromatase Deficiency, both naturally occurring and engineered, will continue to provide valuable insights into energy homeostasis.
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a novel compound heterozygous mutation of the Aromatase gene in an adult man reinforced evidence on the relationship between congenital oestrogen Deficiency adiposity and the metabolic syndrome
Clinical Endocrinology, 2007Co-Authors: Laura Maffei, Evan R Simpson, Vincenzo Rochira, Lucia Zirilli, Claudio Aranda, Elisa Pignatti, Bibiana Fabre, Paula Antunez, Maria Luisa Simone, Souheir HoussamiAbstract:Background Descriptions of new cases of human Aromatase Deficiency are useful for a better understanding of male oestrogen pathophysiology, as some aspects remain controversial. Objective To present a new case of an adult man affected by Aromatase Deficiency, along with a description of clinical phenotype, and hormonal and genetic analysis. Design Case report study. Patient A 25-year-old man with continuing linear growth, eunuchoid body habitus and diffuse bone pain. Measurements Amplification and sequencing of all coding exons with their flanking intronic sequences of the CYP19A1 gene. Aromatase expression of the mutant human cDNAs was compared with wild type. Serum LH, FSH, testosterone, oestradiol, insulin, glucose, glycosylated haemoglobin (HbA1c), serum lipids and liver enzymes were measured. Histological analysis of liver and testis biopsies was performed. Results Two novel heterozygous compound inactivating mutations of the CYP19A1 gene were disclosed. The first mutation is at bp380 (T-->G) in exon IV and the second one at bp 1124 (G-->A) in exon IX. LH and testosterone were normal, FSH was slightly elevated, and serum oestradiol undetectable. The subject showed a metabolic syndrome characterized by abdominal obesity, hyperinsulinaemia, acanthosis nigricans and nonalcoholic fatty liver disease. Conclusions These novel mutations improve our knowledge on genetics of the CYP19A1 gene. This new case of Aromatase Deficiency sheds new light on the heterogeneity of mutations in the CYP19A1 gene causing loss of function of the Aromatase enzyme. The evidence of metabolic syndrome and of obesity associated with congenital oestrogen deprivation emphasizes the role of oestrogens in fat accumulation and distribution in men, a role that has long been partially overlooked in these patients.
Roxana Marino - One of the best experts on this subject based on the ideXlab platform.
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Human Aromatase Deficiency
Encyclopedia of Endocrine Diseases, 2019Co-Authors: Gabriela Guercio, Nora Saraco, Mariana Costanzo, Roxana Marino, Alicia BelgoroskyAbstract:cP450 Aromatase Deficiency is a rare autosomal recessive disorder that impairs androgen conversion to estrogens. New knowledge on cP450 Aromatase Deficiency has contributed to the understanding of the role of estrogens in human health and disease. Currently, 37 cases of Aromatase Deficiency (26 46,XX) have been published. In affected subjects, the clinical phenotype depends on sex, age, and genotype. In affected 46,XX newborns a broad variability in clinical virilization of the external genitalia is observed; however, Aromatase Deficiency should be considered in the etiology of 46,XX DSD, after ruling out congenital adrenal hyperplasia secondary to 21-hydroxylase Deficiency. After birth, in both sexes, the phenotype reflects the effects of estrogen insufficiency on the skeleton, hypothalamic–pituitary–gonadal function, the gonads and the reproductive system, and on glucose and lipid metabolism. Variable or nonclassic forms of the disease have expanded the phenotypic variability in Aromatase insufficiency in humans. The long-term follow-up of patients with Aromatase Deficiency is important to increase our knowledge on the clinical course of the disease and to establish an appropriate therapeutic strategy to prevent the devastating consequences of prolonged estrogen Deficiency.
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five new cases of 46 xx Aromatase Deficiency clinical follow up from birth to puberty a novel mutation and a founder effect
The Journal of Clinical Endocrinology and Metabolism, 2015Co-Authors: Roxana Marino, Gabriela Guercio, Mariana Costanzo, Natalia Perez Garrido, Matias Juanes, Carlos Rocco, Pablo Ramirez, Diana Monica Warman, Marta Ciaccio, Gladys PenaAbstract:Context: Aromatase is the key enzyme for estrogen biosynthesis and is encoded by the CYP19A1 gene. Since 1991, several molecular CYP19A1 gene alterations associated with Aromatase Deficiency have been described in both sexes. Objective: The objective of the study was to detect CYP19A1 mutations in five Aromatase-deficient 46,XX patients, to describe the clinical follow-up from birth to puberty and to perform haplotype analysis associated with the high-frequency c.628G>A splice mutation in Argentinean patients. Design: The design of the study was the sequencing of the coding and flanking intronic regions of the CYP19A1 gene in all patients and parents. Haplotype analysis of patients carrying the c.628G>A mutation was also performed. Patients: Clinical and biochemical findings in five new cases and one previously reported female Aromatase-deficient patient (46,XX) are described. All patients presented with ambiguous genitalia at birth. Congenital adrenal hyperplasia due to 21-hydroxylase Deficiency as well ...
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five new cases of 46 xx Aromatase Deficiency clinical follow up from birth to puberty a novel mutation and a founder effect
The Journal of Clinical Endocrinology and Metabolism, 2015Co-Authors: Roxana Marino, Gabriela Guercio, Mariana Costanzo, Natalia Perez Garrido, Matias Juanes, Carlos Rocco, Pablo Ramirez, Diana Monica Warman, Marta Ciaccio, Gladys PenaAbstract:Fil: Marino, Roxana Marcela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatria "Juan P. Garrahan"; Argentina
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the cytochrome p450 Aromatase lacking exon 5 is associated with a phenotype of nonclassic Aromatase Deficiency and is also present in normal human steroidogenic tissues
Clinical Endocrinology, 2007Co-Authors: Carolina Pepe, Gabriela Guercio, Roxana Marino, Christa E Fluck, N Saraco, Maria Sonia Baquedano, Elisa Vaiani, Amit V Pandey, M A Rivarola, A BelgoroskyAbstract:OBJECTIVE: The previously described c655G>A mutation of the human cytochrome P450 Aromatase gene (P450aro, CYP19) results in aberrant splicing due to disruption of a donor splice site. To explain the phenotype of partial Aromatase Deficiency observed in a female patient described with this mutation, molecular consequences of the c655G>A mutation were investigated. DESIGN: To investigate whether the c655G>A mutation causes an aberrant spliced mRNA lacking exon 5 (-Ex5), P450aro RNA was analysed from the patient's lymphocytes by reverse transcription polymerase chain reaction (RT-PCR) and by splicing assays performed in Y1 cells transfected with a P450aro -Ex5 expression vector. Aromatase activity of the c655G>A mutant was predicted by three dimensional (3D) protein modelling studies and analysed in transiently transfected Y1 cells. Exon 5 might be predicted as a poorly defined exon suggesting a susceptibility to both splicing mutations and physiological alternative splicing events. Therefore, expression of the -Ex5 mRNA was also assessed as a possibly naturally occurring alternative splicing transcript in normal human steroidogenic tissues. PATIENTS: An Aromatase deficient girl was born with ambiguous genitalia. Elevated serum LH, FSH and androgens, as well as cystic ovaries, were found during prepuberty. At the age of 8.4 years, spontaneous breast development and a 194.6 pmol/l serum oestradiol level was observed. RESULTS: The -Ex5 mRNA was found in lymphocytes of the P450aro deficient girl and her father, who was a carrier of the mutation. Mutant minigene expression resulted in complete exon 5 skipping. As expected from 3D protein modelling, -Ex5 cDNA expression in Y1 cells resulted in loss of P450aro activity. In addition, the -Ex5 mRNA was present in placenta, prepubertal testis and adrenal tissues. CONCLUSIONS: Alternative splicing of exon 5 of the CYP19 gene occurs in the wild type (WT) as well as in the c655G>A mutant. We speculate that for the WT it might function as a regulatory mechanism for aromatization, whereas for the mutant a relative prevalence of the shorter over the full-length protein might explain the phenotype of partial Aromatase Deficiency.
Gladys Pena - One of the best experts on this subject based on the ideXlab platform.
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five new cases of 46 xx Aromatase Deficiency clinical follow up from birth to puberty a novel mutation and a founder effect
The Journal of Clinical Endocrinology and Metabolism, 2015Co-Authors: Roxana Marino, Gabriela Guercio, Mariana Costanzo, Natalia Perez Garrido, Matias Juanes, Carlos Rocco, Pablo Ramirez, Diana Monica Warman, Marta Ciaccio, Gladys PenaAbstract:Context: Aromatase is the key enzyme for estrogen biosynthesis and is encoded by the CYP19A1 gene. Since 1991, several molecular CYP19A1 gene alterations associated with Aromatase Deficiency have been described in both sexes. Objective: The objective of the study was to detect CYP19A1 mutations in five Aromatase-deficient 46,XX patients, to describe the clinical follow-up from birth to puberty and to perform haplotype analysis associated with the high-frequency c.628G>A splice mutation in Argentinean patients. Design: The design of the study was the sequencing of the coding and flanking intronic regions of the CYP19A1 gene in all patients and parents. Haplotype analysis of patients carrying the c.628G>A mutation was also performed. Patients: Clinical and biochemical findings in five new cases and one previously reported female Aromatase-deficient patient (46,XX) are described. All patients presented with ambiguous genitalia at birth. Congenital adrenal hyperplasia due to 21-hydroxylase Deficiency as well ...
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five new cases of 46 xx Aromatase Deficiency clinical follow up from birth to puberty a novel mutation and a founder effect
The Journal of Clinical Endocrinology and Metabolism, 2015Co-Authors: Roxana Marino, Gabriela Guercio, Mariana Costanzo, Natalia Perez Garrido, Matias Juanes, Carlos Rocco, Pablo Ramirez, Diana Monica Warman, Marta Ciaccio, Gladys PenaAbstract:Fil: Marino, Roxana Marcela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatria "Juan P. Garrahan"; Argentina