RESUMEN
CONTEXT: Aromatase excess syndrome (AEXS) is a very rare disorder characterized by prepubertal gynecomastia, bone age acceleration, and early growth arrest. Heterozygote submicroscopic rearrangements within the promotor of CYP19A1 result in overexpression of aromatase and enhanced aromatization of androgens. OBJECTIVE: The objective was to study long-term treatment effects of an aromatase inhibitor. METHODS: Data from 7 boys with AEXS were retrospectively collected. Genetic analysis revealed upstream of CYP19A1 a 165 901 bp deletion in 4 German cousins, a 198 662 bp deletion in 2 Japanese brothers, and a 387 622 bp tandem duplication in a Japanese boy. RESULTS: All boys developed prepubertal gynecomastia, at median 9.0 years of age (range: 7.0-11.0). Height was +1.20 standard deviation score (SDS) (-0.24 to +1.98); predicted adult height was -1.29 SDS (-3.29 to +1.09). Four boys were treated with 1.0 mg of anastrozole daily, while 3 reached adult height untreated. Treatment with anastrozole was stopped after 5.6 years (4.0-6.8). Three treated boys exceeded their prognosis by 2.4, 6.9, and 8.1 cm, while 1 untreated boy fell below the prognosis by 8.6 cm. One treated with a low dose and 2 untreated reached their prognosis. Adult heights were -0.91 SDS with anastrozole (-2.86 to -0.29) and -0.15 SDS without (-2.31 to -0.03). Distance to target height was -0.22 SDS with anastrozole (-1.72 to +0.52) and +0.54 SDS without (+0.23 to +1.30). CONCLUSION: Spontaneous growth in AEXS varied, even in the same family. Our data suggest that early started, long-term inhibition by anastrozole promotes adult height in boys with AEXS.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/tratamiento farmacológico , Inhibidores de la Aromatasa/uso terapéutico , Aromatasa/genética , Desarrollo Infantil/efectos de los fármacos , Ginecomastia/tratamiento farmacológico , Infertilidad Masculina/tratamiento farmacológico , Errores Innatos del Metabolismo/tratamiento farmacológico , Adolescente , Anastrozol/farmacología , Anastrozol/uso terapéutico , Aromatasa/metabolismo , Inhibidores de la Aromatasa/farmacología , Estatura/efectos de los fármacos , Niño , Alemania , Humanos , Japón , Masculino , Estudios Retrospectivos , Hermanos , Factores de TiempoRESUMEN
Background Aromatase excess syndrome (AEXS) is a rare autosomal dominant disorder caused by CYP19A1 overexpression. Clinical manifestations of AEXS include pre- or peri-pubertal gynecomastia, advanced bone age and compromised adult height. Case presentation Here we report an 8-year-old boy diagnosed with AEXS by chromosomal array that revealed a 1.1 Mb novel de novo duplication at 15q21.2, with a predicted final height of 157.4 cm. We prescribed letrozole and growth hormone (GH) to maximize his linear growth. Without further bone age advancement, his height increased from 137.7 cm to 144 cm after an 8-month treatment period. Conclusions We identified a novel duplication at 15q21.2 in AEXS, and found that aromatase inhibitor (AI) plus GH might provide a better growth-promoting approach for AEXS patients.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/genética , Trastornos del Desarrollo Sexual 46, XX/patología , Aromatasa/genética , Cromosomas Humanos Par 15/genética , Duplicación de Gen , Ginecomastia/genética , Ginecomastia/patología , Infertilidad Masculina/genética , Infertilidad Masculina/patología , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/patología , Trastornos del Desarrollo Sexual 46, XX/tratamiento farmacológico , Aromatasa/química , Inhibidores de la Aromatasa/uso terapéutico , Niño , Ginecomastia/tratamiento farmacológico , Humanos , Infertilidad Masculina/tratamiento farmacológico , Masculino , Errores Innatos del Metabolismo/tratamiento farmacológico , PronósticoRESUMEN
CONTEXT: Lipoid congenital adrenal hyperplasia (LCAH) is characterized by a disorder of steroidogenesis in both adrenal glands and gonads. 46,XX patients with classic LCAH usually have thelarche and menarche but show anovulatory menstruations and subsequent premature menopause. Only three patients with classic LCAH have been reported to successfully achieve delivery with the aid of assisted reproductive therapies for conception and progesterone replacement therapy during early pregnancy. In contrast, pubertal development and pregnancy outcomes in patients with nonclassic LCAH have not been fully elucidated. CASE DESCRIPTION: We report four Japanese women who had a diagnosis of primary adrenal insufficiency during infancy or childhood and carried compound heterozygous STAR mutations (p.Gln258* and p.Arg188His, p.Gln258* and p.Met225Thr, and p.Gln258* and p.Arg272Cys). In all four patients, thelarche and menarche spontaneously occurred from 10 to 11 years of age and from 12 to 14 years of age, respectively. Subsequently, their menstruation cycles were regular at almost 1-month intervals. Patient 1 conceived naturally twice, and patient 2 conceived with the use of clomiphene citrate for ovulation induction. These two patients maintained the pregnancies without progesterone replacement therapy and successfully delivered children. CONCLUSION: Patients with nonclassic LCAH maintain ovarian function, which enables normal pubertal development and a successful pregnancy outcome without progesterone replacement therapy.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/fisiopatología , Hiperplasia Suprarrenal Congénita/fisiopatología , Trastorno del Desarrollo Sexual 46,XY/fisiopatología , Resultado del Embarazo , Pubertad/fisiología , Trastornos del Desarrollo Sexual 46, XX/complicaciones , Trastornos del Desarrollo Sexual 46, XX/tratamiento farmacológico , Adolescente , Hiperplasia Suprarrenal Congénita/complicaciones , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Adulto , Trastorno del Desarrollo Sexual 46,XY/complicaciones , Trastorno del Desarrollo Sexual 46,XY/tratamiento farmacológico , Femenino , Terapia de Reemplazo de Hormonas , Humanos , Embarazo , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: Increased adrenal androgen hormones in congenital adrenal hyperplasia (CAH) can rarely cause giant ovarian cysts in the neonatal period. Although the exact mechanism of the development of ovarian cysts is unknown, it is thought that increased androgen levels stimulate folicle development by increasing follicle stimulating hormone (FSH) levels. CASE PRESENTATION: A 16-day-old newborn with ambiguous genitalia was presented to our clinic. Laboratory test results were as follows: sodium: 126 mEq/L, potassium: 5.4 mEq/L, renin: 132 pg/mL, adrenocorticotropic hormone (ACTH): 207 pg/mL, cortisole: 7.8 µg/dL, basal 17OH progesterone: 21 ng/mL, androstenedione: 5.1 ng/mL, testosterone: 1188 ng/dL and dehydroepiandrosterone sulfate (DHEAS)>1500 µg/dL. Karyotype analysis resulted in 46,XX. A homozygous mutation of R356W was detected in the CYP21A2 gene. The classical severe form of salt wasting 21 hydroxylase deficiency was diagnosed and treatment was started with hydrocortisone and fludrocortisone. Good metabolic control was ensured by monthly visits but the baby presented with vaginal bleeding as soiling at 4 months. The cystic lesion which extended to the epigastric area from the pelvis in the midline abdomen, had a size of 90×80×60 mm and medially, thin ovarian parenchyma was detected in ultrasonography. CONCLUSIONS: The findings in our patient suggest that a decline in adrenal androgens after glucocorticoid treatment resulted in an increase in gonadotropin levels and the giant cyst is developed by activation of gonadotropin cascade and increased gonadotropin receptors, instead of androgens.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/tratamiento farmacológico , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Gonadotropinas/efectos adversos , Quistes Ováricos/inducido químicamente , Ovario/efectos de los fármacos , Hemorragia Uterina/etiología , Trastornos del Desarrollo Sexual 46, XX/genética , Hiperplasia Suprarrenal Congénita/genética , Sustitución de Aminoácidos , Antiinflamatorios/efectos adversos , Antiinflamatorios/uso terapéutico , Quimioterapia Combinada/efectos adversos , Femenino , Fludrocortisona/efectos adversos , Fludrocortisona/uso terapéutico , Gonadotropinas/uso terapéutico , Homocigoto , Humanos , Hidrocortisona/efectos adversos , Hidrocortisona/uso terapéutico , Recién Nacido , Mutación , Quistes Ováricos/patología , Quistes Ováricos/fisiopatología , Quistes Ováricos/cirugía , Ovario/patología , Ovario/cirugía , Esteroide 21-Hidroxilasa/genética , Resultado del Tratamiento , Carga Tumoral , Hemorragia Uterina/prevención & controlRESUMEN
AIMS: To evaluate the effect of adjuvants during intensive vaginal dilator therapy for functional and anatomical neovagina creation in women with Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH). METHODS: This retrospective cohort study included 75 women with MRKH undergoing intensive vaginal dilator treatment between 2000 and 2014. One specialist nurse performed non-surgical vaginal dilation aided by adjuvants, during inpatient admissions for several dilation sessions per day. Following discharge, women continued dilation at home and were advised to attend fortnightly follow-up appointments. RESULTS: Outcomes from 68 women were analysed. The median age of starting treatment was 18 years (range: 13-36). There was a mean of 3 days per admission (range 1-5) with a median of 10 dilation sessions per admission. Adjuvant treatment was used by 48/68 (71%) women: oestriol cream 29/68 (43%), 50:50 nitrous oxide and oxygen 44/68 (65%), diazepam 8/68 (12%), lidocaine ointment 26/68 (39%), paracetamol 35/68 (51%) and naproxen 2/68 (3%). There were no statistically significant differences for changes in vaginal parameters. Women receiving adjuvants had a median increase of 4.5 cm (0.5-7 cm) in neovaginal length compared with women not receiving adjuvants who had a median increase of 3.25 cm (0-7 cm) during intensive treatment. Women who received adjuvants tolerated more dilation sessions per day (10 vs 6.5 median sessions respectively) than those who did not (P < 0.001). Of those with documented length at discharge, 42/56 (75%) women had an anatomical neovagina of 7 cm or greater length. CONCLUSIONS: Vaginal dilation delivered by intensive treatment and supplemented by adjuvant treatments in a multi-disciplinary centre is a rapid and effective method for creation of a neovagina in women with MRKH.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/terapia , Anomalías Congénitas/terapia , Dilatación , Conductos Paramesonéfricos/anomalías , Vagina/anatomía & histología , Trastornos del Desarrollo Sexual 46, XX/tratamiento farmacológico , Administración Intravaginal , Adolescente , Adulto , Terapia Combinada , Anomalías Congénitas/tratamiento farmacológico , Dilatación/efectos adversos , Estriol/administración & dosificación , Femenino , Humanos , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Aromatase, or CYP19A1, is a type II cytochrome CYP450 enzyme that catalyzes the conversion of C19 androgens to C18 estrogens. Its crucial role in both female and male physiology has been deduced from human and animal studies using aromatase inhibitors, genetically altered mice, and patients with aromatase deficiency. The latter is an extremely rare disorder. Its diagnosis is particularly difficult in males, who go through puberty normally and therefore usually present as adults with elevated testosterone, bone abnormalities (e.g., delayed bone age and low bone mass), and metabolic syndrome. In this report, we describe a new case of a male patient with aromatase deficiency harboring a known mutation who presented with less severe clinical and biochemical features. CASE REPORT: The patient presented with low bone mass and delayed bone age after a finger fracture at age 25years. FSH, LH and testosterone levels were normal, but estradiol and estrone levels were absent or barely detectable, raising suspicion for aromatase deficiency. A homozygous c.628G>A mutation in exon 5 was confirmed by direct sequencing. Unlike previously reported cases of aromatase deficiency, he did not display biochemical features of insulin resistance, dyslipidemia, or overweight/obese status. Therapy with estradiol led to the closure of growth plates and a dramatic increase in bone mass. CONCLUSIONS: Here we explore genotype/phenotype associations of this new case compared to cases reported previously. We conclude that the specific nature of mutation c.628G>A, which can potentially result in several different forms of the aromatase enzyme, may lend an explanation to the variable phenotypes associated with this particular genotype.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/patología , Aromatasa/deficiencia , Ginecomastia/patología , Infertilidad Masculina/patología , Errores Innatos del Metabolismo/patología , Trastornos del Desarrollo Sexual 46, XX/sangre , Trastornos del Desarrollo Sexual 46, XX/tratamiento farmacológico , Adolescente , Adulto , Determinación de la Edad por el Esqueleto , Aromatasa/sangre , Estradiol/sangre , Estradiol/farmacología , Estradiol/uso terapéutico , Fracturas Óseas/diagnóstico por imagen , Fracturas Óseas/tratamiento farmacológico , Fracturas Óseas/patología , Ginecomastia/sangre , Ginecomastia/tratamiento farmacológico , Humanos , Infertilidad Masculina/sangre , Infertilidad Masculina/tratamiento farmacológico , Masculino , Errores Innatos del Metabolismo/sangre , Errores Innatos del Metabolismo/tratamiento farmacológico , Testosterona/sangre , Factores de TiempoRESUMEN
Gonadal dysgenesis and Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) are the most common causes of primary amenorrhoea. Patients with gonadal dysgenesis present with primary amenorrhoea and lack of secondary sexual characteristics, which, in contrast, are present in patients with MRKHS. The coexistence of the 2 syndromes has been reported in only a few studies so far. We describe a case of a 15-year-old girl who presented with short stature and primary amenorrhoea. Investigations revealed hypergonadotropic hypogonadism, and absence of the uterus, and upper two-thirds of the vagina, with presence of the rudimentary lower third of the vagina and non-visualised bilateral ovaries on imaging. Karyotyping obtained by lymphocyte culture GTG banding revealed 45X/46XX. The patient was diagnosed as having a rare case of gonadal dysgenesis with MRKH. She was started on growth hormone therapy. The association of these syndromes is uncommon, and has further implications on fertility and pregnancy, affecting the quality of life.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/diagnóstico , Anomalías Congénitas/diagnóstico , Hormona del Crecimiento/administración & dosificación , Conductos Paramesonéfricos/anomalías , Síndrome de Turner/diagnóstico , Trastornos del Desarrollo Sexual 46, XX/tratamiento farmacológico , Trastornos del Desarrollo Sexual 46, XX/genética , Adolescente , Comorbilidad , Anomalías Congénitas/tratamiento farmacológico , Anomalías Congénitas/genética , Femenino , Hormona del Crecimiento/uso terapéutico , Humanos , Cariotipificación , Mosaicismo , Resultado del Tratamiento , Síndrome de Turner/tratamiento farmacológico , Síndrome de Turner/genéticaRESUMEN
BACKGROUND: Aromatase deficiency may result in a complete block of estrogen synthesis because of the failure to convert androgens to estrogens. In females, this results in virilisation at birth, ovarian cysts in prepuberty and lack of pubertal development but virilisation, thereafter. OBJECTIVE AND METHODS: We studied the impact of oral 17ß-estradiol treatment on ovarian and uterine development, and on LH/FSH and inhibin B during the long-term follow-up of a girl harboring compound heterozygote point mutations in the CYP19A1 gene. RESULTS: In early childhood, low doses of oral 17ß-estradiol were needed. During prepuberty treatment with slowly increasing doses of E2 resulted in normal uterine and almost normal development of ovarian volume, as well as number and size of follicles. Regarding hormonal feedback mechanisms, inhibin B levels were in the upper normal range during childhood and puberty. Low doses of estradiol did not suffice to achieve physiological gonadotropin levels in late prepuberty and puberty. However, when estradiol doses were further increased in late puberty levels of both FSH and LH declined with estradiol levels within normal range. CONCLUSION: Complete aromatase deficiency provides an excellent model of how ovarian and uterine development in relation to E2, LH, FSH and inhibin B feedback progresses from infancy to adolescence.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/tratamiento farmacológico , Aromatasa/deficiencia , Estradiol/administración & dosificación , Terapia de Reemplazo de Estrógeno/métodos , Estrógenos/uso terapéutico , Ginecomastia/tratamiento farmacológico , Infertilidad Masculina/tratamiento farmacológico , Errores Innatos del Metabolismo/tratamiento farmacológico , Ovario/crecimiento & desarrollo , Útero/crecimiento & desarrollo , Trastornos del Desarrollo Sexual 46, XX/metabolismo , Administración Oral , Adolescente , Aromatasa/genética , Aromatasa/metabolismo , Niño , Preescolar , Femenino , Hormona Folículo Estimulante/metabolismo , Ginecomastia/metabolismo , Humanos , Lactante , Infertilidad Masculina/metabolismo , Inhibinas/metabolismo , Hormona Luteinizante/metabolismo , Errores Innatos del Metabolismo/metabolismo , Estudios RetrospectivosRESUMEN
OBJECTIVES: Aromatase deficiency is a rare disorder resulting in estrogen insufficiency in humans. It has been reported in remarkably few men with loss-of-function mutations in the CYP19A1 gene encoding the aromatase, a cytochrome P450 enzyme that plays a crucial role in the biosynthesis of estrogens from androgens. We investigated a non-consanguineous family including an adult man with clinical features of aromatase deficiency, and studied the effects of estrogen replacement in the man. METHODS: We investigated the clinical and biochemical phenotype, performed CYP19A1 mutational analysis in the family and 50 unrelated persons, studied the effects of CYP19A1 mutations on aromatase protein structure, functionally characterized the mutations by cell-based aromatase activity assays, and studied the effects of estrogen replacement on the bone, lipid, liver and glucose metabolism. RESULTS: The man with clinical features of aromatase deficiency had novel compound heterozygous CYP19A1 mutations (Y81C and L451P) that were not found in 50 unrelated persons. Three-dimensional modeling predicted that Y81C and L451P mutants disrupted protein structure. Functional studies on the basis of in vitro expression showed that Y81C and L45P mutants significantly decreased the aromatase activity and catalytic efficiency. Estrogen replacement in the man increased bone mineral density, accelerated bone maturation, improved lipid profile and liver steatosis, and improved glucose levels but not insulin resistance. CONCLUSIONS: We have identified two novel CYP19A1 missense mutations in an aromatase-deficient man. Estrogen replacement in the man shows great impact on recovering the impairments in the bone, lipid, liver and glucose metabolism, but fails to improve insulin resistance.
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Trastornos del Desarrollo Sexual 46, XX , Aromatasa/deficiencia , Densidad Ósea , Terapia de Reemplazo de Estrógeno , Estrógenos/uso terapéutico , Glucosa/metabolismo , Ginecomastia , Infertilidad Masculina , Metabolismo de los Lípidos , Hígado/metabolismo , Errores Innatos del Metabolismo , Trastornos del Desarrollo Sexual 46, XX/tratamiento farmacológico , Trastornos del Desarrollo Sexual 46, XX/genética , Trastornos del Desarrollo Sexual 46, XX/metabolismo , Trastornos del Desarrollo Sexual 46, XX/patología , Adulto , Sustitución de Aminoácidos , Animales , Aromatasa/genética , Aromatasa/metabolismo , Densidad Ósea/efectos de los fármacos , Densidad Ósea/genética , Huesos/metabolismo , Células CHO , Cricetulus , Glucosa/genética , Ginecomastia/tratamiento farmacológico , Ginecomastia/genética , Ginecomastia/metabolismo , Ginecomastia/patología , Humanos , Infertilidad Masculina/tratamiento farmacológico , Infertilidad Masculina/genética , Infertilidad Masculina/metabolismo , Infertilidad Masculina/patología , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Hígado/patología , Masculino , Errores Innatos del Metabolismo/tratamiento farmacológico , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Errores Innatos del Metabolismo/patología , Modelos Moleculares , Mutación Missense , Estructura Terciaria de ProteínaRESUMEN
CONTEXT: Women with primary ovarian insufficiency have significantly lower serum estradiol and T levels compared with regularly menstruating women. They also have significantly reduced bone mineral density (BMD). OBJECTIVE: The objective of the study was to evaluate the efficacy of hormone replacement in maintaining BMD in these young women. DESIGN AND SETTING: This was a randomized, double-blind, single-center, placebo-controlled clinical trial at the National Institutes of Health clinical center (Bethesda, Maryland). PARTICIPANTS: Young women with primary ovarian insufficiency participated in the study. INTERVENTIONS: We compared the effect of estradiol and progestin replacement (n = 72) vs estradiol, progestin, and T replacement (n = 73) on BMD. We also compared findings with a contemporaneous control group of normal women (n = 70). All patients received transdermal estradiol (100 µg/d) plus oral medroxyprogesterone acetate 10 mg/d (12 d/mo) for a 3-month run-in period before being randomized in a double-blinded fashion to the addition of transdermal T (150 µg/d) or placebo. MAIN OUTCOME MEASURE: Change in BMD at the femoral neck was measured by dual-energy x-ray absorptiometry. RESULTS: At screening, patients had significantly lower femoral neck BMD compared with control women (0.77 vs 0.81 g/cm(2), P = .001) and did not differ in body mass index, age at menarche, or education level. Normal control women lost femoral neck BMD over the study period, whereas patients on estradiol and progestin therapy gained BMD; and at the end of the study period, femoral neck BMD of patients on estradiol and progestin therapy did not differ from that of control women (0.80 g/cm(2) in both groups, P = .9). The addition of T showed no further benefit (percentage change in BMD 3.9 vs 2.4, respectively, P = .9). Nonetheless, using a repeated-measures model, the T group achieved a mean BMD in the femoral neck 0.015 g/cm(2) higher than the placebo group at 3 years (95% confidence interval -0.005 to 0.034, P = .13). Similar findings were observed in the lumbar spine BMD as well. CONCLUSION: Long-term physiological transdermal estradiol replacement in combination with oral medroxyprogesterone acetate restores mean femoral neck BMD to normal in young women with spontaneous 46,XX primary ovarian insufficiency. However, the addition of physiological transdermal T replacement did not provide additional benefit.
Asunto(s)
Densidad Ósea/efectos de los fármacos , Estradiol/administración & dosificación , Terapia de Reemplazo de Hormonas/métodos , Insuficiencia Ovárica Primaria/tratamiento farmacológico , Insuficiencia Ovárica Primaria/metabolismo , Testosterona/administración & dosificación , Trastornos del Desarrollo Sexual 46, XX/tratamiento farmacológico , Trastornos del Desarrollo Sexual 46, XX/metabolismo , Absorciometría de Fotón , Administración Cutánea , Adulto , Anticonceptivos Femeninos/administración & dosificación , Método Doble Ciego , Quimioterapia Combinada , Estradiol/sangre , Femenino , Cuello Femoral/diagnóstico por imagen , Cuello Femoral/metabolismo , Humanos , Acetato de Medroxiprogesterona/administración & dosificación , Estudios Prospectivos , Testosterona/sangre , Terapéutica , Adulto JovenRESUMEN
Overexpression of CYP19A1 encoding aromatase results in a rare genetic disorder referred to as aromatase excess syndrome (AEXS). Male patients with AEXS manifest pre- or peri-pubertal onset gynecomastia, gonadotropin deficiency, and advanced bone age, while female patients are mostly asymptomatic. To date, 30 male patients with molecularly confirmed AEXS have been reported. A total of 12 types of submicroscopic rearrangements, i.e., two simple duplications, four simple deletions, two simple inversions, and four complex rearrangements, have been implicated in AEXS. Clinical severity of AEXS primarily depends on the types of the rearrangements. AEXS appears to account for a small number of cases of pre- or peri-pubertal onset gynecomastia, and should be suspected particularly when gynecomastia is associated with an autosomal dominant inheritance pattern, characteristic hormone abnormalities and/or advanced bone age. Treatment with an aromatase inhibitor appears to benefit patients with AEXS, although long-term safety of this class of drugs remains unknown.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/genética , Aromatasa/deficiencia , Ginecomastia/genética , Infertilidad Masculina/genética , Errores Innatos del Metabolismo/genética , Pubertad , Trastornos del Desarrollo Sexual 46, XX/diagnóstico , Trastornos del Desarrollo Sexual 46, XX/tratamiento farmacológico , Adolescente , Adulto , Aromatasa/genética , Inhibidores de la Aromatasa/uso terapéutico , Niño , Quimera , Estradiol/sangre , Femenino , Hormona Folículo Estimulante/sangre , Hormona Folículo Estimulante/deficiencia , Reordenamiento Génico/genética , Genotipo , Hormona Liberadora de Gonadotropina , Ginecomastia/diagnóstico , Ginecomastia/tratamiento farmacológico , Humanos , Infertilidad Masculina/diagnóstico , Infertilidad Masculina/tratamiento farmacológico , Hormona Luteinizante/sangre , Masculino , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/tratamiento farmacológico , Fenotipo , ARN Mensajero/genética , Testosterona/sangreRESUMEN
Aromatase deficiency (AD) is a rare autosomal recessive inheritance syndrome. Its worldwide incidence is unknown, and there are few case reports in the literature. Aromatase dysfunction develops due to CYP19A1 gene mutation and a decrease in estrogen synthesis. Estrogen deficiency can induce delayed epiphyseal closure, eunuchoid body habitus, osteopenia, and osteoporosis in both genders. Our patient was a 27-year-old male who presented with bone pain, recurrent bone fractures associated with minimal trauma starting in puberty, and a progressive increase in height. Laboratory tests revealed that the blood levels of follicle-stimulating hormone and luteinizing hormone were above normal, testosterone level was normal, and estrogen was undetectable. Plain bone radiography of the left wrist and hand demonstrated that the epiphyses were still unfused. Lumbar osteoporosis was detected in bone densitometry. In the genetic analysis, homozygous R375H guanine-adenine (G-A) mutation was detected in the CYP19A1 gene, and a diagnosis of AD was reached. Treatment with 25 µg transdermal estradiol was started. All family members were examined. Homozygous R375H G-A mutation was detected in the patient's younger brother. Heterozygous R375H G-A mutation was found in his mother, father, and older brother. In conclusion, this AD patient requires lifetime estrogen replacement in order to provide sufficient bone mineralization, to reduce the risk of bone fractures, and to lead a healthy life. The best method to prevent the possible complications is to diagnose the AD syndrome at early ages and to provide adequate estrogen replacement starting at puberty.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/genética , Aromatasa/deficiencia , Ginecomastia/genética , Infertilidad Masculina/genética , Errores Innatos del Metabolismo/genética , Trastornos del Desarrollo Sexual 46, XX/tratamiento farmacológico , Adulto , Aromatasa/genética , Aromatasa/metabolismo , Análisis Mutacional de ADN , Estradiol/sangre , Estradiol/uso terapéutico , Estrógenos/sangre , Estrógenos/uso terapéutico , Salud de la Familia , Femenino , Ginecomastia/tratamiento farmacológico , Homocigoto , Humanos , Infertilidad Masculina/tratamiento farmacológico , Masculino , Errores Innatos del Metabolismo/tratamiento farmacológico , Mutación Missense , Linaje , Enfermedades Raras/tratamiento farmacológico , Enfermedades Raras/genética , SíndromeRESUMEN
BACKGROUND: The adequate replacement dose of estrogens during infancy and childhood is still not known in girls. Aromatase deficiency offers an excellent model to study how much estrogens are needed during infancy, childhood and adulthood. OBJECTIVES: We studied the impact of oral 17ß-estradiol treatment, on longitudinal growth, bone age maturation, pituitary gonadotropin feedback, multicystic ovaries and bone mass in the long-term follow-up of a girl compound heterozygote for two point mutations of the CYP19A1 gene. RESULTS: Low doses of 17ß-estradiol were needed to achieve normal height velocity and adequate bone age maturation from early childhood on. Serum estradiol levels needed for breast development and for the appearance of an endometrial reflex were not sufficient to achieve physiological gonadotropin levels. Without 17ß-estradiol treatment the ovaries of the patient showed a multicystic appearance, which reversed on 17ß-estradiol replacement. Bone mass was within normal ranges during the whole follow-up period. CONCLUSION: In summary, we have shown that estradiol is needed not only in puberty but also in childhood for normal growth, bone maturation and achievement of normal bone mass. Particularly, this observation underscores the importance of early low-dose estrogen replacement also in other estrogen-deficient conditions as for instance in Turner's syndrome.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX , Desarrollo Infantil/efectos de los fármacos , Estradiol/farmacología , Estradiol/uso terapéutico , Gónadas/efectos de los fármacos , Ginecomastia , Infertilidad Masculina , Errores Innatos del Metabolismo , Hipófisis/efectos de los fármacos , Trastornos del Desarrollo Sexual 46, XX/tratamiento farmacológico , Trastornos del Desarrollo Sexual 46, XX/metabolismo , Trastornos del Desarrollo Sexual 46, XX/fisiopatología , Adolescente , Aromatasa/deficiencia , Aromatasa/efectos de los fármacos , Aromatasa/genética , Aromatasa/metabolismo , Desarrollo Óseo/efectos de los fármacos , Huesos/efectos de los fármacos , Huesos/fisiología , Niño , Preescolar , Estradiol/administración & dosificación , Terapia de Reemplazo de Estrógeno , Femenino , Estudios de Seguimiento , Gónadas/metabolismo , Ginecomastia/metabolismo , Ginecomastia/fisiopatología , Humanos , Infertilidad Masculina/metabolismo , Infertilidad Masculina/fisiopatología , Errores Innatos del Metabolismo/metabolismo , Errores Innatos del Metabolismo/fisiopatología , Hipófisis/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Aromatase deficiency is a rare autosomal recessive disorder caused by mutations in the CYP19A1 gene and characterized by lack of conversion of androgens to estrogens. It presents with virilization of pregnant mothers during the antenatal period, and virilization of female fetuses at birth. Affected subjects of either gender later manifest with features of estrogen deficiency and androgen excess. PATIENT AND METHODS: We describe the clinical course of an Indian girl with aromatase deficiency from birth to 16 years of age. Estrogen replacement was begun at age 13.5 years. The child's growth, hormonal, radiological, and metabolic parameters were monitored throughout the course of treatment. RESULTS: The child presented with obesity, tall stature, delayed bone age, osteoporosis, hyperinsulinemia with acanthosis nigricans, and hypergonadotropic hypogonadism with cystic ovaries. Estrogen replacement resulted in a plateauing of height, improvement of bone maturation, and pubertal progression with the disappearance of ovarian cysts. However, hyperinsulinemia and acanthosis nigricans persisted despite estrogen replacement and metformin. Genetic analysis revealed a homozygous arginine to cysteine substitution at codon 435 in exon 10 of CYP19A1. CONCLUSIONS: This is the first case of aromatase deficiency reported from India. This case highlights the role of estrogen in skeletal maturation and mineralization and the effect of estrogen deficiency and androgen excess over glucose metabolism in adolescent females.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/genética , Desarrollo Infantil/fisiología , Terapia de Reemplazo de Estrógeno , Trastornos del Crecimiento/etiología , Ginecomastia/genética , Infertilidad Masculina/genética , Errores Innatos del Metabolismo/genética , Trastornos del Desarrollo Sexual 46, XX/tratamiento farmacológico , Adolescente , Hiperplasia Suprarrenal Congénita/diagnóstico , Aromatasa/deficiencia , Aromatasa/genética , Densidad Ósea , Preescolar , Análisis Mutacional de ADN , Etinilestradiol/uso terapéutico , Femenino , Fludrocortisona/uso terapéutico , Trastornos del Crecimiento/tratamiento farmacológico , Ginecomastia/tratamiento farmacológico , Humanos , Hidrocortisona/uso terapéutico , Infertilidad Masculina/tratamiento farmacológico , Resistencia a la Insulina , Masculino , Errores Innatos del Metabolismo/tratamiento farmacológico , Mutación Missense , Linaje , Maduración Sexual/fisiologíaRESUMEN
Estrogen is implicated as playing an important role in aging and tumorigenesis of estrogen responsive tissues; however the mechanisms underlying the mitogenic actions of estrogen are not fully understood. Here we report that estrogen deficiency in mice caused by targeted disruption of the aromatase gene results in a significant inhibition of telomerase maintenance of telomeres in mouse ovaries in a tissue-specific manner. The inhibition entails a significant shortening of telomeres and compromised proliferation in the follicular granulosa cell compartment of ovary. Gene expression analysis showed decreased levels of proto-oncogene c-Myc and the telomerase catalytic subunit, telomerase reverse transcriptase (TERT), in response to estrogen deficiency. Estrogen replacement therapy led to increases in TERT gene expression, telomerase activity, telomere length and ovarian tissue growth, thereby reinstating ovary development to normal in four weeks. Our data demonstrate for the first time that telomere maintenance is the primary mechanism mediating the mitogenic effect of estrogen on ovarian granulosa cell proliferation by upregulating the genes of c-Myc and TERT in vivo. Estrogen deficiency or over-activity may cause ovarian tissue aging or tumorigenesis, respectively, through estrogen regulation of telomere remodeling.