Fisiopatología del síndrome de ovario poliquístico / Pathophysiology of polycystic ovary syndrome

Introducción: En la génesis del síndrome de ovario poliquístico intervienen múltiples factores sistémicos y locales que tienen una relación multidireccional sobre los que persisten muchas cuestiones aún sin dilucidar y cierta confusión e incertidumbre. Objetivo: Describir el enfoque actual sobre las causas y los mecanismos involucrados en el origen y desarrollo del síndrome de ovario poliquístico. Métodos: Se realizó una revisión bibliográfica tipo estado del arte. Se revisaron alrededor de 250 artículos, que se obtuvieron de las bases PubMed, Medline, SciELO y Google Académico. Se describen los factores y las vías que se proponen para explicar la etiopatogenia y fisiopatología de alteraciones genéticas, ambientales, endocrinas y metabólicas asociadas al síndrome y su expresión clínica. Conclusiones: La fisiopatología del síndrome de ovario poliquístico es compleja. Muchos aspectos permanecen sin esclarecerse, pero se tiene cada vez más conocimiento que aporta luz a los enigmas que aún persisten y a la comprensión de fenómenos previamente desconocidos. Existe el convencimiento creciente de que la alteración central es a nivel ovárico, que el síndrome es heterogéneo en todos sus elementos y que conocer la gran diversidad de factores y mecanismos que intervienen en su etiología y patogenia es fundamental no sólo desde lo científico, sino también por su utilidad práctica(AU)

Introduction: Multiple systemic and local factors are involved in the genesis of polycystic ovary syndrome that have a multidirectional relationship about which many there are questions yet to be clarified and some confusion and uncertainty persist. Objective: To describe the current approach to the causes and mechanisms involved in the origin and development of polycystic ovary syndrome. Methods: A state-of-the-art literature review was performed. The factors and pathways proposed to explain the etiopathogenesis and pathophysiology of genetic, environmental, endocrine and metabolic alterations associated with the syndrome and its clinical expression are described. Conclusions: The pathophysiology of polycystic ovary syndrome is complex. Many aspects remain unclear, but there is increasing knowledge that sheds light on the enigmas that still persist and on the understanding of previously unknown phenomena. There is a growing conviction that the central alteration is at the ovarian level, that the syndrome is heterogeneous in all its elements and that knowledge of the great diversity of factors and mechanisms involved is fundamental, not only from the scientific point of view but also for its practical utility(AU)

Consideraciones en el manejo del adulto con Hiperplasia Suprarrenal congénita clásica por déficit de 21-Hidroxilasa / Management considerations for the adult with congenital adrenal hyperplasia due 21-hydroxylase deficiency

La Hiperplasia Suprarrenal Congénita (HSRC) corresponde a un grupo de defectos genéticos en la síntesis de cortisol. El 95% de ellas son debidas al déficit de 21-hidroxilasa por lo que nos referiremos solo a esta deficiencia. La hiperplasia suprarrenal congénita clásica (HSRC-C) debuta en recién nacidos o lactantes con insuficiencia suprarrenal primaria, diferentes grados de hiperandrogenismo clínico en mujeres y puede coexistir con hipotensión, hiperkalemia e hiponatremia si hay un déficit clínico de aldosterona. El objetivo de este artículo es actualizar el conocimiento y enfoques sugeridos para el manejo de la HSRC-C desde el inicio de sus controles en la etapa adulta. El diagnóstico diferencial en retrospectiva de la HSRC-C y la no clásica (HSRC-NC) a veces resulta difícil ya que esta enfermedad es un espectro fenotípico continuo. La insuficiencia suprarrenal y la dependencia a terapia corticoidal son los eventos principales para diferenciar estas dos patologías que tienen enfoques terapéuticos diferentes. El tratamiento de la HSRC-C en adultos abarca 2 objetivos primarios: la adecuada sustitución de la falla suprarrenal y el control de hiperandrogenismo mediante el uso de corticoides en sus dosis mínimas efectivas. En la mujer existen terapias complementarias para el control del hiperandrogenismo como anticonceptivos y otras que se encuentran en diferentes fases de investigación. Esto permite disminuir las dosis de corticoides en algunos casos. Es importante a la vez abordar tres objetivos secundarios: controlar el riesgo cardiometabólico propio de la enfermedad, evitar el sobre tratamiento corticoidal y manejar la infertilidad. La correcta monitorización del tratamiento en adultos tomando en cuenta los objetivos descritos permite una mejor calidad de vida en estos pacientes. Finalmente el consejo genético debe realizarse en todos los pacientes con HSRC que deseen fertilidad y en sus parejas. El estudio requiere de secuenciación del gen CYP21A2 y debe realizarse en un laboratorio de experiencia.

Congenital Adrenal Hyperplasia (CAH) are a group of genetic defects characterized by impaired cortisol synthesis. 95% of them are due to 21-hydroxylase deficiency. We will discuss only this enzyme's deficiency. Classic congenital adrenal hyperplasia (CAH-C) debuts in newborns or infants with primary adrenal insufficiency, some degree of clinical hyperandrogenism in newborn females, and can coexist with hypotension, hyperkalemia, and hyponatremia if there is a clinical aldosterone deficiency. The objective of this article is to update the knowledge and suggested approaches for the management of CAH-C from the beginning of its controls in the adult stage. The retrospective differential diagnosis of CAH-C and non-classical (CAH-NC) is sometimes difficult because this disease is a continuous phenotypic spectrum. Adrenal insufficiency and dependence on corticosteroid therapy are the main events to differentiate these two pathologies that have different therapeutic approaches. In adults, the treatment of CAH-C must include 2 primary objectives: adequate the replacement of adrenal failure and control of hyperandrogenism, through the use of corticosteroids in their minimum effective doses. In women there are complementary therapies for the control of hyperandrogenism, such as contraceptives and others that are in different phases of research. This makes it possible to reduce the doses of corticosteroids in some cases. It is important at the same time to address three secondary objectives: control the cardiometabolic risk of the disease secondary to corticosteroid treatment, avoid corticosteroid overtreatment and manage infertility. The correct monitoring of treatment in adults and taking in to account the objectives described, allows a better quality of life in these patients. Finally, genetic counseling must be carried out in all patients planning for children, with any type of CAH and in their partners. The study requires sequencing of the CYP21A2 gene and must be performed in a certified laboratory.

Salud sexual y reproductiva en pacientes con hiperplasia adrenal congénita asignadas como femeninas / The Reproductive Future of Female-Assigned Patients with Congenital Adrenal Hyperplasia

RESUMEN Introducción: Si bien en la mujer con hiperplasia adrenal congénita la consecución de una función gonadal y fertilidad normales requiere de una adhesión estricta al tratamiento sustitutivo, no siempre esto es suficiente y, desde la adolescencia, aparece algún grado de hiperandrogenismo ovárico que influye de manera negativa. Objetivos: Describir algunos aspectos relacionados con la sexualidad, la salud sexual y reproductiva en pacientes con hiperplasia adrenal congénita asignadas como femeninas. Métodos: Se realizó un estudio descriptivo transversal y observacional, que incluyó todas las pacientes con diagnóstico de hiperplasia adrenal congénita asignadas como femeninas, que fueron atendidas en el Instituto Nacional de Endocrinología durante el periodo 2000-2019. Exploró aspectos demográficos, historia familiar y aspectos relacionados con la salud sexual y reproductiva. Resultados: La muestra quedó constituida por 47 pacientes, con una media de edad actual de 14,76 ± 7,04 años y una edad promedio de inicio del tratamiento de 5,9 años. Se comprobó un predominio de las formas clínicas clásicas en 25 pacientes (53,19 por ciento), y 22 (46,80 por ciento) formas no clásicas. Presentaron algún grado de virilización genital 22 pacientes, de este grupo 14 (68,1 por ciento) habían recibido cirugía genital, 5(10,6 por ciento) clitoroplastia con una media de edad 2,8 ± 0,8 años y 9 (19,1 por ciento) combinado con vaginoplastia. De las 36 pacientes en edad reproductiva, 11 (37,9 por ciento) refirieron haber iniciado relaciones sexuales a los 17,8 ± 3,9 años, como promedio. Conclusiones: Es importante considerar que la subfertilidad de las mujeres con hiperplasia adrenal congénita tiene su origen desde los años peripuberales, por lo que debe ser de interés permanente del endocrinólogo pediatra para mejorar su futuro reproductivo(AU)

ABSTRACT Introduction: Although in women with congenital adrenal hyperplasia, the achievement of normal gonadal function and fertility requires strict adherence to substitution treatment, this is not always sufficient and some degree of ovarian hyperandrogenism appears with a negative effect, which is evident since adolescence. Objective: To characterize some factors related to sexual and reproductive health in patients with congenital adrenal hyperplasia and assigned as female. Methods: A cross-sectional and observational-descriptive study was carried out, including all female-assigned patients with a diagnosis of congenital adrenal hyperplasia and who were treated at the Institute of Endocrinology from 2000 to 2019. The study explored demographic aspects, family history, as well as aspects related to sexual and reproductive health Results: The sample was made up of 47 patients, with current mean age of 14.76 ± 7.04 years and average age for starting treatment of 5.9 years. Predominance of classic clinical forms was verified in 25 patients (53.19 percent), while 22 patients (46.80 percent) presented nonclassical forms. Some degree of genital virilization manifested in 22 patients; of this group, 13 (59.1 percent) had received genital surgery, four (8.5 percent) received clitoroplasty at mean age of 2.8 ± 0.8 years, and nine (19, 1 percent) received an approach combined with vaginoplasty. Of the 36 patients at reproductive age, 11 (37.9 percent) reported having started sexual intercourse relations at an average age of 17.8 ± 3.9 years old. Conclusions: It is important to consider that subfertility of women with congenital adrenal hyperplasia starts in the peripubertal years, a reason why it should be of permanent interest to the pediatric endocrinologist in order to improve their reproductive future(AU)

Tumor ovárico de células de Leydig en una niña de 7 años que se presentó como pubarquia precoz con elevación de 17 hidroxiprogesterona / Ovarian tumor of Leydig cells in a 7-year-old girl who presented as precocious pubarche with elevation of 17 hydroxyprogesterone

Clinical case: a girl of 7 ½ years who consulted for early pubarche without thelark, with a percentile size of 75 for a genetic target size in the 10th percentile, overweight with a 90th percentile BMI, and normal blood pressure. The biochemical study showed high levels of androgens: testosterone: 7.2 ng/dL, androstenedione of 5.1 ng / ml, 17OHP: 15 ng / dL with low normal DHEAS (0.26 ug/ml), Plasma Renin Activity normal low: 0.22 ng/mL/h. Initial imaging study showed a bone age of 10 years 6 months and normal abdominal and pelvic ultrasound. Molecular study showed no pathogenic variants in the CYP21A2 gene (21 Hydroxylase). With a probable diagnosis of non-classical congenital adrenal hyperplasia (HSRNC) and no known mutation, he started treatment with hydrocortisone (12 mg/m2). At 8.7 years, pubertal development begins and braking begins with LHRH analogues, which are administered for 18 months. Despite the treatment, signs of virilization and elevation of androgens (testosterone up to 130 ng/ml) are progressively accentuated, which do not diminish when trying different corticosteroid schemes. MRI of the abdomen and pelvis shows the normal adrenal glands and a solid nodular image of 2.1 x 1.6 cm in the right ovary (Figure 2), later demonstrated with pelvic ultrasound (Figure 2). Right laparoscopic oophorectomy was performed, whose biopsy demonstrated a Leydig cell tumor. One month after surgery, all androgenic levels were normalized, so the gradual suspension of corticosteroids began. Conclusion: Although HSRNC is the most frequent pathological cause of early pubarche, when it is associated with progressive clinical and biochemical hyperandrogenism despite adequate treatment and without pathogenic variants in the CYP21A2 gene, even with high levels of 17OHP, other causes should be considered, specifically, androgen producing tumors.

Caso clínico: niña de 7½ años que consulta por pubarquia precoz sin telarquia, con talla en percentil 75 para una talla objetivo genético en percentil 10, sobrepeso con IMC percentil 90 y presión arterial normal. El estudio bioquímico mostró niveles elevados de andrógenos: testosterona: 7,2 ng/dL, androstenediona de 5,1 ng/ml, 17OHP: 15 ng/dL con DHEAS normal baja (0,26 ug/ml), Actividad de Renina Plasmática normal baja: 0.22 ng/ mL/h. Estudio de imágenes inicial mostró una edad ósea de 10 años 6 meses y ecografía abdominal y pelviana normales. Estudio molecular no mostró variantes patogénicas en el gen CYP21A2 (21 Hidroxilasa). Con diagnosticó probable de hiperplasia suprarrenal congénita no clásica (HSRNC) y sin mutación conocida,inició el tratamiento con hidrocortisona (12 mg/m2). A los 8.7 años comienza desarrollo puberal y se inicia frenación con análogos de LHRH, los cuales se administran por 18 meses. A pesar del tratamiento se acentúan progresivamente los signos de virilización y hayelevación de los andrógenos (testosterona hasta 130 ng/ml), que no disminuyen intentando diferentes esquemas de corticoides. Se realiza RM de abdomen y pelvis que muestra las glándulas suprarrenales normales y una imagen nodular sólida de 2.1 x 1.6 cm en el ovario derecho (Figura 2), demostrada posteriormente con Ecografía pelviana (Figura 2). Se realiza ooforectomía derecha por vía laparoscópica, cuya biopsia demostró un tumor de células de Leydig. Un mes después de la cirugía, se normalizan todos los niveles androgénicos por lo que se inició la suspensión gradual de los corticoides. Conclusión: Aunque la HSRNC es la causa patológica más frecuente de la pubarquia precoz, cuando se asocia con un hiperandrogenismo clínico y bioquímico progresivo a pesar de un tratamiento adecuado y sin variantes patógenicas en el gen CYP21A2, incluso con niveles elevados de 17OHP, otras causas deben ser consideradas, específicamente tumores productores de andrógenos.

Tumor ovárico virilizante en mujer postmenopáusica: reporte de caso / Ovarian virilizing tumor in postmenopausal woman: case report

Ovarian steroid-producing tumors are infrequent entities and are potentially malignant. Testosterone is the hormone that rises more frequently and is associated mostly with signs of virilization. We present the clinical case of a 67-year-old postmenopausal woman who came to the clinic for alopecia, with high levels of testosterone and ovarian mass by ultrasound. Surgical treatment was indicated. The main diagnostic aspects are presented.

Los tumores productores de esteroides ováricos constituyen entidades infrecuentes y son potencialmente malignos. La testosterona es la hormona que se eleva con más frecuencia y se asocia en su mayoría a signos de virilización. Se presenta el caso clínico de una mujer postmenopáusica de 67 años que acude a consulta por alopecia, con niveles elevados de testosterona y masa ovárica por ecografía. Se indicó tratamiento quirúrgico. Se presentan los principales aspectos diagnósticos.

Síndrome de ovario poliquístico / Polycystic ovary syndrome

El síndrome de ovario poliquísticos (SOP) representa una de las endocrinopatías más frecuentes en la mujer y es la principal causa de hiperandrogenismo (HA). Se trata de un trastorno complejo, multifactorial, poligénico con influencias ambientales. Aunque se han propuestos diferentes criterios para su diagnóstico, se prefiere el uso del más abarcativo (Criterio de Rotterdam) con la presencia de 2 de 3 de los siguientes: 1) HA clínico o bioquímico, 2) oligoanovulación crónica (OA), 3) poliquistosis ovárica por ecografía, excluyendo otras etiologías. Es frecuente su asociación con comorbilidades metabólicas (obesidad, diabetes 2, dislipidemia, apnea del sueño, etc.) y trastornos reproductivos (hiperplasia endometrial e infertilidad), sobre todo en los fenotipos clásicos, con HA y OA. El tratamiento estará orientado a las características clínicas de cada paciente y al deseo reproductivo. La pérdida de peso en aquellas con sobrepeso u obesidad o ambos factores puede restaurar los ciclos menstruales y disminuir el riesgo metabólico y representa la primera línea de tratamiento. Los anticonceptivos orales (ACO) son el tratamiento farmacológico de elección ya que atenúan las manifestaciones de HA y ofrecen protección endometrial. En las pacientes con oligoanovulación que buscan embarazo, el citrato de clomifeno es el tratamiento aconsejado en primera instancia. La metformina podría usarse en aquellas con intolerancia a la glucosa o diabetes 2 y también como segunda línea de tratamiento para restaurar los ciclos e inducir la ovulación. (AU)

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women, the main cause of hyperandrogenism (HA). It is a complex, multifactorial polygenic disorder with environmental influences. Although there have been proposed different criteria for diagnosis, using the most comprehensive (Criteria Rotterdam) with the presence of 2 of 3 of the following is preferred: 1) HA clinical or biochemical, 2) oligo-anovulation chronic (OA), 3) polycystic ovaries by ultrasound, excluding other etiologies. It is frequently associated with metabolic comorbidities (obesity, type 2 diabetes, dyslipidemia, sleep apnea, etc.) and reproductive disorders (endometrial hyperplasia and infertility), especially in the classical phenotypes, with HA and OA. The treatment will be oriented to the clinical characteristics of each patient and reproductive desire. Weight loss in those who are overweight and / or obesity can restore menstrual cycles and decrease metabolic risk and represents the first line of treatment. Oral contraceptives (OC) are the pharmacological treatment of choice as it attenuates the manifestations of HA and offer endometrial protection. In patients seeking pregnancy with oligo-anovulation, clomiphene citrate would be used at first instance. Metformin may be used in those with impaired glucose tolerance or type 2 diabetes and also as a second-line treatment to restore cycles and induce ovulation. (AU)

Tear osmolarity and tear function assessment in patients with polycystic ovary syndrome / Avaliação da osmolaridade lacrimal e da função lacrimal em pacientes com síndrome dos ovários policísticos

ABSTRACT Purpose: Polycystic ovary syndrome (PCOS) is an endocrine disease characterized by chronic anovulation and hyperandrogenism. Hormonal changes can affect tear function. This study evaluates tear function and impact of hyperandrogenism on it in PCOS patients. Methods: Fifty patients with PCOS and thirty control volunteers were examined for tear break-up time, Schirmer-I and tear osmolarity. Also, serum levels of total testosterone, FSH, LH and AMH were determined in venous blood samples in the early follicular phase. PCOS patients were divided into two groups by plasma total testosterone level: Group A with normal (≤0.513 ng/ml;n=27), Group B with higher hormone level (>0.513 ng/ml;n=23). Healthy control group indicated as Group C (n=30). Results: LH, total testosterone levels were higher in the PCOS group than in the control group (p=0.012; p=0.025). Mean values of tear break-up time and Schirmer-I were different between groups and especially Group A and C were near to each other differing from B (p>0.05). Tear osmolarity results were higher in Group B, compared to A and C (p=0.049; p=0.033). No significant difference detected in tear osmolarity value means of Group A and C (p=0.107). AMH levels were higher in Group B, compared to A and C (p=0.002; p=0.001). AMH levels in Group A were higher than that of C (p=0.002). Positive correlation between levels of total testosterone and AMH was detected in all PCOS patients (n=50;Pearson's r=0.579; p<0.001). Conclusion: Tear function can be affected in PCOS patients with hyperandrogenism. Tear osmolarity is the most sensitive and objective assessment method for ocular surface changes in PCOS.

RESUMO Objetivo: A síndrome do ovário policístico (SOP) é uma doença endócrina caracterizada por anovulação crônica e hiperandrogenismo. As alterações hormonais podem afetar a função cardíaca. Este estudo avalia a função lacrimal e o impacto do hiperandrogenismo sobre ela em pacientes com SOP. Métodos: Cinquenta pacientes com SOP e trinta voluntárias de controle foram examinadas para tempo de ruptura lacrimal, Schirmer-I e osmolaridade lacrimal. Além disso, os níveis séricos de testosterona total, FSH, LH e HAM foram determinados em amostras de sangue venoso na fase folicular precoce.As pacientes com SOP foram divididas em dois grupos por nível de testosterona plasmática total: Grupo A com nível normal (≤0.513 ng/ml; n = 27), Grupo B com nível superior de hormônio (> 0,513 ng/ml; n = 23). Grupo de controle saudável indicado como Grupo C (n = 30). Resultados: Os níveis de LH e testosterona total foram maiores no grupo com SOP do que no grupo controle (p = 0,012; p = 0,025). Os valores médios de tempo de ruptura lacrimal e Schirmer-I foram diferentes entre os grupos, e especialmente os Grupos A e C estavam próximos um do outro, diferente do B (p > 0,05). Os resultados de osmolaridade lacrimal foram maiores no Grupo B, em comparação com A e C (p = 0,049; p = 0,033). Não houve diferença significativa detectada em valor médio de osmolaridade lacrimal nos Grupos A e C (p = 0,107). Os níveis de HAM foram maiores no Grupo B, em comparação com A e C (p = 0,002; p = 0,001). Os níveis de AMH no Grupo A foram superiores aos de C (p = 0,002). Uma correlação positiva entre os níveis de testosterona total e AMH foi detectada em todas as pacientes com SOP (n = 50; Pearson's r = 0,579; p < 0,001). Conclusão: a função lacrimal pode ser afetada em pacientes com SOP com hiperandrogenismo. A osmolaridade lacrimal é o método de avaliação mais sensível e objetivo para alterações da superfície ocular em SOP.

Tumor de células de Leydig do ovário associado a virilização em paciente na pós-menopausa / Ovarian Leydig cell tumor associated with virilization in postmenopausal patient

Tumores de células de Leydig são neoplasias de células esteroides e correspondem a menos de 0,5% dos tumores ovarianos. Ocorrem mais comumente na pós-menopausa e se apresentam com virilização em metade dos casos. Relatamos o caso de uma mulher de 53 anos com história de virilização. A investigação com ressonância magnética demonstrou altos níveis séricos de testosterona e um nódulo de 2 cm no ovário direito. A paciente foi submetida a ooforectomia bilateral, e a análise patológica confirmou o diagnóstico de tumor de células de Leydig do ovário direito. Um dia após a cirurgia, o nível sérico de testosterona se normalizou. Em quatro meses, a paciente apresentou nível sérico normal de testosterona e regressão parcial da alopecia. Em mulheres pós-menopáusicas com quadro de virilização progressiva, deve-se suspeitar de neoplasias ovarianas produtoras de andrógenos (AU)

Leydig cell tumors are tumors of the steroids cells and represent less than 0.5% of ovarian tumors. They occur most often in postmenopausal women and present with virilization in half of the cases. We report the case of a 53-year-old woman with virilization history. Magnetic resonance imaging showed high serum testosterone levels and a 2-cm nodule in the right ovary. The patient underwent bilateral oophorectomy, and the pathological analysis confirmed the diagnosis of Leydig cell tumor in the right ovary. The day after surgery, serum testosterone level was normalized. In four months, the patient had normal serum testosterone level and partial regression of alopecia. In postmenopausal women with progressive virilization, ovarian neoplasms producing androgens should be investigated (AU)

Female hyperandrogenemia and normal serum levels of testosterone and sex hormone binding globulin

It is well known that the reference values usually employed for endocrine biochemical measurements are those suggested by the suppliers of commercial kits despite their advice that each laboratory should set its own reference values. Our objectives were to (i) determine reference ranges for serum testosterone (T) and sex hormone binding globulin (SHBG) appropriate to our laboratory and population, and (ii) to analyze their influence on evaluating hyperandrogenemia. SHBG and T were measured, and free and bioavailable testosterone calculated, in (a) 30 selected non-hyperandrogenic women, (b) 87 non-selected healthy female blood donors, (c) 53 women with hyperandrogenism, and (d) 38 women with hyperandrogenic disorders but without biochemical hyperandrogenemia according to normal ranges suggested by the kit manufacturer. Mean serum SHBG concentrations were significantly different among all four groups. SHBG levels were significantly higher in selected normal women (group a). Using our results for this selected control group as new reference values, 12 out of 38 (31.6%) women with hyperandrogenic disorders without apparent hyperandrogenemia (group d) were recategorized as hyperandrogenemic. Similarly, 4 out of 63 (6.4%) non-selected, normal weight, women (group b), were recategorized as hyperandrogenic. Therefore, the diagnosis of hyperandrogenemia would improve accuracy by using customized reference SHBG values instead of those suggested by the suppliers.

Con frecuencia los valores de referencia utilizados para las evaluaciones bioquímicas endocrinológicas son los sugeridos por los kits utilizados, a pesar de las recomendaciones de que cada laboratorio debiera obtener sus propios valores de normalidad. Nuestros objetivos fueron (i) analizar los rangos de referencia para testosterona (T) y globulina ligadora de esteroides sexuales (SHBG) apropiados para nuestro laboratorio y población, y (ii) analizar su influencia en la evaluación de la hiperandrogenemia. Se midió T y SHBG y se calculó testosterona libre y biodisponible en un grupo (a) control de 30 mujeres no hiperandrogénicas, (b) 87 mujeres no seleccionadas donantes de sangre, (c) 53 mujeres con hiperandrogenismo, y (d) 38 mujeres con desórdenes hiperandrogénicos pero sin hiperandrogenemia de acuerdo a los rangos de normalidad sugeridos por el kit. La concentración media de SHBG fue significativamente diferente entre los cuatro grupos. Los niveles de SHBG fueron significativamente más altos en las mujeres controles seleccionadas (grupo a). Tomando en consideración los resultados obtenidos en este grupo y estableciendo los rangos de referencia adecuados, 12 de 38 mujeres (31.6%) hiperandrogénicas sin hiperandrogenemia (grupo d) fueron recategorizadas como con exceso androgénico bioquímico. De igual manera, al analizar mujeres normopesas no seleccionadas, en edad reproductiva (grupo b), 4 de 63 (6.4%) pudieron ser definidas como hiperandrogénicas. Utilizando valores adecuados de referencia para SHBG, se mejora la precisión del diagnóstico de exceso androgénico.

Ovarian Leydig cell tumor in a post-menopausal patient with severe hyperandrogenism / Tumor ovariano de células de Leydig em paciente em pós-menopausa com hiperandrogenismo grave

Leydig cell tumors are rare ovarian steroid cell neoplasms. More than 75% of patients show signs of virilization due to overproduction of testosterone. We report a case of an 8-year-old woman with progressive signs of virilization, and presenting vaginal bleeding. Clinical analyses revealed high levels of serum testosterone, delta 4-androstenedione and estradiol, and also inappropriate low levels of gonadotrophins for a post-menopausal woman. Transvaginal ultrasound showed no evidence of ovarian tumor, but pelvic and abdominal computerized axial tomography imaging revealed a left ovarian solid nodule, and no evidence of alteration in the adrenal glands. Total hysterectomy and bilateral salpingoophorectomy were performed. Histopathology and immunohistochemistry confirmed the diagnosis of Leydig cell tumor. After surgery, androgen levels returned to normal, and there was regression of the signs of virilization.

Tumores ovarianos de células de Leydig são neoplasias raras de células ovarianas esteroidogênicas. Mais de 75% dos pacientes apresentam sinais de virilização devido à produção excessiva de testosterona. Relatamos aqui o caso de uma mulher de 81 anos de idade com sinais progressivos de virilização e ocorrência de sangramento vaginal. As análises clínicas mostraram altos níveis de testosterona sérica, delta 4-androstenediona e estradiol, além de níveis inadequadamente baixos de gonadotrofinas para uma mulher em pós-menopausa. O ultrassom transvaginal não apresentou evidências de tumor ovariano, mas a tomografia axial computadorizada da região pélvico-abdominal mostrou um nódulo sólido no ovário esquerdo e nenhuma evidência de alteração nas adrenais. Foi feita uma histerectomia total e salpingooforectomia bilateral. Os exames histopatológicos e a imuno-histoquímica confirmaram o diagnóstico de tumor de células de Leydig. Após a cirurgia, os níveis de androgênios voltaram ao normal, e os sinais de virilização regrediram.

Tumor de células de la granulosa asociado a hiperandrogenismo femenino rápidamente progresivo / Granulosa cell tumour associated with rapidly progressive female hyperandrogenism

Reportamos el caso de una mujer de 21 años con hiperandrogenismo rápidamente progresivo de origen tumoral ovárico. La biopsia informó tumor de células de la granulosa y la resección fue curativa. Se analizan los posibles mecanismos por los que un tumor de origen en células de la granulosa pueda sintetizar andrógenos.

We report a 21 year old woman with rapidly progressive hyperandrogenism of ovaric tumoral origin. The biopsy of the tumor reported a granulosa cell tumor and the surgery was curative. We analyze the possible mechanisms implied in the androgen production in the granulosa cells of the tumor.

Hyperandrogenism produced by ovarian tumors in women at different life stages / Hyperandrogenism produced by ovarian tumors in women at different life stages.

OBJECTIVE: to evaluate the different presentations of hyperandrogenism produced by ovarian tumors in women at different life stages DESIGN: case report. SETTING: academic institutions. PATIENT(S): 3 patients at different life stages, with increased androgen levels. INTERVENTION(S): review of hospital records. MAIN OUTCOME MEASURE(S): clinical and biochemical features, treatment and follow-up. RESULT(S): a 10 year-old girl with Leydig cell tumor presented with hyperandrogenemia, virilization and changes in social behavior. Another patient, at reproductive age, with a tumor>10 cm, presented with signs of virilization and abdominal mass, whose pathologic analysis disclosed a carcinoid tumor of the ovary associated with stromal hyperplasia. The third patient was a postmenopausal woman with severe alopecia, who presented a steroid cell tumor, rare at that age. CONCLUSION(S): the evaluation of women with signs and symptoms of virilization should include a detailed clinical record, thorough physical examination and an appropriate hormonal dosage, especially when images are inconclusive.

Polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is a "multispeciality" disorder suspected in patients with irregular menses and clinical signs of hyperandrogenism such as acne, seborrhoea, hirsutism, irregular menses, infertility, and alopecia. Recently, PCOS has been associated with the metabolic syndrome. Patients may develop obesity, insulin resistance, acanthosis nigricans, Type 2 diabetes, dyslipidemias, hypertension, non-alcoholic liver disease, and obstructive sleep apnoea. Good clinical examination with hematological and radiological investigations is required for clinical evaluation. Management is a combined effort involving a dermatologist, endocrinologist, gynecologist, and nutritionist. Morbidity in addition includes a low "self image" and poor quality of life. Long term medications and lifestyle changes are essential for a successful outcome. This article focuses on understanding the normal and abnormal endocrine functions involved in the pathogenesis of PCOS. Proper diagnosis and management of the patient is discussed.

Síndrome hiperandrogênica em mulher na pós-menopausa: relato de caso / Hyperandrogenic syndrome in a postmenopausal woman: a case report

RESUMO As síndromes hiperandrogênicas englobam doenças que se manifestam através de um aumento da atividade biológica dos androgênios e podem ter origem em patologias neoplásicas ou funcionais. Os tumores ovarianos secretores de androgênios constituem cerca de 1 por cento das neoplasias do ovário. O tumor de células esteroides é um dos tipos mais raros, sendo responsáveis por menos de 0,1 por cento de todos os tumores ovarianos. São habitualmente benignos, de pequenas dimensões e unilaterais. Neste relato, apresenta-se o caso raro de um tumor unilateral de células esteroides. Paciente do sexo feminino, 60 anos, por hirsutismo, hipertorfia do clitóris e elevação dos níveis séricos de estradiol, com quatro meses de evolução. Apresentava níveis elevados de testosterona total e de 17-OH-Progesterona.

ABSTRACT Hyperandrogenic syndromes include diseases that manifest through an increased biological activity of androgens and that can originate from neoplastic or functional diseases. Androgen-secreting ovarian tumors represent about 1 percent of ovarian neoplasias. Steroid cell tumors are among the more rare types which account for less than 0.1 percent of all ovarian tumors. They are usually benign, of small dimensions and unilateral. We report here a rare case of a unilateral steroid cell tumor. A 60-year-old woman was seen after four months of evolution of hirsutism, clitoris hypertrophy and elevation of serum estradiol levels. Her total testosterone and 17-OH-progesterone levels were also increased.

Síndrome do ovário policístico: abordagem dermatológica / Polycystic ovary syndrome: a dermatologic approach

A síndrome do ovário policístico (SOP) é uma das endocrinopatias mais freqüentes nas mulheres em idade reprodutiva. Caracteriza-se por morbidade elevada devido aos aspectos estéticos e por repercussões metabólicas importantes. Embora a sua patogênese permaneça incompletamente conhecida, acredita-se numa desordem multigênica complexa, incluindo anormalidades no eixo hipotálamohipofisário, esteroidogênese e resistência insulínica. Os achados principais para o diagnóstico são: hiperandrogenismo, anovulação crônica e ovários policísticos à ultrassonografia. As manifestações dermatológicas do hiperandrogenismo incluem: hirsutismo, acne, seborréia, alopecia e, em casos mais graves, sinais de virilização. Existe considerável heterogeneidade nos achados clínicos e também pode haver variação na mesma paciente com o passar do tempo. O tratamento visa reduzir as manifestações do hiperandrogenismo, restaurar os ciclos ovulatórios regulares e corrigir a síndrome metabólica. Este artigo apresenta revisão da fisiopatologia, diagnóstico e tratamento da síndrome do ovário policístico. Enfatiza-se a importância do diagnóstico e tratamento precoces no intuito de prevenir as complicações metabólicas e a repercussão emocional que afeta a qualidade de vida das pacientes.

Polycystic ovary syndrome (POS) is one of the most common endocrine abnormalities affecting women of reproductive age. It is a cause of significant social embarrassment and emotional distress. The pathogenesis of the disease is not yet fully understood, but it is thought to be a complex multigenic disorder, including abnormalities in the hypothalamic-pituitary axis, steroidogenesis, and insulin resistance. The main diagnostic findings of the syndrome are: hyperandrogenism, chronic anovulation and polycystic ovarian morphology seen on ultrasound. Hyperandrogenism is generally manifested as hirsutism, acne, seborrhea, androgenic alopecia and, in severe cases, signs of virilization. Treatment may improve the clinical manifestations of excess androgen production, normalize menses and ameliorate metabolic syndrome and cardiovascular complications. This article reviews the diagnosis, clinical manifestations, metabolic complications, and treatment of the syndrome. Early diagnosis and the consequent early treatment may prevent metabolic complications and emotional distress that negatively impact the patients' quality of life.

Dificuldades e armadilhas no diagnóstico da síndrome dos ovários policísticos / Difficulties and pitfalls in the diagnosis of polycystic ovary syndrome

A síndrome dos ovários policísticos é uma das endocrinopatias mais comuns, afetando aproximadamente 7 por cento das mulheres na idade reprodutiva. Embora tenha sido descrita em 1935, somente em 1990 foi elaborado o primeiro consenso com relação ao seu diagnóstico. Hoje, a síndrome é considerada também um fator de risco cardiovascular, com uma alta prevalência de distúrbios metabólicos. Como reflexo dessa nova visão da síndrome, vários documentos, entre Consensos, Posicionamentos e Orientações, têm sido publicados, abordando diversos aspectos da síndrome. O objetivo desta revisão é uma análise crítica desses documentos, obtidos mediante um levantamento na base PubMed, por meio dos unitermos polycystic ovary syndrome, hyperandrogenism e hirsutism, separadamente, tendo como limitador o termo Type of Article (Practice Guideline, Consensus Development Conference, Guideline), sem limitação de data, língua e idade. Foram selecionados apenas os documentos elaborados sob patrocínio de Entidades Médicas e com mais de um autor.

The polycystic ovary syndrome is one of the most common endocrinopathies, affecting approximately 7 percent of women of reproductive age. Although it was described in 1935, only in 1990 was published the first Consensus regarding it its diagnosis. Today, the syndrome is also considered a cardiovascular risk factor, with a high prevalence of metabolic disorders. Reflecting this new vision of the syndrome, several documents, including Consensus, Statement and Guidelines have been published, addressing different aspects of the syndrome. This review is an analysis of documents obtained through a survey in the PubMed database, using the keywords "polycystic ovary syndrome", "hyperandrogenism" and "hirsutism", separately, taking as limiting the term Type of Article (Practice Guideline, Consensus Development Conference, Guideline) without limitation of time, language and age, having been selected only those documents prepared under the sponsorship of Medical Entities and with more than one author.

Participação dos androgênios adrenais na síndrome dos ovários policísticos / Adrenal androgen participation in the polycystic ovary syndrome

OBJETIVO: reavaliar a função adrenal em pacientes com síndrome dos ovários policísticos, após a introdução dos critérios de Roterdã. MÉTODOS: estudo descritivo de corte transversal, incluindo 53 pacientes com média de idade de 26±5,1 anos. Glicose, hemoglobina glicada, lipídios, estradiol, progesterona, 17-OHP4, DHEAS, FSH, LH, TSH, PRL, androstenediona, tiroxina livre, insulina, testosterona total, SHBG e índice de androgênios livres foram estimados. Resistência à insulina, examinada pelo modelo homeostático, foi admitida com índice >2,8. A resposta adrenal à cortrosina foi avaliada pelo incremento hormonal observado após 60 minutos e área sobre a curva. RESULTADOS: entre as 53 pacientes elegíveis, hiperandrogenismo bioquímico foi encontrado em 43 (81,1 por cento). Trinta e três delas, com idade de 25,1±5,0 anos, apresentaram hiperandrogenismo adrenal (62,2 por cento), pesavam 74,9±14,9 kg; tinham IMC de 28,8±6,0 e razão cintura/quadril de 0,8±0,1. DHEAS foi >6,7 nmol/L em 13 (39,4 por cento) e androstenendiona >8,7 nmol/L em 31 (93,9 por cento). Cortisol, 17-OHP4, A e progesterona tiveram incremento de 153 por cento, 163 por cento, 32 por cento e 79 por cento, respectivamente. O modelo usado para avaliar a resistência á insulina foi >2,8 em 14 (42,4 por cento). Não foi encontrada correlação entre as concentrações de insulina ou estradiol com as de cortisol ou androgênios. CONCLUSÕES: a utilização de múltiplos parâmetros hormonais revela alta prevalência de hiperandrogenismo bioquímico na SOP, sendo que as adrenais têm participação em dois terço dos casos. Níveis de estradiol e insulina não influenciam a secreção adrenal de androgênios e cortisol.

PURPOSE: to reassess the adrenal function of patients with PCOS after the introduction of the Rotterdam's criteria. METHODS: descriptive and cross-sectional study including 53 patients 26±5.1 years old. Glucose, glycosylated hemoglobin, lipids, estradiol, progesterone, 17-OHP4, DHEAS, FSH, LH, TSH, PRL, androstenedione, free thyroxine, insulin, total testosterone, SHBG, and free androgen index were measured. Insulin resistance was considered to be present with a homeostatic model assessment index >2.8. The adrenal response to cortrosyn was assessed by the hormonal rise observed at 60 minutes, and by the area under the response curve. RESULTS: biochemical hyperandrogenism was found in 43 of 53 eligible patients (81.1 percent). Thirty-three women had adrenal hyperandrogenism (62.2 percent). The weight of these 33 women, aging 25.1±5.0 years, was 74.9±14.9 kg, BMI was 28.8±6.0 and the waist/hip ratio was 0.8±0.1. DHEAS was >6.7 nmol/L in 13 (39.4 percent) and androstenendione was >8.7 nmol/L in 31 (93.9 percent). The increments in 17-OHP4, cortisol, A, and progesterone were 163 percent, 153 percent, 32 percent, and 79 percent, respectively. The homeostatic insulin resistance model was >2.8 in 14 (42.4 percent). Insulin and estradiol were not correlated with cortisol or androgens. CONCLUSIONS: the use of multiple endocrine parameters showed a high prevalence of biochemical hyperandrogenism in patients with PCOS. Two thirds of the patients had adrenal hyperandrogenism, and estradiol and insulin did not influence adrenal secretion.

Síndrome dos ovários policísticos, síndrome metabólica, risco cardiovascular e o papel dos agentes sensibilizadores da insulina / Polycystic ovary syndrome, metabolic syndrome, cardiovascular risk and the role of insulin sensitizing agents

A Síndrome dos Ovários Policísticos (SOP) afeta de 6 a 10 por cento das mulheres em idade reprodutiva. Resistência à insulina e hiperinsulinemia estão presentes em praticamente todas as pacientes com SOP e desempenham papel central no desenvolvimento tanto do hiperandrogenismo como da síndrome metabólica (SM). SM ocorre em aproximadamente 43 por cento das pacientes com SOP, elevando em até sete vezes o risco de doença cardiovascular nestas pacientes. Vários marcadores séricos, funcionais e estruturais de disfunção endotelial e de aterosclerose subclínica foram descritos em pacientes com SOP, mesmo nas jovens e não-obesas. Entretanto, embora a SOP afete adversamente o perfil cardiovascular, estudos a longo prazo não demonstraram consistentemente aumento da mortalidade cardiovascular, a qual parece ser mais observada no período da pós-menopausa. Recentemente, os anticoncepcionais orais estão sendo substituídos pelos agentes sensibilizadores de insulina (metformina e glitazonas) no tratamento da SOP, devido aos seus efeitos sobre a resistência à insulina e o risco cardiovascular.

The Polycystic Ovary Syndrome (PCOS) affects 6 to 10 percent of women of childbearing age. Insulin resistance and hyperinsulinemia are present in nearly all PCOS patients and play a central role in the development of both hyperandrogenism and metabolic syndrome (MS). MS occurs in approximately 43 percent of PCOS patients, raising the cardiovascular risk to up seven fold in these patients. Several serum, functional and structural markers of endothelial dysfunction and subclinical atherosclerosis were described in PCOS patients, even those young and non-obese. However, despite the fact that PCOS adversely affects the cardiovascular profile, long-term studies did not demonstrate a consistent raise in cardiovascular mortality, which seems to be more observed in the post-menopausal period. Recently, oral contraceptives are being substituted for insulin sensitizing agents (metformin and glitazones) in the PCOS treatment, due to their effects on insulin resistance and cardiovascular risk.

Hiperplasia adrenal congénita no clásica: deficiencia de 21-hidroxilasa / Non classic congenital adrenal hyperplasia: 21-hydroxylase deficiency

Los síndromes de hiperandrogenismo de diferente grado constituyen un motivo de consulta frecuente en un consultorio de Ginecología Infantojuvenil. Estos cuadros suelen provocar preocupación en las adolescentes tanto por sus manifestaciones estéticas (hirsutismo, acné, alopecía) como por la presencia de alteraciones del ciclo mestrual que puede crearles dudas sobre su fertilidad futura. Una de las causas de hiperandrogenismo, la Hiperplasia Adrenal Congénita No Clásica (HACNC), cobra importancia debido a su origen genético y a que no existen elementos de la clínica que permitan diferenciarla de otras etiologías como síndrome de ovarios poliquísticos. El presente trabajo propone una actualización sobre HACNC, en cuanto a su fisiopatología, aspectos genéticos, clínica, metodología diagnóstica y tratamiento. Se consideran en forma particular sus posibles repercusiones sobre la fertilidad, así como el asesoramiento genético que requieren estas pacientes