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.

Prior switching to a second-line nonsteroidal antiandrogen does not impact the therapeutic efficacy of abiraterone acetate in patients with metastatic castration-resistant prostate cancer: a real-world retrospective study / 亚洲男科学杂志(英文版)

Even in the era of novel targeted agents, switching to a second-line nonsteroidal antiandrogen (NSAA) is still widely used in treating metastatic castration-resistant prostate cancer (mCRPC), especially in undeveloped countries. However, whether prior treatment with a second-line NSAA would impact the efficacy of abiraterone acetate (Abi) remains uncertain. In the current study, 87 mCRPC patients treated with Abi were analyzed. Among them, 21 were treated with a second-line NSAA (from bicalutamide to flutamide) before receiving abiraterone, while the remaining 66 received Abi directly. Therapeutic efficacy of Abi was compared between those with and without prior second-line NSAA using Kaplan-Meier curves, log-rank test, and Cox regression models. The therapeutic efficacy of Abi was similar between those with or without the prior switching treatment of flutamide, in terms of either prostate-specific antigen progression-free survival (PSA-PFS, 5.5 vs 5.6 months, P = 0.967), radiographic progression-free survival (rPFS, 12.8 vs 13.4 months, P = 0.508), overall survival (OS, not reached vs 30.6 months, P = 0.606), or PSA-response rate (71.4% [15/21] vs 60.6% [40/66], P = 0.370). This is the first time that the impact of prior switching of treatment to a second-line NSAA on the efficacy of Abi in mCRPC patients has been addressed. Our data support that, use of prior sequential bicalutamide and flutamide does not seem to preclude response to abiraterone, although larger cohort studies and, ideally, a randomized controlled trial are needed. These findings will facilitate doctors' decision-making in the treatment of mCRPC patients, especially for those with previous experience of switching NSAA second-line treatments in the clinic.

Preparation and physicochemical characterization of prazosin conjugated PLGA nanoparticles for drug delivery of flutamide

In the current work, a sustained drug delivery system of flutamide (FLT) was developed using Poly(D,L-lactide-co-glycolide) (PLGA) decorated bypoly(ethylene glycol) (PEG) grafted prazosin (PLGA-PEG-Praz) as a targeting moiety. In a multi-step reaction, PLGA was linked to PEG and prazosin. The structure of the synthesized polymers was confirmed by FTIR and 1H-NMR. Flutamide-loaded nanoparticles were prepared by quasi-emulsion solvent diffusion technique. The nanoparticles were evaluated for size, zeta potential, polydispersity index, drug crystallinity, loading efficiency, and release properties. Also, the physicochemical properties of the nanoparticles were analyzed using Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry, and Powder X-Ray Diffractometry (XRD). The particle size of nanoparticles was ranged between 191 and 249 nm. Loading efficiency of nanoparticles was about 43%-69%. Results showed a steady release rate for nanoparticles compared to that of a pure drug powder. SEM characterization confirmed that particles were in nanosize range. DSC and XRPD results verified a decrease in drug crystallinity in the prepared formulations. In conclusion, the results of this study showed that PLGA-PEG-Praz nanoparticles could be a good choice to improve the physicochemical properties of the drug and these formulations can increase Flutamide efficacy.

Tratamento hormonal da acne baseado em evidências / Hormonal treatment of acne based on evidence

Este trabalho de revisão apresenta o tratamento hormonal da acne baseado em evidências. O trabalho resume a clínica, a classificação, a fisiopatologia e a etiologia da acne. A avaliação de estudos selecionados mostrou que o tratamento hormonal da acne deve ser complementado por tratamento cosmiátrico, e não está indicado para gestantes ou mulheres com planos de engravidar. A primeira escolha para esse tratamento são os contraceptivos hormonais orais, pois são efetivos e seguros para tratamento da acne e também para anticoncepção. Após tempo estabelecido, se o resultado for insatisfatório, outro medicamento, como acetato de ciproterona ou espironolactona, deve ser adicionado. A finasterida é o medicamento indicado para acne de origem idiopática, e a flutamida apresenta efeitos colaterais significativos, não constituindo indicação segura até o momento.

This review shows the hormonal treatment of acne. The review summarizes the clinical aspects, classification, physiopathology and etiology of the acne. The evaluation of selected papers showed that hormonal treatment of acne with hormones has to be complemented by esthetics treatment and is not prescribed for pregnant women or those who want to get pregnant. The first choice of treatment is the hormonal oral contraceptive one, because it is effective and safe for treatment of acne and also for contraception. After an established period with unsatisfactory results, other medicines, such as ciproterone acetate or spironolactone, can be added. The finasteride is prescribed for idiopathic acne and flutamide has many relevant side effects and is also not safe.

Eficacia de la flutamida en el tratamiento del hirsutismo: contribución del uso combinado con anticonceptivos orales en mujeres normoandrogénicas / Effectiveness of flutamide alone or combined with oral contraceptives in the treatment of hirsutism in women

Background: Flutamide is an antiandrogen devoid of other hormonal effects, except for a decrease in the secretion of adrenal androgens such as dehydroepidandrosterone sulphate (DHEA-s) and androstenedione. Aim: To assess the effectiveness of flutamide in the treatment of hirsutism, used as monotherapy or combined with oral contraceptives (OC). Patients and methods: Women with peripheral hirsutism (defined as the presence of normal serum androgen levels and normal ovulatory menstrual cycles) were assigned to receive flutamide alone (500 mg/day) or flutamide plus an OC (ethynylestradiol 0.03 mg and desogestrel 150 µg). Hirsute with hyperandrogenism (polycystic ovary syndrome) were assigned to receive flutamide plus an OC. The degree of hirsutism was assessed using a clinical score (Moncada) at three, six and twelve months of therapy. Results: Twenty five women with peripheral hirsutism received flutamide alone and 18 receive flutamide plus the contraceptive. Eighteen women with polycystic ovary syndrome were studied. At three months, the reduction in hirsutism was 11.2, 15.9 and 24.7 percent in women with peripheral hirsutism receiving flutamide alone or flutamide plus OC and in hyperandrogenic women receiving flutamide plus OC, respectively. At twelve months, the figures were 57.2, 57.3 and 52.5 percent respectively. In hyperandrogenic women, at baseline and three months, serum testosterone levels were 0.96 and 0.42 ng/ml and serum DHEA-s levels were 2,980 and 1,490 ng/ml respectively. No collateral effects of treatment or elevations in serum transaminase levels were observed. Conclusions: Flutamide is effective in the treatment of hirsutism in women with normal or elevated androgen levels. Adding OC did not improve the efficacy of the drug.

Ketoconazole and Flutamide in the treatment of disseminated intravascular clotting from prostate cancer: a case report and review.

Disseminated intravascular clotting (DIC) is a well-recognized complication of malignancy. Prostatic cancer can produce chronic DIC as well as acute severe DIC. Treatment of DIC are general supportive measures including heparin, transfusion of blood, platelets and clotting factors, but the most important aspect is correction of underlying malignant diseases i.e. cancer of the prostate gland. For metastatic prostatic cancer presenting with an emergency oncologic condition, the treatment of choice is surgical orchiectomy, but surgery may not be possible in the presence of severe DIC. Ketoconazole and Flutamide are drugs with different mechanisms for hormonal manipulation of this cancer. Due to severe DIC, we combined both drugs trying to put maximum therapeutic effect on this life threatening profound DIC patient.

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

Hirsutismo - tratamento / Treatment of hirsutism

O hirsutismo representa uma patologia de grande importância para os médicos ginecologistas, näo só pela sua expressiva incidência e pelo aspecto emocional que envolve as pacientes, mas também pela baixa aderência ao tratamento que deve ser a longo prazo.

Evaluation of prostate specific antigen in the prognosis of patients with advanced prostate cancer

Objective: To evaluate the survival rate of patients with advanced prostate cancer in a univariate form, according to the preoperative and first postoperative determination of PSA levels. Materials and Methods: From February 1987 to June 1995, 92 patients were submitted to maximum blockage androgen (subcapsular and antiadrogen orchiectomy), independent of clinical symptons shown upon admission to the Cancer Hospital. The antiandrogens (ciproterone acetate and flutamide) were administered until the patient present progression of the disease. Results: The age of patients varied from 44 to 89, with a median of 70 years old. In the 6th, 36th and 60th months the global survival rate was 80 percent, 38 per cent and 20 per cent, respectively. The preoperative PSA ranged from 2 to 4017 ng/ml, with a median of 98 ng/ml (98 per cent had PSA greater than or equal to 10 ng/ml). The first postoperative PSA ranged from 1 to 3840 ng/ml, with a median of 20 ng/ml. There was a tendency towards a better survival rate only in patients with initial PSA from 2 to 99 ng/ml (p=0.06745). The survival rate of patients at 36 months after initial total blockage androgen, with first PSA level from 1 to 4, 5 to 49 and over 49 ng/ml was 72 per cent, 48 per cent and 8 per cent, respectively (p=0.00004). In the final examination, 34 (37 per cent) patients were considered stable and 58 (63 per cent) had disease progression. Conlusion: The PSA determination performed on the 30th postoperative day is important in the evaluation of advanced prostate cancer prognosis.

Flutamida no tratamento da acne / Flutamide in acne treatment

FUNDAMENTOS - A flutamida é potente antiandrógeno näoö-esteróide, deprovido de outras propriedades hormonais ou näo-hormonais, utilizado no tratamento do câncer prostático avançado, e que possui marcada atividade no tratamento do hirsutismo e no bloqueio das glândulas sebáceas. OBJETIVOS - Avaliar a eficácia e segurança da flutamida oral em doses de 250mg/dia na acne näo responsiva aos tratamentos convencionais. MATERIAL E MÉTODOS - Trinta e oito mulheres voluntárias sadias, em idade fértil, com diferentes graus de intensidade de acne e níveis séricos de andrógenos normais foram tratadas com flutamida oral, 125mg/2x/dia por um período de até 18 meses, com acompanhamento clínico e laboratorial bimensal. RESULTADOS - Houve involuçäo total das lesöes clínicas em 34,2 porcento das pacientes, reduçäo de mais da metade da intensidade da acne em 47,4 porcento e reduçäo de menos de um terço das lesões em 7,8 porcento das pacientes. Em 10,6 porcento o quadro manteve-se inalterado ou até pior. Com essa dosagem, näo se observaram efeitos colaterais, clínicos ou laboratoriais, de monta. Após a suspensäo do fármaco, cerca de um terço das pacientes experimentou recidiva do quadro acnéico, com intensidades variáveis. CONCLUSÄO - Muito embora näo podendo ser considerada droga de rotina no tratamento da acne feminina, a flutamida pode constituir-se em alternativa terapêutica bastante útil no combate do hiperandrogenismo cutâneo para algumas pacientes selecionadas

Blockade of the in vitro effects of testosterone and erythropoietin on Cfu-E and Bfu-E proliferation by pretreatment of the donor rats with cyproterone and flutamide

Erythropoietin is obligatory to support the terminal proliferation and differentiation of erythroid cells but it is not the only agent in modulating red cell production. Previously, we have shown that Testosterone enhances erythropoiesis, at least in part, by increasing renal erythropoietin production. Testosterone may also influence directly the behavior of the erythroid progenitor cells increasing erythroid stem cell proliferation. To gain further insight into the role of testosterone in regulation of erythropoiesis and its interactions with erythropoietin, we studied the effect of testosterone and erythropoietin, using clonal cultures of erythropietic progenitors, to observe CFU-E and late and early BFU-E colonies proliferation from bone marrow cells of donor rats pretreated for 2 days with the androgen antagonists cyproterone (10 mg/Kg/day) and flutamide (160 mg/Kg/day). Specific nuclear receptors for testosterone were demonstrated in marrow erythroid cells. Then, erythroid progenitors may come with their androgen receptors blocked by pretreatment. Cultures were prepared using the methylcellulose technique containing a standard dose of erythropoietin (250 mu/ml) or testosterone (10(-7) M). Results obtained demonstrate that testosterone produced a significant stimulation on CFU-E and BFU-E colony formation. A dose effect correlation was apparent. Testosterone enhances proliferation of late BFU-E more than CFU-E and produce only a slight augmentation of early BFU-E. As expected, erythropoietin markedly stimulate all erythroid colony growth, mainly CFU-E. The effects of testosterone were completely abolished in cultures from bone marrow cells of rats pretreated with cyproterone and flutamide. Activation of the specific androgen nuclear receptors in erythroid cells appears to be necessary for testosterone to develop the erythropoietic effect. Surprisingly, the effects of erythropoietin on erythroid colonies proliferation were also completely blocked by pretreatment with flutamide and partially blocked by pretreatment with cyproterone. Right now, we do not have a satisfactory explanation regarding inhibition of the effects of erythropoietin by pretreatment to marrow donor rats with the androgen antagonists. In conclusion, we postulate triggering late BFU-E cells, a marrow erythropoietin responsive cell population, into active cell cycle, as well as by increasing blood erythropoietin concentration.

Castración quirúrgica con y sin flutamida en el carcinoma avanzado de la prostata / Surgical orchidectomy with and without the use of flutamide in patients with advanced prostatic cancer

Nosotros presentamos nuestra experiencia en el manejo de los pacientes con Carcinoma Avanzado de Próstata estadio D2 con la combinación de Flutamida más castración quirúrgica. Demostrando la eficacia en términos de sobrevida, economía y rendimiento. Sin embargo, creemos que estudios randomizados prospectivos deben ser realizados

Remissäo completa de metástases endobrônquica, parenquimatosa e ganglionar hilar pulmonares de carcinoma de próstata após hormonioterapia antiandrogênica / Complete remission of endobronchial, parenchymal and hilar lymphatic lung metastases of prostatic carcinoma after anti-androgenic hormotherapy

Homem negro de 65 anos de idade referia, há 5 meses, queixas respiratórias e urinarias. A rivestigaçao realizada demonstrou a existência de carcinoma de próstata com metástases ósseas, brônquica, parenquimatosa e ganglionar hilar pulmonar. Biópsias de próstata e de brônquio revelaram carcinoma; a pesquisa de antígeno prostático específico foi positiva em ambas. O paciente foi submetido à prostatectomia e orquiectomia bilateral, bem como hormonioterapia antiandrogênica; houve involuçao das metástases brônquicas, pulmonar e ganglionar, mantendo-se inalteradas as ósseas. Em conclusao: metástases pulmonar e brônquica de carcinoma de próstata podem simular carcinoma brônquico primitivo; o tratamento hormonal foi satisfatório, evitando-se, assim, radio e quimioterapia; regressao completa com terapia antiandrogênica é possível, evitando-se radio e quimioteerapia.

Estudio comparativo de 7 tratamientos antifúgicos en un modelo experimental de criptocococis murina (2§ parte) / Comparative study of 7 antifungal treatments in an experimental model of murine cryptococcosis (2§ part)

Se realizó el estudio comparativo de 7 tratamientos antinfúgicos en un modelo experimental de criptococosis murina. Se inocularon por vía intraperitoneal, con 10§ células de Crytococcus neoformans var. neoformans, 100 ratones Balb C divididos en grupos de 10 animales cada uno. En 7 grupos, 5 días después de la dosis infectante y durante 4 semanas se administraron los siguientes tratamientos: anfotericina B [AMB] (6 mg/kg/día por medio, intraperitonealmente); 5-fluorocitosina [5-FC] sola (300mg/kg/día, por gastroclisis), en combinación con AMB (6mg/kg/día, intraperitonealmente) y con fluconazol [FLU] (l6mg/kg/día; FLU, itraconazol [ITRA] y Sch 39.304 [SCH] (todos ellos en dosis diaria de 16mg/kg, por gastroclisis). Los 3 grupos restantes recibieron los solventes de las drogas y se usaron como controles. La evaluación de la actividad de los distintos tratamientos se estableció a través de los siguientes parámetros: tiempo de sobrevida; aspecto macroscópico del cerebro, pulmón, bazo e hígado en la autopsia; presencia de levaduras capsuladas en el examen microscópico de estos mismos órganos y mediante cultivos de homogeneizados de cerebro y pulmón en forma masiva. La asociación de AMB + 5-FC fue el tratamiento más eficaz; produjo tiempos de sobrevida de 90 días en todos los animales tratados y negativizó los otros parámetros estudiados. El 60% de los animales tratados con AMB tuvo iguales tiempos de sobrevida y aspecto macroscópico de sus órganos que aquellos tratados con AMB+5-FC. También se observaron diferencias parciales en los hallazgos microscópicos, con respecto a los grupos de control, no así en la siembra masiva que fue positiva en todos los casos. SCH fue el compuesto azólico más eficaz. Comparado con AMB sola mostró tiempos de sobrevida algo menores con más alteraciones macroscópicas y mayor número de microscopías positivas. FLU, ITRA, 5-FC sola o en combinación con FLU solamente prolongaron el tiempo de sobrevida sin modificar los restantes parámetros estudiados, con respecto a los grupos de control. La actividad de la combinación de 5-FC+FLU fue similar a la de ambas drogas cuando se administraron separadamente. Todos los tratamientos establecidos durante 4 semanas prolongaron los tiempos de sobrevida cuando se compararon con aquellos obtenidos con tratamientos realizados durante 2 semanas en un trabajo anterior(1). Los animales tratados con anfotericina B sola mostraron menos resultados positivos en la observación microscópica de sus órganos y e

Efecto del bloqueo androgénico periférico sobre las lipoproteinas plasmáticas en pacientes hirsutas / Effect of peripheral androgenic blockade upon plasma lipoproteins in female patients with hirsutism

We studied the effect of flutamide, a peripheral androgenic blocking agent, 500 mg daily for days in 7 non ovalating patients with hirsutism. Totañl and HDL cholestero, triglycerides, testosterone and dehydroepiandrosterone sulphate (S-DHEA) plasma levels were measured in patients and in 6 non ovulating control women of similar age and weight. Only basal HDL levels were lower in patients than in controls (40.2 ñ 1.6 vs 51.4 weight Only basal HDL levels were lower in patients than in controls (40.2 ñ 1.6 vs 51.4 ñ 3.3mg/dl, p < 0.01). A decrease in S-DHEA levels was observed after flutamide in patients with hirsutism (3.2 ñ 0.4 to 2.1 ñ 0.4, p < 0.01) which may be attributed to the lowering of cortisol clearance induced by the drug. total testosterone and plasma lipoproteins reamined stable. Thus, peripheral androgenic blockade does not modify the decreased levels of HDL cholesterol in non ovulating patients with hirsutim