Novel mutation in the gonadotropin-releasing hormone receptor (GNRHR) gene in a patient with normosmic isolated hypogonadotropic hypogonadism / Nova mutação no receptor do hormônio liberador de gonadotrofinas (GNRHR) em um paciente com hipogonadismo hipogonadotrófico isolado normósmico

We report a novel GNRHR mutation in a male with normosmic isolated hypogonadotropic hypogonadism (nIHH). The coding region of the GNRHR gene was amplified and sequenced. Three variants p.[Asn10Lys;Gln11Lys]; [Tyr283His] were identified in the GNRHR coding region in a male with sporadic complete nIHH. The three variants were absent in the controls (130 normal adults). Familial segregation showed that the previously described p.Asn10Lys and p.Gln11Lys are in the same allele, in compound heterozygozity with the novel variant p.Tyr283His. The p.[Asn10Lys;Gln11Lys] are known inactivating mutations. The p.Tyr283His affects a well-conserved residue, and in silico analysis suggested it is a deleterious variant. We describe a novel GNRHR mutation in a male with nIHH. Absence of the mutation in the control group, conservation among species, in silico analysis, and familial segregation suggest that p.Tyr283His, which was identified in compound heterozygozity with the p.[Asn10Lys;Gln11Lys] variants, is an inactivating mutation. Arq Bras Endocrinol Metab. 2012;56(8):540-4.

Relatamos uma nova mutação no gene GNRHR em um homem com hipogonadismo hipogonadotrófico isolado normósmico (HHIn). A região codificadora do gene GNRHR foi amplificada e sequenciada. Três variantes p.[Asn10Lys;Gln11Lys]; [Tyr283His] foram identificadas no GNRHR em um homem com HHIn esporádico. As três variantes estavam ausentes no grupo controle (130 adultos normais). A segregação familiar mostrou que as variantes previamente descritas p.[Asn10Lys;Gln11Lys] se localizavam no mesmo alelo, em heterozigose composta com a nova variante p.Tyr283His. As mutações p.[Asn10Lys;Gln11Lys] são sabidamente inativadoras. A variante p.Tyr283His afeta um resíduo bem conservado, e a análise in silico sugeriu que essa é uma mutação deletéria. Descrevemos uma mutação inédita no gene GNRHR em um paciente com HHIn nIHH. A ausência da variante no grupo controle, a conservação entre as espécies, a análise in silico e a segregação familiar sugerem que a p.Tyr283His é uma mutação inativadora, identificada em heterozigose composta com as mutações p.[Asn10Lys;Gln11Lys]. Arq Bras Endocrinol Metab. 2012;56(8):540-4.

Evaluation of late-onset hypogonadism (andropause) treatment using three different formulations of injectable testosterone / Avaliação do tratamento de pacientes hipogonádicos tardios (andropausa) usando três formulações diferentes de testosterona injetável

OBJECTIVE: To compare the modalities of treatment for male hypogonadism available in Brazil. METHODS: Thirty-two men with late-onset hypogonadism ("andropause") were followed-up in the Hospital de Guarnição de Florianópolis, in Florianópolis, south Brazil. Clinical diagnosis was established according to AMS questionnaire (positive if equal to or higher than 27 points), and laboratorial diagnosis was made through low values of total testosterone (under 300 ng/dL) and/or free calculated testosterone (under 6.5 ng/dL). Patients were randomized to three non-enteral treatment groups (Deposteron® - 11 patients; Durateston® - 11 patients; and Nebido® - 10 patients). RESULTS: Clinically, Nebido® seemed to be superior when compared to Deposteron® (mean value of improvement percentage; p = 0.03) and when compared to Durateston® (post-treatment average AMS score; p = 0.03). According to laboratorial analysis, Nebido® showed higher testosterone levels than Deposteron® and Durateston® (p < 0.001). CONCLUSIONS: All non-enteral testosterone formulas available in the Brazilian market are efficient in raising testosterone levels and in clinical improvement of hypogonadal patients. Nebido® showed both a better clinical and laboratorial effectiveness.

OBJETIVO: Comparar os tratamentos para hipogonadismo masculino disponíveis no Brasil. MÉTODOS: Foram selecionados 32 homens com hipogonadismo tardio ("andropausa") no Hospital de Guarnição de Florianópolis. O diagnóstico foi feito por meio do questionário AMS (acima de 27 pontos) e dos níveis diminuídos de testosterona total dosada (abaixo de 300 ng/dL) e/ou testosterona livre calculada (abaixo de 6,5 ng/dL). Os pacientes foram divididos em três grupos de tratamento parenteral (Deposteron® - 11 pacientes; Durateston® - 11 pacientes; Nebido® - 10 pacientes). RESULTADOS: Clinicamente, o tratamento com Nebido® mostrou-se superior ao tratamento com Deposteron® (média do percentual de melhora; p = 0,03) e ao Durateston® (média do questionário AMS pós-tratamento; p = 0,03). Laboratorialmente, o tratamento com Nebido® mostrou níveis de testosterona superiores ao Deposteron® e Durateston® (p < 0,001). CONCLUSÕES: As três formulações de testosterona parenteral existentes no mercado brasileiro são eficientes em elevar os níveis de testosterona e melhorar clinicamente pacientes hipogonádicos, sendo o Nebido® mais efetivo clínica e laboratorialmente.

Breaking the vicious circle of obesity: the metabolic syndrome and low testosterone by administration of testosterone to a young man with morbid obesity / Quebrando o círculo vicioso da obesidade: síndrome metabólica e baixos níveis de testosterona pela administração de testosterona a um homem jovem com obesidade mórbida

OBJECTIVE: The metabolic syndrome (MS) is associated with low serum testosterone levels. Conversely, low testosterone levels induce MS. These operational mechanisms reinforce one another and induce a vicious cycle. This is a report on a morbid obesity 42 year-old man with the MS and serum testosterone of 5.0 nmol/L (N: 12.0-33.0), who was resistant to treatment with diet and exercise. He was treated with testosterone undecanoate for 16 months. METHODS: Anthropological and laboratory variables were measured before and during testosterone administration. Also the Aging Male Symptom Scale (AMS), the International Index of Erectile Function (IIEF) and Beck's Depression Inventory were assessed. RESULTS: After 16 months, there was a weight loss of 50 kg and a decrease in waist circumference of 36.5 cm. Blood pressure normalized and laboratory variables returned to the normal range. The patient did not meet the criteria for the MS anymore. There were improvements on the AMS, the IIEF and Beck's Depression Inventory. CONCLUSIONS: Normalizing testosterone in men with morbid obesity in combination with diet and exercise, with the MS and low testosterone levels, may rescue them from the MS, improving their mood and their stamina to follow a diet and to exercise.

OBJETIVO: A síndrome metabólica (SM) está associada a baixos níveis séricos de testosterona. Inversamente, baixos níveis de testosterona induzem a SM. Esses mecanismos operacionais se reforçam mutuamente e levam a um círculo vicioso. Este é o relato de um homem de 42 anos, obesidade mórbida com SM e testosterona sérica de 5,0 nmol/L (N: 12,0-33,5), resistente ao tratamento com dieta e exercícios. Ele foi tratado com undecanoato de testosterona por 16 meses. MÉTODOS: Variáveis antropológicas e laboratoriais foram medidas antes e durante a administração de testosterona. Também foram avaliados a Escala de Envelhecimento Masculino (AMS), o Índice Internacional de Função Erétil (IIEF) e a Escala de Beck para Depressão. RESULTADOS: Após 16 meses, houve uma perda de peso de 50 kg e diminuição de 36,5 cm da circunferência abdominal. A pressão arterial foi normalizada e as variáveis laboratoriais também retornaram para os limites de normalidade. O paciente não preenchia mais os critérios para SM. Houve melhoras da AMS, do IIEF e da Escala de Beck para Depressão. CONCLUSÕES: A normalização da testosterona em homens com obesidade mórbida, combinada à dieta e a exercícios, com SM e baixos níveis de testosterona, pode livrá-los da SM, melhorando o humor e o vigor para seguir uma dieta e exercícios.

Efeitos dos esteroides anabólicos androgênicos sobre o útero e parâmetros reprodutivos de ratas adultas / Effects of androgenic anabolic steroids on the uterus and reproductive parameters of adult female rats

OBJETIVO: avaliar os efeitos da administração de dois esteroides sintéticos sobre a morfologia do útero e parâmetros reprodutivos de ratas adultas. MÉTODOS: quarenta ratas foram aleatoriamente distribuídas nos grupos experimentais: controle (C; solução fisiológica); tratados com decanoato de nandrolona (DN; 7,5 mg/kg de peso corpóreo); composto de ésteres de testosterona (T; 7,5 mg/kg de peso corpóreo); e, simultaneamente, com DN e T (7,5 mg/kg de peso corpóreo de cada esteroide), em uma única dose/semana, intraperitoneal, durante oito semanas. Cinco fêmeas de cada grupo foram sacrificadas e os cornos uterinos foram coletados, pesados e preparados para avaliação histológica e morfométrica. As ratas restantes foram acasaladas com machos normais para avaliação dos parâmetros reprodutivos, constituindo os grupos tratados durante o período pré-gestacional. Outro grupo de 20 ratas recebeu os tratamentos durante o período gestacional (7º-14º dias). Foi aplicada a análise de variância não paramétrica de Kruskal-Wallis, complementada com o teste de Dunn ou de Student-Newman-Kleus para análise dos dados (5 por cento de significância). RESULTADOS: houve aumento significativo no peso corpóreo das fêmeas androgenizadas (DN: 305±50; T: 280±35; DN+T: 275±30 versus C: 255±22 g) (p<0,05). O peso uterino não foi afetado pelos tratamentos esteroidais (DN: 0,6±0,2; T: 0,4±0,04; DN+T: 0,7±0,1 versus C: 0,4±0,09 g). Todas as fêmeas androgenizadas apresentaram aciclicidade estral e endométrio caracterizado pelo revestimento luminal papilífero, estroma edematoso com áreas hemorrágicas e atividade secretora. Houve alterações nos parâmetros morfométricos de espessura do epitélio luminal, miométrio e perimétrio, em função do grupo androgenizado. Nenhuma rata exibiu prenhez quando tratada com os esteroides no período pré-gestacional, e o tratamento durante a organogênese afetou negativamente os parâmetros reprodutivos. CONCLUSÕES: os agentes esteroidais alteram ...

PURPOSE: to evaluate the effects of the administration of two synthetic steroids in the uterus morphology and in the reproductive parameters of adult female rats. METHODS: divided into four experimental groups: control (C; physiological solution); treated with nandrolone decanoate (DN; 7.5 mg/kg of body weight); with a testosterone esters compound (T; 7.5 mg/kg); and simultaneously with DN and T (7.5 mg/kg of each steroid), in a single intraperitoneal weekly dose, for eight weeks. Five females of each group were sacrificed and the uterine horns were collected, weighted and prepared for histological and morphometrical evaluation. The remaining rats were mated with normal male rats for reproductive parameters evaluation, composing the groups treated during the pre-gestational period. Another group of 20 female rats were treated during the gestational period (7th-14th days). For data analysis, the Kruskal-Wallis non-parametric variance analysis was used, followed by the test of Dunn or of Student-Newman-Keus (5 percent significance level). RESULTS: there was a significant body weight increase in the androgenized females (ND: 305±50; T: 280±35; ND+T: 275±30 versus C: 255±22 g; p<0.05). Uterine weight was not affected by the steroidal treatment (ND: 0.6±0.2; T: 0.4±0.04; ND+T: 0.7±0.1 versus C: 0.4±0.09 g). All the androgenized females presented estral acyclicity and endometrium characterized by papilliferous luminal lining, oedematous stroma with hemorrhagic areas and secretory activity. There were changes in the morphometrical thickness parameters of the luminal epithelium, myometrium and perimetrium in the androgenized groups. None of the female rats got pregnant when treated with steroids in the pre-gestational period and the treatment during organogenesis affected negatively the reproductive parameters. CONCLUSIONS: steroidal agents alter the uterine structure and impair fertility and gestational outcome in female rats.

effect of oral testosterone undecanoate replacement therapy used in treating hypogonadal men on the development of prostate cancer

Objective: To evaluate the effect of oral testosterone undecanoate replacement therapy on the development of prostatic cancer in hypogonadal men of the fifth, sixth, and seventh decades

Patients and Methods: From September 2002 to September 2007, 172 hypogonadal men [44 of the fifth, 60 of the sixth, and 68 of the seventh decade] were treated with oral testosterone undecanoate at the outpatient departments of Urology and Dermatology, Andrology, and Sexually Transmitted Diseases of Alnoor Specialist Hospital, The Holy Makkah, Kingdom of Saudi Arabia. Before starting treatment and every 6 months during the treatment period, all patients underwent routine laboratory investigations in addition to total serum testosterone level. Serum prolactin level was measured only before treatment. They were also evaluated by digital rectal examination [DRE], total prostatic specific antigen [PSA], and transrectal ultrasound [TRUS] of the prostate to exclude prostatic cancer and BPH [with lower urinary tract symptoms, LUTS]. Prostatic biopsy was done in selected cases. Comparative statistical analysis of pretreatment and posttreatment results was done

Results: The mean change of PSA values was insignificant and no patient developed clinical prostatic cancer. However, one patient with evident PSA level change was diagnosed as prostatic intraductal neoplasia [PIN] on prostatic biopsy. In addition, significant prostatic volume mean change of 34.9% +/- 5% was reported. LUTS were encountered in 4 patients

Conclusions: From the current study, it could be concluded that oral testosterone undecanoate replacement therapy does not increase the risk of prostate cancer in selected patients, but may increase prostatic volume or increase the incidence of benign prostatic hyperplasia manifestations

Algunas consideraciones sobre el síndrome de PADAM / Some considerations on the PADAM syndrome

A diferencia de la mujer, en la que existe un acontecimiento perceptible (cese de la menstruación) que marca cronológicamente el fin de la función gonadal, en el hombre que envejece la declinación androgénica no ocurre de una forma clara y definida en tiempo y su progreso no es uniforme. Esta ha tomado identidad bajo el nombre de síndrome de declinación parcial androgénica en el envejecimiento masculino (PADAM), caracterizado por manifestaciones clínicas, bioquímicas y psicológicas que pueden confluir con intensidad variable sin existir ningún elemento que marque cronológicamente su momento de aparición. Diferentes estudios han demostrado la existencia de una disminución en los niveles de testosterona total y libre durante el envejecimiento. A pesar de no estar bien definidos dichos niveles, se ha utilizado la terapia de reemplazo hormonal como alternativa terapéutica, y en especial de su principal queja sintomática: la disfunción sexual eréctil (DSE). A la luz de los conocimientos y evidencias actuales, se realiza una revisión del tema declinación de la función gonadal masculina durante el envejecimiento, que abarca la fisiología testicular durante el envejecimiento, manifestaciones clínicas, diagnóstico, arsenal terapéutico e impacto en la calidad de vida. Se concluye que el síndrome de PADAM requiere especial atención por los médicos, especialmente urólogos y endocrinólogos. Existen muchos factores que influyen en la declinación androgénica. Se impone realizar estudios longitudinales en poblaciones sanas, con el objetivo de precisar cómo se comporta el eje hipofisotesticular por grupos de edades y su correlación con la aparición de las manifestaciones clínicas(AU)

Perspectives of contraceptive choices for men.

Apart from condoms and vasectomy, which have several limitations of their own, no other methods of contraception are available to men. Various chemical, hormonal, vas based and herbal contraceptives have been examined and few of them have reached the stage of clinical testing. Promising leads have been obtained from testosterone buciclate/undecanoate, alone or in combination with levonorgestrel butanoate or cyproterone acetate, RISUG, an injectable intravasal contraceptive and a few herbal products, particularly the seed products of Carica papaya. It is feasible that an ideal male contraceptive, that meets out all the essential criteria will be made available to the community in the near future.

Effect of medroxy progesterone acetate and testosterone enanthate on vas deferens of rats.

Effects of medroxy progesterone acetate (MPA; 5 mg/kg) and MPA + testosterone enanthate (TE) (3 mg + 2 mg/kg) were investigated in vas deferens and on fertility (along with reversibility study) for 60 days through histopathology, morphometric and certain biochemical parameters such as total proteins, sialic acid, ATPase, SDH and testosterone. The study revealed for altered histopathology and contratile pattern of vas deferens resulting in reduced fertility. The study also indicated androgen antagonistic effect. These effects were found to be reversible 4 and 3 months after withdrawal of MPA and MPA + TE injections respectively. Thus, both types generated functional sterility in the rat, but MPA affected histophysiology of vasal tissue.

Efecto de las hormonoas gonadales sobre el dimorfismo sexual en substrato de desnutrición / Effect of gonodal hormones on the sexual dimorphism in malnutrition substrate

El efecto ambiental sobre el crecimiento y el dimorfismo sexual es mediado por disfunciones endócrinas. Se ha comprobado que la desnutrición compromete al eje hipotalámico-hipofisario-glandular. Se realizó una experiencia en ratas Wistar con objeto de determinar el efecto de la administración de hormonas gonadales sobre componentes craneanos funcionales cuyo dimorfismo sexual fue alterado por desnutrición postnatal y analizar el tipo de efecto que estas hormonas tienen sobre el dimorfismo sexual. Se constituyeron cuatro tratamientos: control con consumo de dieta stock ad-libitum; subnutrición (50 por ciento del consumo promedio control); subnutrición+hormonas con inyecciones periódicas de testosterona y estradiol a machos y hembras respectivamente y sham-operado, en el cual la hormona fue sustituida por el vehículo oleoso. Se realizó un estudio radiológico longitudinal entre los 20 y 80 días de edad. Sobre cada radiografía se relevaron longitud, ancho y altura neuro y esplacnocraneanas. Con los datos obtenidos se realizó análisis de varianza y test de Mann-Whitney por medio del programa SYSTAT7.0. Los resultados obtenidos indicaron que ambas hormonas restituyeron el dimorfismo craneano sexual ya sea estimulando (testosterona) o inhibiendo (estradiol) el crecimiento de los componentes craneanos.

Specificity of antisera to sex steroid II--effect of unsaturation in ring-B of testosterone.

In a testosterone coated tube enzyme immunoassay format, a structurally modified enzyme label 6-dehydrotestosterone-17-hemisuccinate-penicillinase (6-DT) shows lower crossreactivity (25%) towards 5 alpha-dihydrotestosterone (5 alpha-DHT) as compared to testosterone-17-hemisuccinate-penicillinase (45%). The antiserum, generated against testosterone-3-0-carboxymethyloxime-BSA conjugate, showed high crossreactivity with 5 alpha-DHT when evaluated with a RIA (44.8%) using tritiated testosterone tracer. The results suggest that the conformational changes in the new modified testosterone heterologous enzyme tracer (6-DT) brings about desired changes in crossreactivity of antisera against 5 alpha-DHT. The new assay format presents a novel approach to minimize interference due to 5 alpha-DHT crossreactivity in testosterone immunoassays.

Androgenic regulation of glycolytic and HMP pathway in epididymis and vas deferens of rhesus monkey.

The androgenic regulation of the eleven enzymes of glycolytic pathway and two key enzymes of HMP pathway was studied in the initial segment, caput, corpus and cauda regions of the epididymis and in the vas deferens of rhesus monkey. The specific activities of enzymes were expressed as units of activity per mg DNA. Results in control animals indicate a marked difference in energy metabolism of epididymis and vas deferens. However, the epididymal duct itself did not show much regional variation in enzyme activities along its length. All the enzymes of the two pathways studied showed significant reduction after castration, the regulatory enzymes being affected more severely. On treatment with exogenous dihydrotestosterone, most of these enzymes showed stimulation in castrated monkeys, but none of them could be restored to normal level. The stimulation of these enzymes on treatment with exogenous dihydrotestosterone varied along the epididymal duct itself being maximum in the initial segment and minimum in the cauda region. The changes in the vas deferens were less marked as compared to the epididymis following castration and androgen replacement.

Biochemical and morphological changes of spermatozoa in progestin-androgen injected rats.

Bimonthly injections (im) of medroxyprogesterone acetate (MPA, 5 mg/0.2 ml) and testosterone enanthate (TE, 2.5 mg/0.2 ml) to rats for 30 and 60 days induced oligospermia. The sperms from epididymis had defective metabolism, alterations in their morphology, viability and acrosome integrity. Thus this altered sperm function resulted in reduction in the fertility rate of MPA+TE treated animals.

Effect of depot medroxyprogesterone acetate and testosterone ananthate on the testis of albino rats: ultrastructural and biochemical studies.

Male albino rats were treated with depot medroxyprogesterone acetate (1 mg/animal/day) + testosterone ananthate (100 micrograms/100 g body weight/day) for 30 and 60 days. After 30 days of treatment, all the testicular enzymes like beta-glucuronidase, hyaluronidase, sorbitol dehydrogenase, lactate dehydrogenase, acid and alkaline phosphatase, registered non-significant decrease in their values. Fifty percent of the treated animals achieved sterility after 30 days of treatment. After 60 days of treatment the testis showed degenerative changes in Golgi phase and late spermatids. Changes in the Golgi phase spermatids were related with degeneration of the nuclear membrane. Changes in the late phase spermatids included mitochondrial hypertrophy of the midpieces, membrane lysis, absence of cristae and degeneration of annulus leading to detachment of tail. Cytoplasm of luminal area displayed hypertrophied mitochondria devoid of cristae, prominent appearance of Golgi bodies, intense lysosomal activity and ample vacuolation. Tail fragments of degenerated spermatids prevailed in luminal cytoplasm. Except for beta-glucuronidase which registered a significant decrease, levels of all the other testicular enzymes, viz. hyaluronidase, lactate dehydrogenase, sorbitol dehydrogenase, acid phosphatase and alkaline phosphatase were within their control limits. The ultrastructural and biochemical changes are correlated.

Effect of fertility regulating agents on motility and zona-free hamster egg penetration by spermatozoa of bonnet monkey.

Administration of STS-557 (17 alpha-cyanomethyl-17 beta-hydroxyestra 4,9(10)-dien-3-one; 12 mg/monkey daily) for 4 weeks either alone or in combination with 20 Aet-1 (testosterone-trans-4-n-butyl cyclohexyl carboxylate; code CDB 1781; 40 mg/monkey single administration) had no significant effect on motility and zona free hamster egg penetration by spermatozoa of bonnet monkey, but continuation of the treatment for 12 weeks reduced (in one monkey treated with STS-557) or abolished (one treated with STS-557 and two with STS-557 + 20 Aet-1) the motility as well as zona-free hamster egg penetration (by spermatozoa of all treated monkeys). Motility and the ability to penetrate zona-free hamster egg returned to normalcy after 10 weeks of withdrawal of treatments. Active immunization of monkeys with ovine FSH (4 weeks after booster) had no adverse effect on motility of spermatozoa but none of the zona-free hamster eggs was fertilized. The correlation between motility and the capacity to penetrate the zona-free hamster eggs by monkey spermatozoa varies with the treatment. Such correlation was apparent in monkeys treated with STS-557 but not in monkeys immunized with ovine FSH.

Increased concentration of prostatic inhibin following orchidectomy in rat.

Inhibin, a predominant secretory protein of prostate has been shown earlier to increase in proliferative prostatic diseases. Since the prostate gland is under the profound influence of androgens, it's withdrawal by orchidectomy is many a time included in the therapy to prostate cancer. Hence it was interesting to study the reflection of long term orchidectomy on prostatic inhibin. With this aim two groups of bilaterally orchidectomised male Sprague-Dawley rats were sacrificed 15 days and 30 days after castration respectively. Another group of rats was administered with testosterone enanthate after 30 days of castration. As protein concentration and weight showed a significant decrease after orchidectomy, inhibin concentrations (estimated by RIA) were expressed per gland. The inhibin concentration was increased to a 5-6 fold higher value after 15 days of castration. While a remarkable 10-15 fold elevation of inhibin concentration was observed in 30 day castrated prostates. Concurrently the circulating inhibin levels were also found to be heightened. All these effects of orchidectomy were almost reversed on androgen administration. Thus in contrast to the decrease in the weight and concentration of other prostatic proteins after orchidectomy, the increase in inhibin appears to be striking.