RESUMEN
Forty-eight morbidly obese patients were placed on a very low calorie (800 kcal) formula diet (OPTIFAST) for a 10-week period with the goal of achieving 10% weight loss within this time. Weekly serum leptin measurements were performed to determine whether changes in this adipose protein would serve as a useful marker of acute and chronic weight loss compliance. In the basal state, serum leptin averaged 56.9 +/- 5.8 ng/ml (SE) in the 24 successful (S) patients, and 67.7 +/- 6.7 ng/ml in the non-successful (N-S) group. During the first week of weight loss there was little change in leptin despite an average weight loss of 2.2%, but after 4 weeks serum leptin decreased by 36% in the S group, and 20% in the N-S group. After 10 weeks, the S group averaged 13.6% weight loss and the serum leptin decreased to 50% of starting levels. In the 24 N-S patients, the mean weight loss was 7.0%, and serum leptin decreased by 22%, remaining unchanged in the final 6 weeks despite a weight loss of 3.6% in this time. On a week-to-week basis serum leptin changed concordantly with weight loss only two-thirds of the time. In a subgroup of 14 patients (8 S+6 N-S), serial assessments of serum leptin, insulin and tumor necrosis factor-alpha (TNF-alpha) were performed. Serum insulin levels decreased with weight loss similar in magnitude to that noted for leptin; however, the insulin changes occurred more rapidly. Serum TNF-alpha also decreased with weight loss, but the weekly changes were more erratic, with a concordance rate of only 48%. In summary, serum leptin, insulin and TNF-alpha all decreased during a rapid weight loss program but at differing rates and variability, precluding their usefulness as markers of week-to-week weight loss compliance.
Asunto(s)
Dieta Reductora , Insulina/sangre , Leptina/sangre , Obesidad Mórbida/sangre , Obesidad Mórbida/dietoterapia , Factor de Necrosis Tumoral alfa/análisis , Pérdida de Peso , Índice de Masa Corporal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/patología , Factores de TiempoRESUMEN
Gonadal steroids are known to alter GH secretion as well as tissue metabolism. The present study was designed to examine the effects of short term (2- to 3-week) alterations in gonadal steroids on basal pulsatile (nonstimulated) and exercise- and GH-releasing hormone-stimulated GH secretion, urinary nitrogen excretion, and basal and exercise-stimulated oxygen consumption. Two protocols were conducted, which reflect a total of 18 separate studies. In the first paradigm, 5 healthy young men were each studied in a double blind, randomized manner during 3 different gonadal hormone manipulations, in which serum testosterone was varied from hypogonadal (induced by leuprolide) to eugonadal (saline injections) to high levels (testosterone enanthate, 3 mg/kg.week, i.m.). There was a washout period of 8 weeks between treatments. In the second protocol, 3 of the original subjects were studied after 2 weeks of treatment with stanozolol (0.1 mg/kg.day). Two to 3 weeks after the desired changes in serum testosterone, each subject was admitted to the General Clinical Research Center for study. The hypogonadal state (serum testosterone, 33 ng/dL) increased urinary nitrogen loss (by 34%; P < 0.005) and decreased basal metabolic rate (by 12%; P < 0.02) compared with the eugonadal state (testosterone, 796 ng/dL). High dose testosterone (1609 ng/dL) further decreased urinary nitrogen loss over the eugonadal state (by 16%; P < 0.05). Stanozolol yielded the lowest urinary nitrogen excretion of all (P < 0.03). Like urinary nitrogen, the basal metabolic rate showed the greatest change between the hypogonadal and eugonadal states (12%; P < 0.02), with a lesser change during high dose testosterone treatment (4%). Analogously, end-exercise oxygen consumption rose by 11% between the hypogonadal and eugonadal states (P < 0.05). Between the hypogonadal and eugonadal states, no significant changes in pulsatile (nonstimulated), exercise-stimulated, or GRF-stimulated GH secretion or serum insulin-like growth factor I concentrations were observed. Raising testosterone to supraphysiological levels increased pulsatile GH secretion by 62% over that with leuprolide and by 22% over that with saline (P < 0.05). High dose testosterone treatment also increased serum insulin-like growth factor I concentrations by 21% and 34% over those during the eugonadal and hypogonadal states, respectively (P < 0.01). Testosterone did not affect either exercise- or GRF-stimulated GH secretion. In protocol 2, stanozolol did not affect any parameter of GH secretion. To examine the interaction between GH secretion and testosterone on urinary nitrogen excretion and basal metabolic rate, a one-way analysis of covariance was undertaken. Statistical examination of GH production as the covariate and testosterone (by tertile) as the interactive factor demonstrated significant relationships between serum testosterone levels and either urinary nitrogen (P < 0.02) or basal metabolic rate (P < 0.01), but not GH secretion (P = NS). In summary, these results demonstrate that short term modulation of the androgen milieu affects metabolic outcome without necessitating changes in GH secretion. These results have significance for both normal physiology and for the treatment of hypogonadal GH-deficient patients.
Asunto(s)
Ejercicio Físico/fisiología , Hormona Liberadora de Hormona del Crecimiento/farmacología , Hormona de Crecimiento Humana/metabolismo , Testosterona/sangre , Adulto , Dihidrotestosterona/sangre , Método Doble Ciego , Estradiol/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Cinética , Leuprolida , Masculino , Nitrógeno/orina , Globulina de Unión a Hormona Sexual/metabolismo , Testosterona/análogos & derivadosRESUMEN
The healthy aging male reproductive axis tends to exhibit a progressive decline in serum concentrations of biologically available testosterone with gradual concomitant reciprocal increases in both LH and FSH concentrations. However, relatively little is known about the sex steroid-mediated negative feedback regulation of physiologically pulsatile gonadotropin release in general, and episodic FSH release in particular, in older males. To examine the steroid hormone negative feedback control of pulsatile FSH secretion in healthy older men, we applied multiparameter deconvolution analysis to serum FSH (immunoradiometric assay) profiles obtained by sampling every 10 min over 24 h during steady state (4.5-day) infusions of estradiol (E2; 48 micrograms/day), 5 alpha-dihydrotestosterone (DHT; 7.0 mg/day), or 5% dextrose in water in five healthy older men, aged 60-73 yr. We observed the following principal responses: 1) both E2 and DHT significantly suppressed mean and 24-h integrated serum FSH concentrations (P < 0.032); 2) the calculated daily secretion rate of FSH fell significantly in all five individuals during DHT infusion; 3) the apparent half-life of FSH decreased during E2 (but not DHT) infusion; 4) DHT infusion reduced the mass and frequency of FSH secretory bursts significantly; 5) neither E2 nor DHT treatment significantly attenuated the release of FSH stimulated by consecutive iv injections of GnRH (10 and 100 micrograms); and 6) integrated 24-h serum LH (immunoradiometric assay) concentrations decreased significantly during both DHT and E2 infusions, whereas mean LH release after the serial GnRH injections was not altered. Compared to younger men studied earlier in an identical fashion, older men had significantly reduced FSH intersecretory burst intervals, reflecting a higher FSH pulse frequency at baseline and during the steroid infusions and a significantly lower mass of FSH secreted per burst during E2 infusion. We conclude that healthy older men maintain intact negative feedback responsiveness of the hypothalamo-pituitary gonadotroph unit to exogenously delivered sex steroid hormones, and that individual sex steroid hormones differentially regulate specific features of pulsatile FSH release and half-life in older men.
Asunto(s)
Envejecimiento/metabolismo , Hormona Folículo Estimulante/metabolismo , Hormonas Esteroides Gonadales/fisiología , Anciano , Dihidrotestosterona/farmacología , Estradiol/farmacología , Retroalimentación , Hormona Folículo Estimulante/antagonistas & inhibidores , Hormona Folículo Estimulante/sangre , Semivida , Homeostasis , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Flujo Pulsátil , Valores de Referencia , Manejo de Especímenes , Factores de TiempoRESUMEN
To investigate the nature of neuroendocrine disturbances of the hypothalamo-pituitary-gonadal axis in idiopathic male infertility, we studied 14 infertile men with oligoasthenozoospermia (OLIGO) and 15 age-, body mass index-, and community-matched euspermic controls by blood withdrawal at 10-min intervals for 12 h to encompass basal (8-h) and exogenous GnRH-stimulated (4-h) pulsatile release of LH and FSH (by immunoradiometric assay) as well as testosterone (by RIA). Deconvolution analysis was used to estimate endogenous LH and FSH half-lives, secretory burst frequency, amplitude, duration, and mass. OLIGO men exhibited normal serum concentrations of total, free, and percent dialyzable testosterone and estradiol, but distinct dynamic alterations within the LH and FSH axes; namely (P < 0.05), 1) a prolonged half-life of LH (OLIGO, 95 +/- 19 min; control, 80 +/- 9.3 min) and a reduced half-life of FSH (OLIGO, 260 +/- 79 min; control, 320 +/- 93 min); 2) a low LH, but normal FSH, secretory burst frequency (OLIGO, 12 +/- 3.4; control, 15 +/- 3.0 LH pulses/day); 3) a decreased serum testosterone peak frequency (OLIGO, 16 +/- 4.3; control, 21 +/- 3.2 peaks/day); and 4) an amplified mass of LH (1.1- to 1.3-fold higher in OLIGO) and FSH (2.4- to 2.7-fold higher in OLIGO) secreted per burst basally as well as after GnRH injection. These disturbances were readily distinguishable from the neuroendocrine dysregulation described in other states of male hypogonadotropism (e.g. uremia, fasting, and aging).
Asunto(s)
Hormona Folículo Estimulante/metabolismo , Infertilidad Masculina/fisiopatología , Hormona Luteinizante/metabolismo , Oligospermia/fisiopatología , Periodicidad , Adulto , Hormona Liberadora de Gonadotropina , Humanos , Masculino , Testosterona/metabolismoRESUMEN
To investigate the pathophysiology of altered growth hormone (GH) and prolactin secretion in endstage renal disease, we sampled blood at 10-min intervals for 24 h and applied deconvolution analysis to calculate hormone half-lives and pulsatile secretion rates. Two-site immunoradiometric assays were employed to quantitate presumptively intact GH and prolactin in nine middle-aged men with chronic renal failure and 14 gender-, age-, body weight- and community-matched controls. We observed that the half-lives of endogenous GH and prolactin were prolonged significantly in uremia: for GH, control 17 +/- 1.4 versus uremia 21 +/- 1.3 min (p < 0.05); for prolactin, control 66 +/- 9.3 versus uremia 112 +/- 10 min (p < 0.01). Daily GH secretion rates exceeded sex-, age- and weight-predicted values in eight of nine uremic individuals, while values for prolactin were variable but on average twofold higher in uremia. In both the somatotropic and lactotropic axes, the frequency of secretory bursts was increased significantly (for GH, control 11 +/- 1.1 versus uremia 15 +/- 0.84 secretory events/24 h: for prolactin, control 20 +/- 0.90 versus uremia 27 +/- 1.3 pulses/24 h, p < 0.05). Although there were no significant alterations in the mean amplitude, duration or mass of GH secretory bursts, prolactin secretory burst amplitudes were elevated threefold in uremia (p < 0.01). These distinctive mechanisms brought about higher 24-h mean serum concentrations of GH (0.70 +/- 0.17 control versus 1.22 +/- 0.32 micrograms/l uremia) and prolactin (7.3 +/- 2.4 control versus 26 +/- 6.1 micrograms/l uremia, p < 0.05). Lastly, serum concentrations of estradiol were increased but those of unconjugated estriol decreased in uremia. We conclude that hypersomatotropinemia and hyperprolactinemia in uremic men result from prolonged hormone half-lives combined with increased frequencies of secretory events driven by unknown stimuli within the respective axes, and/or by defects in their negative-feedback regulation. We postulate that the latter may arise from partial tissue resistance to hormone action in hemodialyzed men.
Asunto(s)
Hormona del Crecimiento/metabolismo , Fallo Renal Crónico/fisiopatología , Sistemas Neurosecretores/fisiopatología , Prolactina/metabolismo , Uremia/fisiopatología , Hormona del Crecimiento/sangre , Humanos , Masculino , Persona de Mediana Edad , Prolactina/sangreRESUMEN
A variety of plasma androgens, estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, cortisol, and thyroid parameters were examined in 10 men followed serially before and after cadaver kidney transplantation. Before transplantation, plasma testosterone levels were below normal in 8 of the 10 men. Free testosterone, follicle-stimulating hormone, and luteinizing hormone were at the lower range of normal values, yet plasma estradiol levels were elevated 3-fold, and prolactin levels were also high. One month after transplantation, all hormones measured were suppressed, probably reflecting high-dose steroids and multiple-drug regimens used in the period following the operation. After 3 months, when other immunosuppressants were reduced and cyclosporine dosage was stabilized, plasma testosterone, androgens, follicle-stimulating hormone, and luteinizing hormone levels were restored toward normal. After 12 months, plasma testosterone levels exceeded pretransplant levels. Plasma estradiol and prolactin levels dramatically decreased after transplantation and remained in the normal range thereafter. These data indicate that abnormalities of plasma estradiol and prolactin levels observed in patients with end-stage renal disease are restored toward normal after cadaver kidney transplantation. Androgen levels that were suppressed in the period immediately after transplantation were restored to normal levels in the succeeding months despite chronic usage of cyclosporine, suggesting that cyclosporine, in currently used doses, does not prevent the restoration of the hypothalamic-pituitary-testicular axis.
Asunto(s)
Ciclosporina/uso terapéutico , Sistema Hipotálamo-Hipofisario/fisiología , Trasplante de Riñón/fisiología , Hipófisis/fisiología , Sistema Hipófiso-Suprarrenal/fisiología , Testículo/fisiología , Adulto , Andrógenos/sangre , Cadáver , Relación Dosis-Respuesta a Droga , Estradiol/sangre , Hormona Folículo Estimulante/sangre , Rechazo de Injerto/tratamiento farmacológico , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Células Intersticiales del Testículo/fisiología , Hormona Luteinizante/sangre , Masculino , Hipófisis/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Prolactina/sangre , Testículo/efectos de los fármacos , Testosterona/sangreRESUMEN
Serum GH concentrations are increased in fasted or malnourished human subjects. We investigated the dynamic mechanisms underlying this phenomenon in nine normal men by analyzing serum GH concentrations measured in blood obtained at 5-min intervals over 24 h on a control (fed) day and on the second day of a fast with a multiple-parameter deconvolution method to simultaneously resolve endogenous GH secretory and clearance rates. Two days of fasting induced a 5-fold increase in the 24-h endogenous GH production rate [78 +/- 12 vs. 371 +/- 57 micrograms/Lv (Lv, liter of distribution volume) or 0.24 +/- 0.038 vs. 1.1 +/- 0.16 mg/m2 (assuming a distribution volume of 7.9% body weight), P = 0.0001]. This enhanced GH production rate was accounted for by 2-fold increases in the number of GH secretory bursts per 24 h (14 +/- 2.3 vs. 32 +/- 2.4, P = 0.0006) and the mass of GH secreted per burst (6.3 +/- 1.2 vs. 11 +/- 1.6 micrograms/Lv, P = 0.002). The latter was a result of increased secretory-event amplitudes (maximal rates of GH release attained within a burst) with unchanged secretory burst durations. GH was secreted in complex volleys composed of multiple discrete secretory bursts. These secretory volleys were separated by shorter intervals of secretory quiescence in the fasted than fed state (respectively, 88 +/- 4.2 vs. 143 +/- 14 min, P = 0.0001). Similarly, within volleys of GH release, constituent individual secretory bursts occurred more frequently during the fast [every 33 +/- 0.64 (fasted) vs. every 44 +/- 2.0 min (fed), P = 0.0001]. The t1/2 of endogenous GH was not significantly altered by fasting [18 +/- 2.2 (fasted) vs. 20 +/- 1.5 min (fed), P = 0.47]. Serum insulin-like growth factor I concentrations were unchanged after 56 h of fasting. In conclusion, the present data suggest that starvation-induced enhancement of GH secretion is mediated by an increased frequency of GHRH release, and longer and more pronounced periods of somatostatin withdrawal.
Asunto(s)
Ayuno/sangre , Hormona del Crecimiento/sangre , Hormona del Crecimiento/farmacología , Adulto , Índice de Masa Corporal , Estradiol/sangre , Ayuno/fisiología , Hormona del Crecimiento/metabolismo , Humanos , Hidrocortisona/orina , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino , Tasa de Depuración Metabólica/fisiología , Radioinmunoensayo , Testosterona/sangre , Factores de TiempoRESUMEN
OBJECTIVE: To explore the clinical usefulness of the antiandrogen flutamide in the treatment modality for hirsutism in women. DESIGN: Nine women with hirsutism were assessed before and then monthly for 3 months on a regimen of flutamide 250 mg three times a day as the sole therapeutic agent. Blood samples were taken at each assessment time for a battery of androgenic parameters. SETTING: Patients were followed in the Out-Patient Department of the Hospital das Clinicas, Sao Paulo, Brazil. Hormonal assays were performed in the Hormone Laboratories of Hospital das Clinicas and the Endocrine Research Laboratory at Newark Beth Israel Medical Center, Newark, New Jersey. PATIENTS: Nine women with moderate hirsutism were treated with flutamide. Six women were previously diagnosed as having idiopathic hirsutism, and three women were diagnosed as having polycystic ovary syndrome. INTERVENTION: All women were treated with flutamide 250 mg three times a day for 3 months. MAIN OUTCOME MEASURE: Improvement of hirsutism was assessed using the Ferriman-Gallwey hair density index. Side effects of drug therapy (deterioration of menses and dry skin) were explored. Androgen parameters included testosterone (T), sex hormone-binding globulin, bound, nonbound, and free T, androstanediol glucuronide, and others. RESULTS: After 3 months of flutamide alone, Ferriman-Gallwey scores improved in seven of nine women with mean scores decreasing from 28.1 +/- 0.6 to 24.5 +/- 0.6. None of the androgenic parameters changed during this period of time. Follicle-stimulating hormone and luteinizing hormone response to gonadotropin-releasing hormone was unchanged after flutamide. CONCLUSION: Flutamide favorably influenced hirsutism in women, with differences noted after only 3 months of therapy. More prolonged and detailed studies of this drug as the sole therapeutic agent for treatment of hirsutism seems warranted.
Asunto(s)
Flutamida/uso terapéutico , Hirsutismo/tratamiento farmacológico , Adulto , Análisis de Varianza , Androstano-3,17-diol/análogos & derivados , Androstano-3,17-diol/sangre , Androstenodiona/sangre , Deshidroepiandrosterona/análogos & derivados , Deshidroepiandrosterona/sangre , Sulfato de Deshidroepiandrosterona , Estradiol/sangre , Femenino , Hirsutismo/sangre , Hirsutismo/etiología , Humanos , Síndrome del Ovario Poliquístico/diagnóstico , Globulina de Unión a Hormona Sexual/metabolismo , Testosterona/sangre , Resultado del TratamientoRESUMEN
Morbid obesity has been previously shown to be associated with excessive production and metabolism of a variety of androgens and estrogens. Further, SHBG is lowered, resulting in high levels of 'free' testosterone. We have re-examined these parameters in morbidly obese women with upper vs lower body adipose distribution. Upper body obesity was associated with greater increases in production and clearance of testosterone and dihydrotestosterone compared to lower body obesity. Further, SHBG levels were lower resulting in high serum levels of free T and free E2 in this obesity phenotype. By contrast, lower body obesity was associated with increased peripheral aromatization of androstenedione resulting in higher urinary E1 production rates. The biologic significance of these hormonal differences in obesity phenotypes as well as the potential role of the androgen-estrogen environment in determining body fat distribution is considered.
Asunto(s)
Tejido Adiposo/patología , Hormonas Esteroides Gonadales/metabolismo , Obesidad/metabolismo , HumanosRESUMEN
Androgen and estrogen production rates were examined in 29 morbidly obese women with upper or lower body obesity. Although blood production rates of testosterone (T), dihydrotestosterone, and androstenedione (A4) were elevated in all of these women, those with upper body obesity (waist-height ratios, greater than 0.85) had higher T and production rates than women with lower body obesity (waist-height ratio less than 0.75). A4 was equally elevated in women with upper and lower body obesity. Peripheral aromatization of A4 to estrone (E1) averaged 1.67% in women with upper body obesity, but was elevated at 2.54% in women with lower body obesity. Urinary E1 production rates averaged 466 +/- 295 nmol/day (172 +/- 109 micrograms/day) in women with upper body obesity. Thus, women with lower body obesity had higher E1 production rates due entirely to increased peripheral aromatization. Women with upper body obesity were observed to have higher serum T and estradiol (E2) levels than women with lower body obesity. Further, upper body obesity was associated with decreased levels of sex hormone-binding globulin (16.1 +/- 5.7 nmol/L vs. 18.9 +/- 6.1 in women with lower body obesity). As a result, free T levels averaged 98.8 +/- 39.2 pmol/L in women with upper body obesity vs. 82.2 +/- 33 in women with lower body obesity. Similarly, serum free E2 levels were higher in women with upper body vs. lower body obesity. The data demonstrate that sex hormone production and metabolism are different in morbidly obese women with these differing phenotypes. Women with upper body obesity have higher androgen production rates and higher free T and free E2 levels, whereas women with lower body obesity make increased amounts of E1 from peripheral aromatization. The biological significance of increased aromatization may be offset by increased free E2 levels in women with upper body obesity.
Asunto(s)
Andrógenos/metabolismo , Estrógenos/metabolismo , Obesidad/metabolismo , Adulto , Andrógenos/biosíntesis , Composición Corporal , Femenino , Glucosa/metabolismo , Humanos , Obesidad/clasificación , Fenotipo , Grosor de los Pliegues Cutáneos , Somatotipos , Testosterona/metabolismoRESUMEN
Cyproterone acetate given as a single intramuscular dose of 300 mg monthly for 6 months resulted in significant reduction of hirsutism without appreciable side effects. This regimen resulted in decreased levels of luteinizing hormone (LH) and estradiol in the eight women studied. No significant changes were observed in total serum testosterone (T) levels, however, there was a reduction in sex hormone binding globulin (SHBG), resulting in lowered SHBG-bound T, and an increase in non-SHBG-T over this time. Serum androstanediol glucuronide levels decreased in three of four women, although not to normal levels.
Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Ciproterona/análogos & derivados , Hirsutismo/tratamiento farmacológico , Adolescente , Adulto , Albúminas/metabolismo , Ciproterona/uso terapéutico , Acetato de Ciproterona , Relación Dosis-Respuesta a Droga , Femenino , Hirsutismo/metabolismo , Humanos , Globulina de Unión a Hormona Sexual/metabolismo , Testosterona/sangreRESUMEN
Concentrations of 3 alpha-diol glucuronide (3 alpha-diol G) in plasma and/or random urine samples were determined in seven subjects with familial male pseudohermaphroditism (FMP) due to 5 alpha-reductase deficiency (5 alpha-RD). All subjects were natives of an isolated Turkish village with a high incidence of consanguineous marriage. A specific and sensitive antibody to 3 alpha-diol was used for radioimmunoassay of 3 alpha-diol G after hydrolysis and chromatographic purification. The mean plasma 3 alpha-diol G in three subjects (31 ng/dL) was much lower than the normal male concentration (516 +/- 50) (+/- SE) and was even lower than normal female values (119 +/- 10.9 ng/dL). In five subjects, mean urinary 3 alpha-diol G in random urine samples was 7.6 (range 2.1 to 12.7) ng/mg creatinine. This was considerably decreased compared with the mean adult male concentration of 65.4 +/- 9.4 and even lower than normal age-matched nonhirsute female values (19.6 +/- 2.1 ng/mg Cr). To validate the use of 3 alpha-diol G/creatinine ratios in random urine samples, correlations of three consecutive eight-hour samples with 24-hour values were determined in 8 male and 3 female age-matched controls. There was an excellent correlation (r = .95) and the linear regression line (y = 0.51x + 2.58) indicates that the 24-hour excretion of 3 alpha-diol G in microgram/24 h is approximately twice the random urinary concentration in ng/mg Cr.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/deficiencia , Androstano-3,17-diol/metabolismo , Androstanoles/metabolismo , Trastornos del Desarrollo Sexual/metabolismo , Adolescente , Adulto , Androstano-3,17-diol/análogos & derivados , Androstano-3,17-diol/sangre , Androstano-3,17-diol/orina , Trastornos del Desarrollo Sexual/sangre , Trastornos del Desarrollo Sexual/genética , Trastornos del Desarrollo Sexual/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radioinmunoensayo , Valores de Referencia , TurquíaRESUMEN
We examined the effect of medical adrenalectomy on the clinical and hormonal responses in 50 men with disseminated prostatic carcinoma. Patients refractory to initial hormonal therapy were treated with aminoglutethimide and hydrocortisone (AG-HC) and evaluated by the criteria of the National Prostatic Cancer Project. Eight patients showed a partial response (PR), and 17 remained stable while receiving these medications. Survival times for these two groups averaged 87.8 and 38 weeks, respectively. In contrast, 17 men were unresponsive to this therapy, exhibiting progressive disease with a mean survival time of 18 weeks. Eight patients could not tolerate the drug regimen or were lost to follow-up. Serum and urinary hormone profiles determined serially during AG-HC therapy revealed that all measured serum androgens and estrogens were significantly lowered by AG-HC treatment; however, specific hormones, including free testosterone, dihydrotestosterone, estrone, and estradiol were suppressed to a greater degree in responders (R) as compared with nonresponders (NR). Urinary excretion of 17-ketosteroids did not change during AG-HC therapy, but specific androgen metabolites, including testosterone glucuronide and androstanediol glucuronide, were suppressed by 50% during AG-HC therapy. We showed modest clinical benefit of AG-HC therapy in advanced prostatic cancer. That greater hormonal suppression was associated with greater responsiveness to this therapy raises the hope that further manipulations directed against suppression of extratesticular androgens may be a useful approach as second-line treatment of advanced prostatic cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Aminoglutetimida/administración & dosificación , Aminoglutetimida/efectos adversos , Andrógenos/sangre , Estrógenos/sangre , Humanos , Hidrocortisona/administración & dosificación , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/sangre , RadioinmunoensayoRESUMEN
The functional characteristics of the hypothalamic-pituitary-testicular axis were examined quantitatively in 10 chronic alcoholic men without hepatic dysfunction or clinical nutritional deficiencies. Spontaneous gonadotropin pulsatility was analyzed in blood sampled every 20 minutes over a 24-hour period 3 to 16 days after abstinence from alcohol and again 29 to 39 days later. The numbers of LH and FSH pulses per 24 hours were normal in these alcoholic men compared with controls. However, we found increased mean 24-hour concentrations of immunoactive LH (P = 0.012) and FSH (P = 0.018), increased peak heights for LH (P = 0.035) and FSH (P = 0.004), decreased fractional LH (P = 0.002) and FSH (P = 0.044) pulse amplitudes and increased interpulse valley mean LH (P = 0.010) and FSH (P = 0.018) concentrations. Serum levels of total testosterone, total estradiol and estrone were normal, whereas concentrations of free testosterone and free estradiol were increased. Pituitary release of LH and FSH was normal in response to low (5-micrograms) and high (95-micrograms) doses of GnRH given intravenously. The present observations indicate that in chronically alcoholic men, acute abstinence from ethanol is associated with elevated circulating concentrations of immunoactive gonadotropins in the presence of intact spontaneous gonadotropin pulsatility, preserved pituitary responsiveness to exogenous GnRH, and increased concentrations of free testosterone and free estradiol. Such findings are consistent with alterations in the endogenous feedback actions of sex steroid hormones in this setting.
Asunto(s)
Alcoholismo/metabolismo , Hormona Folículo Estimulante/metabolismo , Hormona Luteinizante/metabolismo , Adulto , Estradiol/sangre , Hormona Folículo Estimulante/sangre , Humanos , Hormona Luteinizante/sangre , Masculino , Persona de Mediana Edad , Testosterona/sangre , Factores de TiempoRESUMEN
Serum androstanediol glucuronide (3 alpha-diol G), a metabolite of the active androgens dihydrotestosterone and androstanediol, was elevated in 28 consecutive women with idiopathic hirsutism (IH). The mean 3 alpha-diol G level in the women with IH was 487 +/- 192 (+/- SD) ng/dL compared to 119 +/- 37 ng/dL in normal women (n = 50), and only 1 patient had a value overlapping with the normal range. Since 3 alpha-diol G appears to be formed entirely in target organs and has a long serum half-life, we studied its clinical usefulness by following women with IH during treatment. In 15 of 17 women with IH treated for 1-4 yr with glucocorticoids, contraceptives, or spironolactone, serum 3 alpha-diol G levels changed concordantly with clinical responses, in contrast to the poor concordance of serum testosterone (5 of 17), free testosterone (7 of 17), and androstenedione (7 of 17). Specifically, in IH patients treated with spironolactone, serum testosterone, free testosterone, and androstenedione levels changed little, yet clinical improvement frequently occurred, and this improvement was reflected by concomitantly lowered 3 alpha-diol G levels. Further, in 4 IH patients, discontinuation of effective therapy resulted in prompt increases in serum 3 alpha-diol G as harbingers of worsening hair growth. We, thus, conclude that serum 3 alpha-diol G measurements are clinically useful in evaluating hirsute women and correlate with the clinical responses to therapy.
Asunto(s)
Androstano-3,17-diol/sangre , Androstanoles/sangre , Hirsutismo/sangre , Adolescente , Adulto , Androstano-3,17-diol/análogos & derivados , Anticonceptivos Orales Combinados/uso terapéutico , Anticonceptivos Sintéticos Orales/uso terapéutico , Combinación de Medicamentos , Femenino , Hirsutismo/tratamiento farmacológico , Humanos , Mestranol/uso terapéutico , Monitoreo Fisiológico , Noretindrona/uso terapéutico , Prednisona/uso terapéutico , Espironolactona/uso terapéutico , Factores de TiempoRESUMEN
We undertook a study of the separate and combined effects of age and sex on the pulsatile pattern of GH secretion. The 24-h secretory profile of GH was generated by 20-min sampling in 10 young women (aged 18-33 yr), 10 young men (aged 18-33 yr), 8 postmenopausal women (aged greater than 55 yr), and 8 older men (aged greater than 55 yr). A computer-assisted pulse analysis program was used to assess both total GH secretion, as reflected in the 24-h integrated GH concentration (IGHC), and pulsatile secretion, as denoted by pulse frequency, duration, amplitude, and the fraction of GH secreted in pulses during the 24-h period (FGHP). IGHC was significantly greater in women than in men (P less than 0.025) and greater in the young than in the old (P less than 0.003). The mean pulse amplitude, duration, and FGHP were each greater in the young (P less than 0.006, P less than 0.03, and P less than 0.0001, respectively), but not significantly different between the sexes. The mean pulse frequency was not affected by sex or age. The serum concentration of free estradiol, but not free testosterone, correlated with IGHC (r = 0.46; P less than 0.005), pulse amplitude (r = 0.53; P less than 0.001), and FGHP (r = 0.59; P less than 0.0002). After correcting for the effects of estradiol, neither sex nor age influenced IGHC or mean pulse amplitude, while the effect of age on FGHP was reduced from 81% to 29%. Of the indices of GH secretion, FGHP had the strongest correlation (r = 0.43; P less than 0.006) with somatomedin-C. Somatomedin-C declined significantly with age in both sexes. Our results indicate that sex and age have independent and interrelated effects on GH secretion. These effects can be largely accounted for by corresponding variations in endogenous estradiol levels. These observations suggest an amplifying action of estradiol on the neuroendocrine regulation of pulsatile GH release.
Asunto(s)
Envejecimiento , Ritmo Circadiano , Estradiol/sangre , Hormona del Crecimiento/metabolismo , Adolescente , Adulto , Anciano , Estradiol/fisiología , Humanos , Factor I del Crecimiento Similar a la Insulina/sangre , Masculino , Persona de Mediana Edad , Pulso Arterial , Factores Sexuales , Testosterona/sangreRESUMEN
Thirteen healthy postmenopausal volunteers were studied under basal conditions and at intervals (days 1, 5, 10, and 30) after intravaginal placement of a polysiloxane ring impregnated with 400 mg of estradiol. Mean serum estradiol concentrations rose 26-fold with a twofold increase in serum estrone concentrations. Serum delta 4-androstenedione, dehydroepiandrosterone sulfate, and total testosterone did not change, but absolute and percent free testosterone concentrations declined significantly by day 5. Concurrently, serum concentrations of immunoactive follicle-stimulating hormone declined progressively, while serum luteinizing hormone and free alpha-subunit concentrations exhibited a biphasic pattern of suppression. Serum levels of prolactin increased monophasically and those of growth hormone, somatomedin C, and thyroid-stimulating hormone did not change.
Asunto(s)
Estradiol/uso terapéutico , Hormonas Esteroides Gonadales/sangre , Menopausia/efectos de los fármacos , Hormonas Adenohipofisarias/sangre , Estradiol/administración & dosificación , Estradiol/sangre , Estrona/sangre , Femenino , Humanos , Persona de Mediana Edad , Factores de TiempoRESUMEN
Twenty-five short term hCG stimulation tests were performed in seven prepubertal girls, aged 3-11 yr, who were being evaluated for short stature. Provocative testing revealed GH deficiency in all patients, but reevaluation of one girl at a later date showed normal somatotropin levels. The study protocol lasted 18 months and included testing before, during, and after 1 yr of GH therapy. Delta 4-Androstenedione, testosterone, estrone, and estradiol were determined 0, 24, 48, and 72 h after initiation of a two-injection course of CG. Significant responses (approximately 2-fold over baseline) to the stimulation tests occurred for all steroids except testosterone, though no augmented effects were found in the presence of human GH. The results indicate functional capability of the prepubertal ovary when exposed acutely to a LH-like material, but no role for somatotropin in gonadal steroid production in the prepubertal female.
Asunto(s)
Gonadotropina Coriónica/farmacología , Hormona del Crecimiento/fisiología , Ovario/efectos de los fármacos , Androstenodiona/sangre , Niño , Preescolar , Estradiol/sangre , Estrona/sangre , Femenino , Hormona Folículo Estimulante/orina , Hormona del Crecimiento/deficiencia , Humanos , Hormona Luteinizante/orina , Pubertad , Testosterona/sangreRESUMEN
Blood production rates of testosterone, dihydrotestosterone (DHT), and 3 alpha-androstanediol (3 alpha-diol) were found to be approximately 2-fold elevated in morbidly obese, nonhirsute, normally menstruating women. Values were intermediate between those found in normal women and those in a group of nonobese normally menstruating women with idiopathic hirsutism. Elevated androgen production rates in obese women were associated with 2- to 3-fold increases in MCRs, presumably due to decreased levels of sex hormone-binding globulin. Thus, increased production rates were offset by increased MCRs, resulting in plasma testosterone, DHT, and 3 alpha-diol concentrations that were similar in the obese and normal women. By contrast, women with hirsutism had increased production rates associated with elevated plasma androgens as well as increased MCRs. Urinary excretion of testosterone glucuronide and 3 alpha-diol glucuronide (3 alpha-diol G) were elevated in both obese and hirsute women, paralleling the increased androgen production rates. Despite increased production rates and excretion of androgens, obese women exhibited no menstrual abnormalities, hirsutism, or other signs of virilism. To explore the apparent ineffectiveness of increased androgen production to produce virilizing symptoms, we measured plasma 3 alpha-diol G levels as a measure of peripheral androgen action. The mean +/- SE plasma 3 alpha-diol G was 53 +/- 8 ng/dl in obese women and 36 +/- 6 in normal women; by contrast, women with idiopathic hirsutism had levels of 440 +/- 99, a 12-fold elevation. Plasma testosterone glucuronide in obese and hirsute women were only 2- to 3-fold elevated, while plasma DHT glucuronide was not increased in obese women and was only 2-fold elevated in hirsute women. Thus, obesity is a state of increased androgen production and accelerated clearance. 3 alpha-diol G levels in obese women were only minimally elevated, in contrast to values in the hirsute women, perhaps reflecting the apparent androgen ineffectiveness.
Asunto(s)
Andrógenos/metabolismo , Obesidad/metabolismo , Adulto , Andrógenos/biosíntesis , Androstano-3,17-diol/sangre , Androstano-3,17-diol/orina , Dihidrotestosterona/sangre , Dihidrotestosterona/orina , Femenino , Glucuronatos/sangre , Glucuronatos/orina , Hirsutismo/metabolismo , Humanos , Tasa de Depuración Metabólica , Obesidad/sangre , Obesidad/orina , Testosterona/sangre , Testosterona/orinaRESUMEN
We have tested the participation of endogenous opiate pathways in the negative feedback actions of gonadal steroids on pulsatile properties of luteinizing (LH) hormone release in normal men. To this end, sex steroid hormones were infused intravenously at dosages that under steady state conditions selectively suppressed either the frequency or the amplitude of the pulsatile LH signal. The properties of pulsatile LH secretion were assessed quantitatively by computerized analysis of LH series derived from serial blood sampling over 12 h of observation. When the pure (nonaromatizable) androgen, 5-alpha-dihydrotestosterone, was infused continuously for 108 h at the blood production rate of testosterone, we were able to achieve selective inhibition of LH pulse frequency akin to that observed in experimental animals after low-dosage androgen replacement. Under these conditions, serum concentrations of testosterone and estradiol-17 beta did not change significantly, but serum 5 alpha-dihydrotestosterone concentrations increased approximately two- to threefold, with a corresponding increase in levels of its major metabolite, 5 alpha-androstan-3 alpha, 17 beta-diol. In separate experiments, the infusion of estradiol-17 beta at its blood production rate over a 4.5-d interval selectively suppressed LH pulse amplitude without influencing LH pulse frequency. Estrogen infusion increased serum estradiol-17 beta levels approximately twofold without significantly altering blood androgen concentrations. We then used these schedules of selective androgen or estrogen infusion to investigate the participation of endogenous opiates in the individual inhibitory feedback actions of pure androgen or estrogen on pulsatile LH release by administering a potent and specific opiate-receptor antagonist, naltrexone, during the infusions. Our observations indicate that, despite the continuous infusion of a dosage of 5 alpha-dihydrotestosterone that significantly suppresses LH pulse frequency, co-administration of an opiate-receptor antagonist effectively reinstates LH pulse frequency to control levels. Moreover, during the infusion of a suppressive dose of estradiol-17 beta, opiate receptor blockade significantly augments LH pulse frequency and increases LH peak amplitude to control levels. Thus, the present studies in normal men demonstrate for the first time that the selective inhibitory action of a pure androgen on LH pulse frequency is effectively antagonized by opiate-receptor blockade. This pivotal observation indicates that opiatergic and androgen-dependent mechanisms specifically and coordinately control the hypothalamic pulse generator for gonadotropin-releasing hormone (GnRH)