RESUMO
Blast cells from 24 patients with acute lymphoblastic leukemia of Burkitt's cell type were studied for lymphocyte surface markers. The leukemia cells were of B-cell origin in 23 cases and showed a non-B, non-T phenotype in 1 case. Surface immunoglobulins on blast cells were monoclonal, with a striking predominance of cases with light chains of lambda type. They consisted most often of high-density IgM usually without associated IgD. However, 3 patients had cells with surface IgG and 1 had surface IgA. The blast cells lacked detectable IgG Fc receptors in more than half the patients. Serum immunoglobulins were studied in 15 cases: A monoclonal IgM was found in 5 patients (whose blast cells had surface IgM) and a Bence Jones protein was found in 2 others, both of whom had blasts with surface IgG lambda.
Assuntos
Linfoma de Burkitt , Leucemia Linfoide/patologia , Adolescente , Adulto , Idoso , Anticorpos Antineoplásicos/imunologia , Antígenos de Neoplasias/imunologia , Antígenos de Superfície/imunologia , Linfócitos B/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Cadeias lambda de Imunoglobulina/imunologia , Leucemia Linfoide/imunologia , Masculino , Pessoa de Meia-Idade , Receptores Fc/imunologia , Formação de RosetaRESUMO
PURPOSE: The French Society of Pediatric Oncology MDH82 study demonstrated the effectiveness of 20 Gy irradiation of involved fields after doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or mechlorethamine, vincristine, procarbazine, and prednisone/ABVD chemotherapy in children with localized Hodgkin's disease (HD). The response to primary chemotherapy was the only predictor of survival. To reduce long-term treatment complications without compromising efficacy, the MDH90 study was based on a new chemotherapy regimen devoid of both alkylating agents and anthracycline, followed by 20 Gy of radiotherapy (RT) for good responders. PATIENTS AND METHODS: From January 1990 to July 1996, 202 children were enrolled from 30 institutions. Good responders to four cycles of vinblastine, bleomycin, etoposide (VP16), and prednisone (VBVP) were given 20 Gy of RT and no further therapy. Poor responders were given vincristine, procarbazine, prednisone, and doxorubicin. After a second evaluation, good responders were given 20 Gy of RT, and poor responders were given 40 Gy of RT. RESULTS: One hundred seventy-one patients (85%) were good responders to VBVP, 27 (15%) were poor responders, and four did not respond. With a median follow-up of 74 months (range, 25 to 117 months), the 5-year overall survival rate (mean +/- SD) is 97.5% +/- 2.1%, and the event-free survival rate (mean +/- SD) is 91.1% +/- 1.8%. Significant predictors of worse event-free survival in multivariate analysis were hemoglobin < 10.5 g/L, "b" biologic class, and nodular sclerosis. CONCLUSION: These results suggest that most children with clinical stage I and II HD can be treated with chemotherapy devoid of alkylating agents and anthracycline, followed by low-dose RT.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/radioterapia , Adolescente , Bleomicina/administração & dosagem , Criança , Pré-Escolar , Terapia Combinada , Dacarbazina/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Doença de Hodgkin/patologia , Humanos , Masculino , Prednisona/administração & dosagem , Dosagem Radioterapêutica , Resultado do Tratamento , Vimblastina/administração & dosagemRESUMO
PURPOSE: To determine whether the use of a recombinant human granulocyte colony-stimulating factor ([G-CSF] lenogastrim) can increase the chemotherapy dose-intensity (CDI) delivered during consolidation chemotherapy of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Sixty-seven children with very high-risk ALL were randomized (slow early response to therapy, 55 patients; translocation t(9;22) or t(4;11), 12 patients). Consolidation consisted of six courses of chemotherapy; the first, third, and fifth courses were a combination of high-dose cytarabine, etoposide, and dexamethasone (R3), whereas the second, fourth, and sixth courses included vincristine, prednisone, cyclophosphamide, doxorubicin, and methotrexate (COPADM). G-CSF was given after each course, and the next scheduled course was started as soon as neutrophil count was > 1 x 10(9)/L and platelet count was > 100 x 10(9)/L. CDI was calculated using the interval from day 1 of the first course to hematologic recovery after the fifth course (100% CDI = 105-day interval). RESULTS: CDI was significantly increased in the G-CSF group compared with the non-G-CSF group (mean +/- 95% confidence interval, 105 +/- 5% v 91 +/- 4%; P <.001). This higher intensity was a result of shorter post-R3 intervals in the G-CSF group, whereas the post-COPADM intervals were not statistically reduced. After the R3 courses, the number of days with fever and intravenous antibiotics and duration of hospitalization were significantly decreased by G-CSF, whereas reductions observed after COPADM were not statistically significant. Duration of granulocytopenia was reduced in the G-CSF group, but thrombocytopenia was prolonged, and the number of platelet transfusions was increased. Finally, the 3-year probability of event-free survival was not different between the two groups. CONCLUSION: G-CSF can increase CDI in high-risk childhood ALL. Its effects depend on the chemotherapy regimen given before G-CSF administration. In our study, a higher CDI did not improve disease control.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Neutropenia/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Trombocitopenia/induzido quimicamente , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Dexametasona/administração & dosagem , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Humanos , Lactente , Recém-Nascido , Masculino , Metotrexato/administração & dosagem , Neutropenia/prevenção & controle , Prednisona/administração & dosagem , Proteínas Recombinantes , Trombocitopenia/prevenção & controle , Resultado do Tratamento , Vincristina/administração & dosagemRESUMO
Acquired pure monosomy-7 is associated with various myeloproliferative disorders (MPD), myelodysplasias (MDS), and acute myeloblastic leukemias (AML) in children and a poor prognosis. A series of 14 malignant blood disorders with pure monosomy-7 in children (eight MPD, two refractory anemia with excess of blasts, (RAEB), and four AML) is reported and compared with cases in the literature. The median age is significantly different in the patients with MPD and those with MDS or AML: 23, 80.5, and 112 months, respectively. The outcomes of MPD and RAEB are characterized by a high risk of rapid blastic transformation and resistance to polychemotherapy. Bone marrow transplantation (BMT) seems to be the best treatment, and one survival of two years in complete remission after autologous BMT in a child with AML is reported. Several myeloid cell lineages are involved in the proliferation, which partly explains the difficulties of cytologic classification and suggests that a pluripotent stem-cell is at the origin of the disease.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 7 , Doenças Hematológicas/genética , Monossomia , Adolescente , Crise Blástica/genética , Crise Blástica/patologia , Transplante de Medula Óssea , Criança , Pré-Escolar , Feminino , Doenças Hematológicas/patologia , Humanos , Lactente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/cirurgia , Masculino , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Prognóstico , Indução de RemissãoRESUMO
Retinoic acid, vitamin D3, and dexamethasone are known inducers of myeloid leukemic cell differentiation. Recent evidence indicates that these drugs mediate their biological effects through binding to a nuclear receptor which belongs to the steroid/thyroid hormone receptor superfamily. This paper shows that the ligands of the other receptors of this family, estrogens, progesterone, androgens and thyroid hormone, do not induce leukemic cell differentiation. However, thyroid hormone potentiates, by one order of magnitude, the dose-response effect of retinoic acid in HL-60 cells.
Assuntos
Granulócitos/efeitos dos fármacos , Leucemia Experimental/patologia , Leucemia Mieloide/patologia , Hormônios Tireóideos/farmacologia , Tretinoína/farmacologia , Diferenciação Celular/efeitos dos fármacos , Colecalciferol/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Granulócitos/citologia , Humanos , Leucemia Experimental/tratamento farmacológico , Leucemia Experimental/metabolismo , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/metabolismo , Oxigênio/metabolismo , Estimulação Química , Tri-Iodotironina/farmacologia , Células Tumorais CultivadasRESUMO
Aromatase activity (AR) was studied in pubic skin fibroblasts from eight patients with isolated gynecomastia (PSFG) and five normal subjects (PSFC). Cell monolayers were incubated in the presence of [3H]androstenedione (2 nM) for 4 or 24 h. Culture medium was extracted after addition of [14C] carriers to monitor recovery. Metabolites were separated by two successive chromatographic steps. Estrone (E1) and estradiol (E2) were characterized by crystallization, the other metabolites: 16-hydroxyestrone (16 alpha-OHE1) estriol (E3), and epiestriol (epiE3) by their chromatographic migration. AR was expressed either as femtomoles of E2 per microgram DNA (ARE2) or as total aromatized metabolites (ART = E1 + E2 + 16 alpha-OHE1 + E3 + epiE3/microgram DNA). After 4 h of incubation, no ARE2 could be measured in PSFC; it was low but significant in PSFG (0.03 +/- 0.02 (SEM) fmol/microgram DNA, P less than 0.01). The difference in ART was even more striking: 0.28 +/- 0.1 fmol/microgram DNA in PSFC, 3.15 +/- 2.88 in PSFG (P less than 0.05). 16 alpha-OHE1 represented in this latter group 62.5% of total aromatized metabolites vs. 39% in PSFC. After 24 h, ART was 4.17 +/- 3.70 and 1.02 +/- 0.42 fmol/microgram DNA in PSFG and PSFC, respectively (P less than 0.05); E3 + epiE3 represented 50% of the metabolites in both groups. In conclusion, AR is increased in PSFG relative to PSFC and an important oxidative metabolism of estrogens exists in both types of cells. This increased peripheral AR could result in increased formation of estrogens at the target cell site and represent an element of androgen-estrogen imbalance which would favor the development of gynecomastia.
Assuntos
Aromatase/análise , Fibroblastos/enzimologia , Ginecomastia/enzimologia , Adolescente , Adulto , Androstenodiona/metabolismo , Células Cultivadas , Estradiol/metabolismo , Estrona/metabolismo , Virilha , Humanos , Masculino , Pessoa de Meia-Idade , Pele/enzimologia , Testosterona/biossínteseRESUMO
The effect of dihydrotestosterone [17 beta-hydroxy-5 alpha-androstone-3-one (DHT) in the negative regulation of LH was studied throughout 3 months of percutaneous administration of this steroid to six normal male volunteers and six patients with primary testicular hypogonadism. In addition, testosterone (T) was administered according to the same protocol to the six hypogonadal patients. Plasma T, DHT, estradiol, sex hormone-binding globulin, and LH levels were measured by RIA before and weekly during treatment. In normal men, plasma DHT rose regularly from 0.5 +/- 0.2 to 3.3 +/- 0.9 ng/ml after 3 months of treatment. Concurrently, T decreased from 5.5 +/- 2.0 to 2.9 +/- 0.3 ng/ml, and sex hormone-binding globulin levels decreased from 1.2 +/- 0.1 to 0.9 +/- 0.05 mg/liter. Mean basal LH levels remained stable between 1.9 +/- 1.3 and 3.1 +/- 1.1 mIU MRC, LH 68/40 per ml throughout treatment. In hypogonadal men after DHT treatment, basal LH levels were not suppressed. In contrast, after T administration, plasma LH decreased from 19.8 +/- 5.4 mIU/ml to normal levels (3.4 +/- 2.7 mIU/ml). From these studies, we conclude that 1) high levels of plasma DHT, maintained over a long period, were unable to lower plasma LH in either normal or hypogonadal patients, and 2) in contrast, during the same length of time, high levels of plasma T were perfectly capable of achieving feedback regulation of LH secretion. From these data, it seems unlikely that circulating DHT plays an important role in the physiological regulation of LH secretion.
Assuntos
Di-Hidrotestosterona , Hipogonadismo/fisiopatologia , Hormônio Luteinizante/metabolismo , Doenças Testiculares/fisiopatologia , Adulto , Castração , Criptorquidismo/fisiopatologia , Di-Hidrotestosterona/sangue , Estradiol/sangue , Humanos , Hormônio Luteinizante/sangue , Masculino , Testosterona/sangueRESUMO
Hyperprolactinemia in men is frequently associated with hypogonadism. Normalization of serum PRL levels is generally associated with an increase in serum testosterone (T) to normal. To determine the mechanism of the inhibitory effect of hyperprolactinemia on the hypothalamic-pituitary-gonadal axis, we studied the effect of intermittent pulsatile GnRH administration on LH pulsatility and T levels in four men with prolactinomas. All patients had high PRL values (100-3000 ng/ml), low LH (mean +/- SEM, 2.2 +/- 0.1 mIU/ml), and low T values (2.3 +/- 0.3 ng/ml), with no other apparent abnormality of pituitary function. GnRH was administered iv using a pump delivering a bolus dose of 10 micrograms every 90 min for 12 days. No LH pulses were detected before treatment. Pulsatile GnRH administration resulted in a significant increase in basal LH levels (6.7 +/- 0.6 mIU/ml; P less than 0.001) and restored LH pulsatility. In addition, T levels increased significantly to normal values in all patients (7.8 +/- 0.4 ng/ml; P less than 0.001) and were normal or supranormal as long as the pump was in use, although PRL levels remained elevated. These data, therefore, suggest that hyperprolactinemia produces hypogonadism primarily by interfering with pulsatile GnRH release.
Assuntos
Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Luteinizante/sangue , Neoplasias Hipofisárias/sangue , Prolactina/sangue , Testosterona/sangue , Adulto , Esquema de Medicação , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/sangue , Humanos , Masculino , Prolactina/metabolismoRESUMO
To determine if progesterone (P) does affect gonadotropin secretion by acting directly on the pituitary, six women with hypothalamic gonadotropin deficiency were studied. They were treated with 17 beta-estradiol (E2; 2 mg/day, orally) to induce P receptors and maintain constant plasma E2 levels during two 15-day periods separated by 1 month. GnRH was administered iv at a dose of 10 microgram/pulse every 90 min during the last 5 days of E2 treatment. Either P (400 mg/day) or a placebo was administered intravaginally in a cross-over randomized design during the 5 days of pulsatile GnRH therapy. A baseline study of pulsatile LH secretion was performed, with sampling performed every 10 min for 8 h. The sampling was then repeated on day 15 of each study period at the end of pulsatile GnRH administration. Plasma levels of E2 and P were measured every day during the 5 days of either GnRH and P or GnRH and placebo treatment. In the six patients, the observed apulsatile pattern of LH during the baseline study confirmed the diagnosis of complete gonadotropin deficiency. Plasma E2 levels were not significantly different at the time of each pulse analysis (288 +/- 61 vs. 252 +/- 77 pmol/L). The plasma P level achieved with the vaginal pessaries was 22 +/- 5 nmol/L. P treatment resulted in all cases in a significant increase in the mean plasma LH level (5.2 +/- 0.9 vs. 3.6 +/- 0.7 IU/L after GnRH plus placebo; P less than 0.001). Furthermore, LH pulse amplitude was significantly increased by P compared to placebo (3.1 +/- 0.3 vs. 1.4 +/- 0.1 IU/L, respectively; P less than 0.01). Mean plasma FSH levels were significantly increased by GnRH regardless of whether P or placebo was present. In conclusion, these data indicate that a short exposure to physiological levels of P in the range of early luteal phase levels has a stimulatory effect on LH secretion by acting directly at the pituitary level.
Assuntos
Estradiol/uso terapêutico , Hormônio Liberador de Gonadotropina/deficiência , Hipogonadismo/fisiopatologia , Hormônio Luteinizante/metabolismo , Hipófise/efeitos dos fármacos , Progesterona/uso terapêutico , Ciclos de Atividade , Administração Intravaginal , Administração Oral , Adulto , Estradiol/administração & dosagem , Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Hipogonadismo/tratamento farmacológico , Cinética , Hormônio Luteinizante/sangue , Hipófise/metabolismo , Progesterona/administração & dosagem , Progesterona/sangueRESUMO
The effects of angiotensin have been studied in four adult patients with the simple virilizing form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. They were treated with hydrocortisone (25 mg/day) throughout this investigation. Plasma ACTH was normal in three cases, and androstenedione was normal in all cases. However, urinary pregnanetriol, plasma 17-hydroxyprogesterone (17 OHP), aldosterone, and renin activity was increased. The patients were then submitted to three protocols: sodium depletion (10 meq Na/day) for 5 days, sodium repletion (200 meq Na/day) for 5 days, and angiotensin infusion (sufficient to maintain a pressor response) for 60 min. Urinary pregnanetriol, plasma 17 OHP, and androstenedione levels increased in all patients after sodium depletion and decreased after sodium repletion. Plasma ACTH levels were not modified by changes in the sodium balance. Furthermore, angiotensin infusion increased aldosterone and 17 OHP plasma concentrations without any change in the plasma ACTH level. This study shows the direct action of angiotensin on adrenal steroidogenesis, at least in 21-hydroxylase deficiency. It confirms that even in the simple virilizing form, combined treatment with glucocorticoids and mineralocorticoids helps to normalize plasma 17 OHP levels.
Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Hiperplasia Suprarrenal Congênita , Hiperplasia Suprarrenal Congênita/metabolismo , Aldosterona/sangue , Angiotensina II/fisiologia , Hidroxiprogesteronas/sangue , Esteroide Hidroxilases/deficiência , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Adulto , Androstenodiona/sangue , Dieta Hipossódica , Feminino , Humanos , Hidrocortisona/uso terapêutico , Masculino , Pregnanotriol/urina , Renina/sangueRESUMO
According to the 2-cell theory, ovarian steroidogenesis requires the coordinate action of both FSH and LH. To evaluate the relative importance of these hormones in follicular maturation, a randomized cross-over study was performed in 10 women with complete gonadotropin deficiency (absence of pulsatile LH secretion and no LH response to LHRH). Five women were treated with highly purified FSH (LH bioactivity, 0.09%) and 3 months later with human menopausal gonadotropin (hMG; LH bioactivity, 65%), each given for 10 days at a daily dose of 225 IU FSH, im. The sequence was reversed in the other 5 women. hCG (5000 IU) was administered im 24 h after the last injection of FSH or hMG. Plasma estradiol (E2), estrone (E1), androstenedione (A), testosterone, LH, and FSH concentrations and urinary LH and FSH were measured daily by RIA. Ultrasonography was performed during each treatment and 2 days after each hCG injection. After FSH treatment, mean plasma and urinary FSH levels increased, mean plasma LH did not change, and urinary LH increased slightly but not significantly from 91 +/- 32 (SE) to 164 +/- 55 mIU/24 h (10(-3) IU/24 h). After hMG treatment, mean plasma and urinary LH and FSH levels increased accordingly. The mean basal plasma E2 [11 +/- 1 pg/mL (40 +/- 4 pmol/L)] and E1 [14 +/- 4 pg/mL (52 +/- 15 pmol/L)] levels increased after FSH treatment to 207 +/- 69 pg/mL (760 +/- 253 pmol/L) and 82 +/- 21 pg/mL (303 +/- 78 pmol/L), respectively (P less than 0.01), but plasma A did not change. In response to hMG, the mean plasma E2, E1, A, and testosterone levels increased more than during FSH treatment. Ultrasonography revealed multiple preovulatory follicles (greater than or equal to 16 mm) in 2 women after hMG and 1 woman after FSH treatment; therefore, hCG was not administered. In 3 women given FSH, hCG did not induce ovulation. hCG induced ovulation in 8 women given hMG and in 6 women given FSH, based on ultrasonography and plasma progesterone levels. Thus, in the presence of profound gonadotropin deficiency pharmacological doses of FSH, with minute LH contamination, are capable of stimulating ovarian follicular maturation, underlining the key role of FSH in folliculogenesis.
Assuntos
Hormônio Foliculoestimulante/farmacologia , Gonadotropinas/deficiência , Folículo Ovariano/efeitos dos fármacos , Adolescente , Adulto , Androstenodiona/sangue , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Menotropinas/farmacologia , Folículo Ovariano/crescimento & desenvolvimentoRESUMO
A randomized cross-over study was done to compare the therapeutic efficacy of cyproterone acetate (CPA) and a depot preparation of the LHRH superagonist (DTrp6-LHRH) in 10 patients with polycystic ovarian disease (PCO). All patients were treated with both agents (50 mg/day CPA, orally and (3 mg DTrp6-LHRH, im, approximately once a month) for 3 months, the 2 treatment periods being separated by 6 months. Both treatments resulted in marked clinical improvement, with diminished acne and seborrhoea and normalization of ovarian size by ultrasonographic criteria. In response to CPA treatment, basal plasma gonadotropin levels decreased, but the response to a LHRH test was not completely suppressed. Plasma estradiol, estrone, testosterone, and androstenedione levels significantly decreased, but urinary 3 alpha-androstanediol and plasma dehydroepiandrosterone sulfate levels did not change significantly. In contrast to CPA treatment, both basal and stimulated gonadotropin levels were completely suppressed after 3 weeks of treatment with DTrp6-LHRH. After a slight initial evaluation on day 2, plasma estrogen and androgen levels, with the exception of dehydroepiandrosterone sulfate fell into the castrate range urinary 3 alpha-androstanediol excretion decreased significantly. Thus, in patients with PCO, LHRH-A induced more complete gonadotropin inhibition than did CPA. After cessation of either therapy, the disease rapidly recurred.
Assuntos
Ciproterona/análogos & derivados , Hormônio Liberador de Gonadotropina/análogos & derivados , Síndrome do Ovário Policístico/tratamento farmacológico , Adulto , Androstano-3,17-diol/urina , Androstenodiona/sangue , Ciproterona/uso terapêutico , Acetato de Ciproterona , Preparações de Ação Retardada , Estradiol/sangue , Estrona/sangue , Feminino , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Síndrome do Ovário Policístico/sangue , Testosterona/sangue , Pamoato de TriptorrelinaRESUMO
UNLABELLED: The antiprogesterone steroid RU 486 (17 beta-hydroxy-11 beta-4-dimethyl-aminophenyl)17 alpha(1-propynyl)estra-4,9-dien-3-one) was given orally to 32 normally cycling women for 4 days, starting on the fourth day of the luteal phase. Uterine bleeding occurred on the third day of RU 486 administration in all 14 women treated with 100 mg/day, in 7 of the 8 women treated with 50 mg, and in 8 of 10 women receiving 25 mg/day. Premature luteal regression induced by RU 486 occurred in 8 women treated with 100 mg/day, in 3 treated with 50 mg, and in 2 receiving 25 mg/day. Plasma LH was measured every 15 min from 0800-1200 h for 5 days in 17 women. Mean LH levels decreased and pulsatile release disappeared in 7 of the 8 women treated with 100 mg, in 2 of 4 receiving 50 mg, and in 1 of 5 treated with 25 mg. RU 486 had no effect when given to 5 women with anovulatory cycles for 4 days starting on day 18 of the cycle. IN CONCLUSION: 1) RU 486, given to normally cycling women at midluteal phase, provokes uterine bleeding. 2) This effect occurs whether or not luteal regression is induced by the compound, indicating that RU 486 acts directly upon the endometrial tissue, very likely at the progesterone receptor level. 3) The drug may impair simultaneously or separately luteal function and gonadotropin secretion in a dose-dependent manner. 4) The lack of antiglucocorticosteroid activity, at the dosage of 100 mg/day, suggests that RU 486 may be useful for fertility control.
PIP: The antiprogesterone steroid RU 486 (17beta-hydroxy-11beta-4-dimethyl-aminophenyl)17alpha(1-propynyl)estra-4,9-dien-3-one) was given orally to 32 normally cycling women for 4 days, starting on the 4th day of the luteal phase. Uterine bleeding occurred on the 3rd day of RU 486 administration in all 14 women treated with 100 mg/day, in 7 of the 8 women treated with 50 mg and in 8 of 10 women receiving 25 mg/day. Premature luteal regression induced by RU 486 occurred in 8 women treated with 100 mg/day, in 3 treated with 50 mg, and in 2 receiving 25 mg/day. Plasma LH was measured every 15 minutes from 0800-1200 hours for 5 days in 17 women. Mean LH levels decreased and pulsatile release disappeared in 7 of 8 women treated with 100 mg, in 2 of 4 women receiving 50 mg, and in 1 of 5 treated with 25 mg. RU 486 had no effect when given to 5 women with anovulatory cycles for 4 days starting on day 18 of the cycle. The following were conclusions drawn. 1) RU 486, given to normally cycling women at midluteal phase, provokes uterine bleeding. 2) This effect occurs whether or not luteal regression is induced by the compound, indicating that RU 486 acts directly on the endometrial tissue, very likely at the progesterone receptor level. 3) The drug may impair simultaneously or separately luteal function and gonadotropin secretion in a dose-dependent manner. 4) The lack of antiglucocorticosteroid activity, at a dosage of 100 mg/day, suggests that RU 486 may be useful for fertility control.
Assuntos
Estrenos/farmacologia , Fase Luteal/efeitos dos fármacos , Hormônio Adrenocorticotrópico/sangue , Adulto , Aldosterona/sangue , Anovulação/sangue , Estradiol/sangue , Feminino , Gonadotropinas/sangue , Humanos , Hidrocortisona/sangue , Menstruação/efeitos dos fármacos , Mifepristona , Testes de Função Adreno-Hipofisária , Progesterona/sangue , Renina/sangueRESUMO
In men with hypogonadotropic hypogonadism, prolonged treatment with LH and FSH induces spermatogenesis. To compare the respective role of exogenous testosterone and intratesticular testosterone on the induction and maintenance of spermatogenesis, 10 men with hypogonadotropic hypogonadism and without history of cryptorchidism were studied. They were treated with human gonadotropins (hMG; 150 IU FSH and LH and 1500 IU hCG, im, three times weekly) or pure FSH (150 IU, im, three times a week) and testosterone (T: 250 mg, im, once a week). Five men were treated first with hMG-hCG and then with pure FSH plus T. The other five men started with pure FSH plus T. Each treatment period lasted 24 months. In all men, hMG-hCG induced spermatogenesis after 24 months, with normal motility and quality. The combination of pure FSH and T was not able to induce spermatogenesis after 24 months. In addition, sperm count dropped dramatically to 0.3 +/- 0.1 x 10(6)/mL within 3 months and to 0 after 6 months when pure FSH and T followed [corrected] hMG-hCG. Plasma T levels were increased by both treatments, but significantly more after pure FSH and T (35.3 +/- 5.2 nmol/L) than after hMG-hCG (20.4 +/- 5.2 nmol/L; P < 0.05). Plasma estradiol levels after treatment with pure FSH and T were also increased, but the difference from those obtained during hMG-hCG treatment was not significant. In conclusion, in men with complete gonadotropin deficiency, FSH and exogenous T are not able to induce spermatogenesis. Furthermore, spermatogenesis induced by LH plus FSH (hMG-hCG) cannot be maintained when exogenous T replaced LH in the regimen. Thus, exogenous T is unable to replace LH (and intratesticular T) to induce spermatogenesis. These data are noteworthy in the prospect of male contraception after a complete blockade of gonadotropin activity.
Assuntos
Hormônio Foliculoestimulante/farmacologia , Hipogonadismo/tratamento farmacológico , Espermatogênese/efeitos dos fármacos , Testosterona/farmacologia , Adulto , Gonadotropina Coriônica/administração & dosagem , Quimioterapia Combinada , Hormônio Foliculoestimulante/administração & dosagem , Humanos , Hipogonadismo/fisiopatologia , Masculino , Menotropinas/administração & dosagem , Testosterona/administração & dosagemRESUMO
The present study reports the case of a 25-yr-old man with congenital adrenal hyperplasia due to 21-hydroxylase deficiency in whom bilateral testicular tumors did not regress after suppressive treatment with dexamethasone. Catheterization of left testicular and adrenal veins confirmed the enzyme deficiency in the gonadal lesions. The presence of specific 11 beta-hydroxylated steroids (11 beta-hydroxyandrostenedione, 21-deoxycortisol, and 21-deoxycorticosterone) in the gonadal vein demonstrated the adrenal nature of the testicular tumor. In addition, catheterization allowed further study of the secretion of mineralocorticoids and androgens in the adrenal venous effluent. Plasma levels of deoxycorticosterone were increased in the peripheral vein and decreased in the adrenal vein, confirming the conversion of progesterone by peripheral 21-hydroxylase activity. Plasma levels of delta 5-3 beta-hydroxysteroids, particularly dehydroepiandrosterone and its sulfate, were very low, suggesting a sustained stimulation of 3 beta-hydroxysteroid dehydrogenase activity. This study documents that in patients with congenital adrenal hyperplasia and bilateral testicular tumors, catheterization of a gonadal vein measuring specific 11 beta-hydroxylated steroids confirms the adrenal nature of the gonadal lesions.
Assuntos
Corticosteroides/metabolismo , Hiperplasia Suprarrenal Congênita/sangue , Androgênios/metabolismo , Neoplasias Testiculares/sangue , Corticosteroides/sangue , Glândulas Suprarrenais/irrigação sanguínea , Glândulas Suprarrenais/metabolismo , Hiperplasia Suprarrenal Congênita/complicações , Adulto , Androgênios/sangue , Estradiol/sangue , Estradiol/metabolismo , Humanos , Masculino , Progesterona/sangue , Progesterona/metabolismo , Neoplasias Testiculares/complicações , Testículo/irrigação sanguínea , Testículo/metabolismo , VeiasRESUMO
In functional hypothalamic amenorrhea (HA), it has been reported that administration of opioid receptor antagonists restores gonadotropin secretion and ovarian function. However, endogenous opioids may modulate gonadotropin secretion only in the presence of ovarian steroids. To further study these conflicting results, a group of nine women with secondary functional HA who wished to become pregnant were studied. The opiate antagonist naltrexone (Nal; 100 mg/day) was administered for two 30-day periods, starting on either day 22 (Nal 1) of a well characterized replacement regimen with estradiol (E2) and progesterone (P), or on day 22 (Nal 2) of the luteal phase induced by exogenous pulsatile GnRH administration (10 micrograms/pulse, iv, every 90 min). Plasma LH and FSH were measured every 10 min for 8 h before treatment and on day 12 of each treatment period (Nal 1, pulsatile GnRH, and Nal 2). Ovulation was monitored during each treatment. Plasma E2 levels were measured on days 12 and 22, and P levels on day 22 of each treatment. During exogenous E2 and P administration, plasma steroid levels reached luteal phase levels. However, during Nal 1, plasma E2 levels fell to prestudy levels and remained low. No follicular growth occurred, and the pulsatile study showed pretreatment frequency, amplitude, and mean plasma levels of LH. On day 12 of pulsatile GnRH administration, plasma E2 levels increased, and LH and FSH pulses followed each GnRH pulse during the frequent sampling study. Ovulation occurred in all women during pulsatile GnRH treatment. During Nal 2 treatment, plasma E2 levels returned to prestudy levels without follicular growth, and the pulsatile study was similar to those prior treatment and during Nal 1 administration. In conclusion, Nal, started during priming either with exogenous E2 and P treatment or gonadotropin stimulation induced by pulsatile GnRH administration, was unable when continued alone to initiate or maintain gonadotropin secretion in women with HA. Thus, the exclusive role of opioids in HA and the effect of Nal even in the presence of ovarian steroids are questionable.
Assuntos
Amenorreia/fisiopatologia , Estradiol/uso terapêutico , Terapia de Reposição de Estrogênios , Hormônio Liberador de Gonadotropina/uso terapêutico , Hipotálamo/fisiopatologia , Naltrexona/uso terapêutico , Indução da Ovulação , Progesterona/uso terapêutico , Adulto , Amenorreia/sangue , Esquema de Medicação , Feminino , Hormônio Foliculoestimulante/sangue , Hormônio Foliculoestimulante/metabolismo , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Liberador de Gonadotropina/farmacologia , Humanos , Hormônio Luteinizante/sangue , Hormônio Luteinizante/metabolismo , Gravidez , Estatísticas não ParamétricasRESUMO
A case of false hyperthyrotropinemia was investigated. The serum of the patient contained heterophilic antibodies against rabbit immunoglobulins secondary to immunization with rabbit serum. Some vaccines against viral or bacterial diseases contain animal serum capable of inducing heterophilic antibodies in man. This technical problem can be prevented by the routine addition of control rabbit serum or immunoglobulins to the TSH RIA.
Assuntos
Anticorpos Heterófilos , Imunoglobulina G/imunologia , Tireotropina/sangue , Animais , Reações Falso-Positivas , Feminino , Humanos , Imunoglobulinas , Pessoa de Meia-Idade , Coelhos/imunologia , RadioimunoensaioRESUMO
The antigonadal effects of GnRH agonists (GnRH-A) are mediated both through pituitary and testicular inhibitory mechanisms in the rat. To investigate these effects in men, we studied patients having no gonadotropin secretion and compared their testicular response to hCG in the absence or in the presence of GnRH-A. Thirteen patients with acquired pituitary hypogonadotropism had plasma testosterone levels below 1.5 ng/ml and no gonadotropin responses to acute GnRH administration (100 micrograms iv). Testicular responsiveness was evaluated using a single im injection of hCG (5000 IU im). Plasma levels of testosterone, dihydrotestosterone, androstenedione, 17-hydroxyprogesterone (17-OHP), and progesterone were determined before and 4, 12, 24, 48, and 72 h after hCG stimulation. The same protocol was also used in the same patients on day 4 of a 6-day course of treatment with the GnRH-A, D-Ser-(TBU)6, des-Gly NH2 GnRH ethylamide (Buserelin) (3 sc injections of 250 micrograms/day). During the first 4 days of GnRH-A administration, plasma LH, FSH, and testosterone levels were measured daily in order to establish the completeness of the gonadotropin deficiency. Before treatment with hCG, plasma testosterone levels were 0.56 +/- 0.15 and 0.96 +/- 0.22 ng/ml (mean +/- SE) in the absence of GnRH-A and during GnRH-A administration, respectively. The administration of hCG elicited a significant increase in plasma testosterone in both situations; integrated testosterone concentrations were 123.7 +/- 24.9 and 155.5 +/- 27.9 ng/ml . 72 h (P greater than 0.1) in the absence of GnRH-A and during GnRH-A administration, respectively. Likewise the ratios of 17-OHP to progesterone, androstenedione to 17-OHP, and dihydrotestosterone to testosterone after hCG injection were similar in the presence or absence of GnRH-A. Since short term administration of buserelin did not inhibit hCG-induced testosterone secretion in patients with gonadotropin deficiency, we suggest that Buserelin does not grossly modify the function of testicular steroidogenesis enzymes. The antigonadal effects of GnRH-A in man appear to be mediated exclusively through the pituitary.
Assuntos
Busserrelina/farmacologia , Hormônios Esteroides Gonadais/biossíntese , Gonadotropinas/deficiência , Testículo/efeitos dos fármacos , Gonadotropina Coriônica , Hormônios Esteroides Gonadais/sangue , Humanos , Masculino , Testículo/metabolismo , Testosterona/biossíntese , Testosterona/sangueRESUMO
The glucocorticoid and progesterone antagonist RU 486 normalizes the clinical and biochemical features of hypercortisolism in patients with nonpituitary Cushing's syndrome, presumably by antagonizing the action(s) of cortisol. Since RU 486 has progesterone agonist activity in addition to its progesterone antagonist action, the possibility that it might have some glucocorticoid agonist action did not seem unreasonable. To test this hypothesis we examined the effects of RU 486 on pituitary ACTH secretion in 10 patients with primary adrenal insufficiency in whom glucocorticoid replacement was withheld for 36 h. Each patient received, in randomized sequence 3-7 days apart, an oral dose of placebo, RU 486 (20 mg/kg), cortisol (0.1 mg/kg), or a combination of RU 486 and cortisol at 1800 h. Two hours later, an iv bolus dose of ovine CRH (1 microgram/kg) was administered, and plasma ACTH levels were measured serially for 3 h. RU 486 suppressed ovine CRH-stimulated ACTH secretion, albeit less than cortisol. Its glucocorticoid agonist effect was calculated to be approximately 1/250th that of cortisol on a weight basis. Additionally, RU 486 partially antagonized cortisol-induced suppression of ACTH secretion. These findings suggest that RU 486 is a partial glucocorticoid agonist and offer some insight as to its action in patients with Cushing's syndrome. Whether this degree of glucocorticoid agonist activity is adequate to support life, however, is not known.
PIP: The purpose of this study was to assess the glucocorticoid agonist activity of the antiprogestin steroid RU-486 by examining its ability to exert a glucocorticoid-like negative feedback effect on pituitary adrenocorticotropic hormone secretion. 10 patients with nonpituitary Cushing's syndrome, from whom cortisol therapy had been withheld for 36 hours, were given an oral dose of either a placebo, cortisol, or 20mg/kg of RU-480. 2 hours later, they were given an intravenous injection of lug/Kg of ovine corticotropin-releasing hormone. Blood samples were taken 15 minutes before the injection, at the time of the injection, and 15, 30, 60, 90, 120, and 180 minutes afterwards to measure adrenocorticotropic hormone and cortisol levels. Blood samples from the patients who received the RU-486 showed that RU-486 had suppressed the ovine corticotropin-releasing hormone-stimulated secretion of adrenocorticotropic hormone. However, the RU-486-induced suppression of the secretion of adrenocorticotropic hormone was only 80% that of the suppression induced by .1 mg/kg of cortisol, i.e., RU-486 had only 1/250 the glucocorticoid agonist effect of cortisol. RU-486, therefore, is a partial glucocorticoid agonist, but the effect is not of sufficient magnitude to prevent adrenal insufficiency in patients with nonpituitary Cushing's syndrome.
Assuntos
Hormônio Adrenocorticotrópico/sangue , Hormônio Liberador da Corticotropina/farmacologia , Estrenos/farmacologia , Glucocorticoides/antagonistas & inibidores , Progestinas/antagonistas & inibidores , Doença de Addison/sangue , Doença de Addison/fisiopatologia , Adrenalectomia , Adulto , Animais , Síndrome de Cushing/sangue , Síndrome de Cushing/fisiopatologia , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , MifepristonaRESUMO
Androgen insensitivity has been reported to be present in as many as 40% of patients with severe oligospermia. In order to evaluate further the role of androgen resistance in male infertility we studied 24 men with severe oligospermia. Plasma T and LH were measured by RIA and the T X LH product was calculated. Fibroblasts were grown from genital skin obtained during testicular biopsies and androgen receptor maximal binding capacity (BMAX) and affinity (KD) were measured in fibroblast monolayers. Pubic skin 5 alpha-reductase activity, an androgen-dependent enzyme, was measured in skin homogenates. Plasma T values were in the upper normal range [7.0 +/- 1.7 (SEM) ng ml-1] whereas the T X LH product was high (greater than 50) in only six patients. Mean BMAX and KD values for the androgen receptor were normal [BMAX: 788 +/- 259 fmol mg DNA-1 (patients, n = 20), 726 +/- 227 (normal men, n = 20), and KD: 0.27 +/- 0.24 (patients, n = 20), 0.18 +/- 0.09 (normal men, n = 15), respectively]. However, four men had supranormal KD values. The mean BMAX was also normal when the group of men with sperm densities below 10(6) per ejaculate was considered separately. Public skin 5 alpha-reductase activity was normal in all but four patients (patients: 177.1 +/- 91 fmol/mg skin/h, n = 30, normal men: 210 +/- 45, n = 20 patients). In conclusion, androgen receptor BMAX levels were normal in all patients studied, regardless of the sperm density and the T X LH product. Pubic skin 5 alpha-reductase activity was also normal in all but four patients. In these four patients, a qualitative defect of the androgen receptor cannot be excluded. In this group of patients with severe oligospermia, infertility did not seem to be related to quantitative abnormality of the androgen receptor as was previously reported.