RESUMEN
During long term replacement with a GnRH regimen that restores their gonadotropin and sex steroid levels to normal, men with idiopathic hypogonadotropic hypogonadism (IHH) exhibit excessive secretion of pituitary free alpha-subunit (FAS). To characterize further the dose and duration of exogenous GnRH required to elicit this response, FAS, LH, FSH, and testosterone were determined during the first 8 weeks of GnRH administration in 10 men with IHH. The GnRH dose was increased stepwise every 2 weeks from 5 to 100 ng/kg every 2 h. Hormonal responses were compared with normative data for both pubertal boys and adult men. Low baseline levels of LH (mean +/- SEM, 0.9 +/- 0.03 IU/L), FSH (2.5 +/- 0.4 IU/L), FAS (148 +/- 21 ng/L), and testosterone (2.5 +/- 0.3 nmol/L) increased progressively after GnRH replacement. Mean FAS levels and pulse amplitudes significantly exceeded those in normal adult men by 4-6 weeks when their LH responses to GnRH administration remained below adult norms. By week 8 (50 ng GnRH/kg every 2 h), mean levels of LH, FSH, and FAS (13.7 +/- 2.1 IU/L, 15.4 +/- 4.0 IU/L, 627 +/- 75 ng/L, respectively) significantly exceeded adult male concentrations (P < 0.03). However, mean LH and FSH concentrations were not significantly different from midpubertal controls, in whom FAS levels were comparable to those in normal adults, verifying the excessive nature of FAS secretion relative to intact gonadotropins in the IHH patients. As this imbalance between FAS and dimeric gonadotropin secretion was established early in the current study when low doses of GnRH presumably resulted in low levels of receptor occupancy in vivo, it does not appear to result from partial pituitary desensitization induced by pharmacological GnRH stimulation. Rather, it appears to represent an inherent property of the GnRH-deficient state that is unmasked when GnRH input to the pituitary is restored. Further work will be necessary to elucidate the mechanism of this apparent defect in FAS regulation in GnRH-deficient men.
Asunto(s)
Glicoproteínas/sangre , Hormona Liberadora de Gonadotropina/deficiencia , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Hipogonadismo/sangre , Hipogonadismo/tratamiento farmacológico , Hormona Luteinizante/sangre , Masculino , Valores de Referencia , Testosterona/sangreRESUMEN
OBJECTIVES: We sought to determine the effectiveness of a gonadotropin-releasing hormone antagonist compared with an agonist in suppressing a spontaneous luteinizing hormone surge in women undergoing controlled ovarian hyperstimulation for in vitro fertilization and gamete intrafallopian transfer and to examine whether in vivo administration of these analogs effects granulosa-lutein cells steroidogenesis in vitro. STUDY DESIGN: This prospective case-control study included 30 healthy women undergoing ovarian hyperstimulation with human menopausal gonadotropins. Fifteen women received the Nal-Glu antagonist, 5 mg intramuscularly daily, when the lead follicle was > or = 15 mm or serum estradiol level was > or = 500 pg/ml. The control group included 15 women who underwent oocyte retrieval on the same day as the study subjects and were given the agonist leuprolide acetate, 250 micrograms subcutaneously daily, starting on cycle day 1. Granulosa-lutein cells were purified from follicular aspirates from six subjects and six controls and cultured in parallel, evaluating basal progesterone production, progesterone response to follicle-stimulating hormone or luteinizing hormone and aromatase activity. RESULTS: No difference was demonstrated in the total amount of gonadotropins received by the two groups. Overall, the gonadotropin-releasing hormone antagonist was given for only 2.5 +/- 0.2 (mean +/- SEM) days before human chorionic gonadotropin administration. The antagonist group showed significantly lower levels of serum luteinizing hormone than did the agonist group, 1.0 +/- 0.2 versus 4.2 +/- 0.5 mIU/ml (p = 0.0001) on the day of human chorionic gonadotropin administration. Serum estradiol levels were significantly lower in the antagonist than the agonist group, 820 +/- 120 versus 1361 +/- 110 pg/ml (p = 0.003) on the day of human chorionic gonadotropin administration. There was no difference in the number of retrieved oocytes, but the antagonist group had a higher proportion of mature oocytes, 82% +/- 4% versus 62.4% (p = 0.02), and a higher proportion of embryos of good quality, 69.8% +/- 9.8% versus 44.3% +/- 7.2% (p = 0.03) in the agonist group. Granulosa-lutein cells from antagonist-treated women showed significantly lower aromatase activity the first 6 hours after retrieval, 17.6 +/- 1.6 versus 31.3 +/- 7.4 ng/ml per 6 hours estradiol (p = 0.03), whereas basal and gonadotropin-stimulated with progesterone responses were similar. CONCLUSION: Gonadotropin-releasing hormone antagonist administration during the late follicular phase resulted in lower serum luteinizing hormone and estradiol levels and more mature oocytes and embryos of better quality compared with gonadotropin-releasing hormone agonist administration. These results suggest that gonadotropin-releasing hormone antagonist administration in ovarian hyperstimulation has practical advantages over the agonist regimen. Gonadotropin-releasing hormone analogs may have direct action on ovarian function with differential effects on granulosa-lutein cell aromatase activity. This could explain the lower serum estradiol levels routinely observed in women given gonadotropin-releasing hormone antagonist.
Asunto(s)
Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Células de la Granulosa/efectos de los fármacos , Leuprolida/uso terapéutico , Células Lúteas/efectos de los fármacos , Ciclo Menstrual/efectos de los fármacos , Inducción de la Ovulación , Progesterona/biosíntesis , Adulto , Aromatasa/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Estradiol/sangre , Femenino , Fertilización In Vitro , Hormona Folículo Estimulante/farmacología , Fase Folicular , Transferencia Intrafalopiana del Gameto , Hormona Liberadora de Gonadotropina/uso terapéutico , Células de la Granulosa/enzimología , Células de la Granulosa/metabolismo , Humanos , Células Lúteas/enzimología , Células Lúteas/metabolismo , Hormona Luteinizante/sangre , Hormona Luteinizante/farmacología , Oocitos/citología , Oocitos/efectos de los fármacos , Estudios ProspectivosRESUMEN
GnRH regulates gonadotropin biosynthesis and release in the anterior pituitary via specific receptors. Although extrapituitary expression and action of GnRH have been shown in some species, in the human it is not clear whether GnRH has a peripheral action. In this study we sought to determine whether the human ovary expresses GnRH receptor (GnRHR) messenger ribonucleic acid (mRNA). Ovarian tissues from 11 women (32-61 yr old) and granulosa-lutein (GL) cells purified from follicular aspirates of 51 women undergoing oocyte retrieval for in vitro fertilization were analyzed by ribonuclease protection assay and reverse transcriptase-polymerase chain reaction (RT-PCR). Human pituitaries, lymphocytes, and placenta were also studied. Measurable levels of GnRHR mRNA were found by ribonuclease protection assay in 2 of 10 ovaries, in 2 of 4 GL cells preparations from women whose ovarian hyperstimulation involved a GnRH agonist, in GL cells from 3 women whose ovarian hyperstimulation involved a GnRH antagonist, and in human pituitaries. Relative to the total amount of RNA analyzed, the level of GnRHR mRNA was about 200-fold lower in the ovary than in the pituitary. A sequence of 314 basepairs of GnRHR mRNA was amplified by RT-PCR in the pituitary, in 9 of 10 ovaries, and in 4 of 5 GL cell preparations. No message could be amplified in human lymphocytes, and placental specimens showed a weak signal. The relative GnRHR mRNA levels in GL cells from 13 women analyzed by quantitative RT-PCR showed a wide range of individual differences. These results suggest that GnRHR mRNA is expressed in GL cells and the human ovary across different functional stages, implying that multiple ovarian compartments may express GnRH receptors. The administration of GnRH analogs may have a further direct action on the human ovary.
Asunto(s)
Expresión Génica , Células de la Granulosa/fisiología , Células Lúteas/fisiología , Ovario/fisiología , Receptores LHRH/genética , Adulto , Secuencia de Bases , Femenino , Humanos , Persona de Mediana Edad , Sondas Moleculares/genética , Datos de Secuencia Molecular , Hibridación de Ácido Nucleico , ARN Mensajero/metabolismo , Ribonucleasas , Transcripción GenéticaRESUMEN
The clinical manifestations of gonadotroph adenomas are almost always neurological, consequences of their large size, and are rarely endocrinological. We report an exception, a 39-yr-old woman whose gonadotroph adenoma caused supranormal serum concentrations of FSH, which resulted in the development of multiple ovarian cysts, persistent elevation of her serum estradiol concentration, and endometrial hyperplasia. She initially presented because of amenorrhea at age 30 yr and was treated for an intrasellar mass by transsphenoidal surgery at age 31 yr and again at age 36 yr. Before and after the second operation she had persistently supranormal plasma estradiol concentrations (> 1840 pmol/L) and endometrial hyperplasia. When she was evaluated at age 39 yr, transvaginal ultrasound showed multiple ovarian cysts and endometrial thickening. Her plasma estradiol level was markedly supranormal (2160 pmol/L), FSH was mildly supranormal (17.8 IU/L), and alpha-subunit was markedly supranormal (23.3 micrograms/L). Characteristic of gonadotroph adenomas, her LH beta level increased by 69% in response to TRH. Neither FSH nor alpha-subunit decreased in response to administration of the GnRH antagonist, Nal-Glu-GnRH (5 mg/12 h for 4 weeks). Excised adenoma tissue exhibited morphological features of a gonadotroph adenoma. This patient appears to be unique, in that her gonadotroph adenoma caused slightly, but persistently, supranormal concentrations of FSH, which caused ovarian stimulation, including supranormal plasma estradiol concentrations, multiple ovarian cysts, and endometrial hyperplasia. We propose that gonadotroph adenomas be considered in the differential diagnosis of patients who have this constellation of abnormalities.
Asunto(s)
Adenoma/metabolismo , Hormona Folículo Estimulante/metabolismo , Gonadotropinas/metabolismo , Síndrome de Hiperestimulación Ovárica/etiología , Neoplasias Hipofisarias/metabolismo , Adenoma/complicaciones , Adenoma/patología , Adulto , Femenino , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina/análogos & derivados , Humanos , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/patología , Hormona Liberadora de Tirotropina , UltrasonografíaRESUMEN
We report the evaluation of a 46-yr-old asymptomatic menopausal woman whose serum hCG concentrations remained persistently supra-normal for 3 yr (mean +/- SD, 20 +/- 10 IU/L; n = 19). Holo-hCG and beta-core fragments were detected in the patient's urine by Ultragel chromatography, followed by specific RIAs. Trophoblastic, germ cell, and other malignancies appeared to be excluded by the absence of serum tumor markers and imaging procedures of the pelvis, abdomen, breast, and chest. Administration of a single bolus dose of synthetic GnRH (100 micrograms) increased the serum hCG concentration by 50% (from 26 to 40 IU/L). Administration of the Nal-Glu GnRH antagonist (5 mg, sc, every 12 h for 1 week) decreased the serum hCG concentration from 27 to 4.6 IU/L. The pronounced decrease in the serum hCG concentration during antagonism of the action of endogenous GnRH by administration of Nal-Glu GnRH suggests that the pituitary is the source of the supra-normal serum hCG concentrations, because the pituitary is exposed to the highest concentration of endogenous GnRH.
Asunto(s)
Gonadotropina Coriónica/metabolismo , Endometrio/patología , Hormona Liberadora de Gonadotropina , Menopausia/fisiología , Adulto , Amenorrea/sangre , Androstenodiona/sangre , Biomarcadores de Tumor/sangre , Gonadotropina Coriónica/sangre , Gonadotropina Coriónica/orina , Femenino , Hormona Folículo Estimulante/sangre , Humanos , Hormona Luteinizante/sangre , Radioinmunoensayo , Valores de Referencia , Testosterona/sangreRESUMEN
The effects of acute gonadal suppression on sexual function and behavior were studied in eight normal men. Administration of a newly developed, potent gonadotropin-releasing hormone antagonist induced azoospermia and reduced levels of serum testosterone, luteinizing hormone, and follicle-stimulating hormone. These effects coincided with a reduction in outward-directed aggression in all men. Self-reported measures of anxiety and sexual desire revealed less consistent change over time. Measures of anger control, inward-directed anger, and affective state were unaffected.
Asunto(s)
Agresión/efectos de los fármacos , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Conducta Sexual/efectos de los fármacos , Adulto , Emociones/efectos de los fármacos , Estudios de Seguimiento , Hormona Liberadora de Gonadotropina/farmacología , Humanos , Libido/efectos de los fármacos , Masculino , Persona de Mediana Edad , Oligospermia/inducido químicamente , Testosterona/sangre , Testosterona/farmacologíaRESUMEN
PIP: Little progress has been made over the last century in developing contraceptives for men and men continue to have only a very small range of contraceptive options from which to choose. The most popular methods used by men remain condoms and vasectomy. Condom use remains, however, largely casual even despite recent interest in preventing the sexual transmission of HIV. Vasectomy is a permanent method of male contraception. There are many reasons why progress has been slow in developing male contraceptives, but they relate primarily to the physiology of the male reproductive system. The ideal male contraceptive should be practical, inexpensive, easily available, rapidly effective, promptly reversible, free of side effects, and should not interfere with sexual intercourse. The author describes approaches to male contraception in sections on the suppression of gonadotropins and immunocontraception, and closes with future considerations.^ieng
Asunto(s)
Anticonceptivos Masculinos , Femenino , Hormona Liberadora de Gonadotropina/análogos & derivados , Humanos , Masculino , Oligospermia , Espermatozoides/inmunología , Testosterona/análogos & derivados , VacunasRESUMEN
OBJECTIVE: To evaluate whether the chronic administration of a GnRH antagonist supplemented with T enanthate affects sperm motion parameters. DESIGN: Prospective study. SETTING: Academic medical research environment. PATIENTS/PARTICIPANTS: Six normospermic men of reproductive age. INTERVENTION: A 20-week treatment included the administration of 10 mg of GnRH antagonist every day and 25 mg of T enanthate once a week. MAIN OUTCOME MEASURE: Computerized sperm motion analysis on each participant every 2 weeks for a period of 11 months. RESULTS: Sperm concentration decreased after 4 weeks of the GnRH antagonist administration, accompanied by a reduction of sperm motility from an initial mean value of 56% to 34% on treatment week 4 and 21% on treatment week 6. In contrast, sperm velocity, linearity, amplitude of the lateral head displacement, and beat cross-frequency values did not significantly change in spite of reduced overall sperm concentration and motility. Azoospermia was reached within 6 to 12 weeks of the GnRH administration, and it was sustained during the treatment period. During recovery of spermatogenesis, sperm movement parameters returned to initial values earlier than sperm concentration and normal morphology. All participants recovered initial semen parameters 20 weeks after the end of treatment. CONCLUSION: The administration of a GnRH antagonist supplemented with T enanthate successfully induced reversible suppression of spermatogenesis. The sperm motion characteristics appeared to be the last parameters to decline and the first to return to initial values after the treatment.
Asunto(s)
Hormona Liberadora de Gonadotropina/análogos & derivados , Motilidad Espermática/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Testosterona/farmacología , Pamoato de Triptorelina/análogos & derivados , Adulto , Hormona Folículo Estimulante/biosíntesis , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Hormona Liberadora de Gonadotropina/farmacología , Humanos , Hormona Luteinizante/biosíntesis , Masculino , Recuento de Espermatozoides/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Espermatozoides/ultraestructura , Factores de TiempoRESUMEN
Because administration for 1 week of the GnRH antagonist Nal-Glu GnRH had been shown to decrease FSH secretion from supranormal to normal in men with gonadotroph adenomas, we investigated the effect of prolonged administration of Nal-Glu on the size of gonadotroph adenomas. To quantitate the effect of Nal-Glu GnRH on gonadotroph adenoma size, we first developed a technique for calculating adenoma volume. The technique involved collecting magnetic resonance (MR) imaging data from each adenoma at 1-mm slice intervals in the coronal, axial, and sagittal views and using the Softvu computer program to calculate adenoma volume from the MR data. The precision of this technique, as judged by the coefficients of variation of the calculations of the same view of the same study three times, was 1.7%, 1.0%, and 1.0% for each of three studies. When Nal-Glu GnRH (5 mg, sc, every 12 h) was self-administered for 3-12 months to five men with gonadotroph adenomas and supra-normal serum FSH concentrations, the serum FSH concentrations decreased to normal or below normal for the entire treatment period. Adenoma size, however, did not change during treatment in any of the five men. We conclude that calculating pituitary adenoma volume from MR data using the Softvu computer program is a highly reproducible technique, but that Nal-Glu GnRH is not an effective treatment for reducing gonadotroph adenoma size. The failure of Nal-Glu to reduce adenoma size despite its success in reducing FSH secretion suggests that FSH secretion from gonadotroph adenomas is dependent on endogenous GnRH, but growth of gonadotroph adenomas is not.
Asunto(s)
Adenoma/tratamiento farmacológico , Hormona Liberadora de Gonadotropina/análogos & derivados , Neoplasias Hipofisarias/tratamiento farmacológico , Adenoma/sangre , Adenoma/patología , Adulto , Anciano , Basófilos/patología , Endocrinología/métodos , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Hormona Luteinizante/sangre , Masculino , Persona de Mediana Edad , Hipófisis/patología , Neoplasias Hipofisarias/sangre , Neoplasias Hipofisarias/patología , Visión OcularRESUMEN
PIP: Male contraception is still an unresolved problem because scientists do not yet clearly understand spermatogenesis, particularly hormonal regulation and identification of growth factors responsible for spermatozoa development. Suppression of luteinizing hormone and of follicle stimulating hormone is a possible approach. Yet, it takes 60 days to achieve azoospermia and it is necessary to substitute an androgen. Despite the fact that many trials using steroids (androgens, progestins and androgens) or a gonadotropin releasing hormone (GnRH) agonist with androgens have been conducted, not every subject achieves azoospermia. Initial trials of GnRH antagonists in association with testosterone enanthate show that this combination achieved azoospermia in almost all subjects. This approach must be improved by developing long acting antagonists and a more physiological testosterone substitution. Another approach, which inhibits reversible secretion of gonadotropins, leans toward the production of an anti-GnRH vaccine. So far, studies have not produced acceptable results, despite a reduction in the production of spermatids. No animal achieves azoospermia. Isolation and cloning of human sperm surface glycoproteins would lead to another type of contraceptive vaccine. This antigen would prevent sperm from joining with the egg.^ieng
Asunto(s)
Anticoncepción Inmunológica , Anticoncepción , Hormonas Liberadoras de Hormona Hipofisaria , Bloqueadores de Espermatogénesis , Vacunas Anticonceptivas , Biología , Anticonceptivos , Anticonceptivos Masculinos , Sistema Endocrino , Servicios de Planificación Familiar , Hormonas , FisiologíaRESUMEN
Haloperidol (0.02 mg/kg, intravenous) did not stimulate aldosterone secretion in six normal controls or in six schizophrenic subjects. This is contrary to our hypothesis, which was based on the finding that peripheral D2 receptor antagonists stimulate aldosterone secretion, including haloperidol in rats and chlorpromazine in man. We speculated that a different dose of haloperidol would stimulate aldosterone in man. As expected, prolactin release was markedly stimulated in both groups of subjects, but no difference was found between groups.
Asunto(s)
Aldosterona/sangre , Haloperidol/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Adulto , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Prolactina/sangre , Esquizofrenia/sangreRESUMEN
In both the rodent and primate, administration of progesterone elicits an acute surge-like release of LH in the setting of prior estrogen treatment. Whether these facilitative effects of estrogen and progesterone on gonadotropin secretion reside at pituitary or hypothalamic loci is not known. To further investigate the mechanisms by which estrogen combined with progesterone amplifies gonadotropin secretion, we studied the responses of seven estrogen-primed postmenopausal women to progesterone administration with or without cotreatment with a potent GnRH antagonist, [Ac-D2Nal1,D4ClPhe2,D3Pal3,Arg5,DGlu6(AA), DAla10]GnRH. Repetitive blood sampling for the later measurement of serum concentrations of LH, FSH, and PRL was begun 4 h before the administration of progesterone and continued for 36 h. We observed that progesterone administration after 72 h of priming with ethinyl estradiol resulted in a surge-like release of LH and FSH in all subjects. Concomitant administration of the GnRH antagonist abolished the surge-like release of both gonadotropins in all subjects. In contrast, administration of the antagonist had no effect on PRL release. These results indicate that endogenous GnRH action is an obligatory component of the progesterone-induced surge-like release of both gonadotropic hormones in the estrogen-primed human.
Asunto(s)
Estrógenos/fisiología , Hormona Folículo Estimulante/metabolismo , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/fisiología , Hormona Luteinizante/metabolismo , Progesterona/fisiología , Etinilestradiol/antagonistas & inhibidores , Femenino , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Hormona Liberadora de Gonadotropina/farmacología , Humanos , Hormona Luteinizante/sangre , Menopausia , Persona de Mediana Edad , Progesterona/antagonistas & inhibidores , Prolactina/sangreRESUMEN
GnRH antagonists suppress pituitary and gonadal function by competing with endogenous GnRH for binding to receptors on pituitary gonadotrophs. We studied the effects of GnRH antagonist administration to men in a protocol simulating a likely male contraceptive regimen combined with a low dose of testosterone. The GnRH antagonist Nal-Glu was given daily (10 mg, sc) for 20 weeks to eight normal men, and a low dose of testosterone enanthate (25 mg, sc) was given every week. Sperm counts started declining during week 4, and complete azoospermia was reached within 6-12 weeks in six of the eight subjects. Subjects 7 and 8, whose sperm counts and serum gonadotropin levels were not suppressed after 10 weeks, were given 20 mg Nal-Glu starting at week 10. One became azoospermic at week 16, while the other's total sperm counts continued declining and reached a nadir of 1.4 million by week 20. Sperm motility and viability in this subject were completely suppressed after week 14. Sperm counts returned to baseline levels 12-14 weeks after the end of Nal-Glu administration. The mean serum LH level of the first six subjects decreased from 3 +/- 03. U/L at baseline to less than 0.1 U/L until week 20, and then levels returned to baseline. FSH levels similarly decreased from a combined mean of 3.6 +/- 0.9 U/L at baseline to below 0.3 U/L after 4 weeks of Nal-Glu administration. Serum mean testosterone levels between weekly injections of testosterone enanthate ranged from 27.4 +/- 5.9 to 4.8 +/- 1.4 nmol/L, but remained in the hypogonadal range (less than 10 nmol/L) for 4 of the 7 days. None of the subjects, however, complained of decreased libido or potency, as assessed by a questionnaire. No systemic or significant local side-effects were observed, other than a minimal reaction at the injection site. These data suggest that complete sustained azoospermia can be achieved in man, without loss of libido, by chronic administration of a GnRH antagonist plus testosterone.
Asunto(s)
Anticonceptivos Masculinos , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Libido/efectos de los fármacos , Oligospermia/inducido químicamente , Testosterona , Adulto , Supervivencia Celular/efectos de los fármacos , Anticonceptivos Masculinos/efectos adversos , Combinación de Medicamentos , Hormonas Esteroides Gonadales/sangre , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Recuento de Espermatozoides/efectos de los fármacos , Motilidad Espermática/efectos de los fármacos , Testosterona/efectos adversosRESUMEN
Effects of gonadotropins and gonadal steroids on androgen-binding protein (ABP) production by the testis and its secretion into the blood and transport into the epididymis were studied in 20- and 30-day-old rats. These animals had been treated with hCG, FSH, the Nal-Glu GnRH antagonist [Ac-D2Nal1,D4ClDPhe2,D3Pal3,Arg5,DGlu6(AA) ,DAla10]LHRH (antagonist), testosterone propionate, or estradiol benzoate, alone or in combination, for 10 days before assessment of ABP. Antagonist administration suppressed the testicular content (nanograms per organ) of ABP to below control (untreated) levels in both age groups. When hCG or testosterone was given along with the antagonist, they overcame the effect of the antagonist, and the resultant ABP values exceeded untreated control levels in both the 20- and 30-day-old rats. Treatment of rats with these hormones in the absence of the GnRH antagonist also elevated the ABP content of the testis above that of untreated controls. FSH administered with antagonist was able to prevent the antagonist-induced suppression of testicular ABP content. When rats were treated with FSH alone, the content of ABP in the testis was increased above untreated control levels in the 30-day-old group, but not in the 20-day-old group. The simultaneous administration of FSH and hCG did not result in an increase in testicular ABP content above that caused by hCG or testosterone alone. The increase in the ABP content of the testis caused by FSH administration was only about one sixth that caused by hCG or testosterone. Since testosterone or hCG, even in the presence of antagonist, was able to maximally stimulate ABP production by the testis of both age groups, we conclude that testosterone is the major in vivo regulator of its synthesis. Only combined treatment with hCG and FSH was able to increase transport of ABP into the epididymis of 20-day-old rats. All treatments that increased the testicular content of ABP in the 30-day-old rats also increased its transport into the epididymis. Treatments that drastically reduced the content of ABP in the testis of 20-day-old rats (antagonist, estradiol, estradiol plus antagonist) also reduced ABP secretion into the serum. Only treatment with estradiol reduced the secretion of ABP into the serum of 30-day-old rats. None of the treatments increased the ABP secretion into the bloodstream above untreated control levels.
Asunto(s)
Proteína de Unión a Andrógenos/biosíntesis , Gonadotropina Coriónica/farmacología , Epidídimo/metabolismo , Estradiol/metabolismo , Hormona Folículo Estimulante/farmacología , Testículo/metabolismo , Testosterona/farmacología , Animales , Epidídimo/anatomía & histología , Epidídimo/efectos de los fármacos , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Hormona Liberadora de Gonadotropina/farmacología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Valores de Referencia , Testículo/anatomía & histología , Testículo/efectos de los fármacos , Testosterona/sangreRESUMEN
Gonadotroph adenomas may exhibit qualitative and quantitative defects in gonadotropin biosynthesis and secretion. Hypersecretion of immunoreactive FSH dimers by these adenomas occurs frequently; however, it has not been known whether this FSH is biologically active. Using the granulosa cell aromatase bioassay and a highly specific immunoradiometric assay for FSH, we studied the serum bioactivity and bio- to immunoactivity (B/I) ratios of 14 men with FSH-secreting adenomas and compared these values to those of 11 age-matched normal men. In addition, three adenoma patients received TRH (400 micrograms, iv). The mean basal serum FSH level (international units per L), as measured by both bio- and immunoassays, and the FSH B/I ratios were significantly higher (P less than 0.02, by Kolmogorov-Smirnov test) in the adenoma patients than in normal men (mean +/- SEM; adenoma patients: bioactivity, 68.8 +/- 10.4; immunoreactivity, 34.8 +/- 13.7; B/I ratio, 3.4 +/- 0.6; normal men: bioactivity, 5.8 +/- 1.2; immunoreactivity, 6.4 +/- 0.8; B/I ratio, 0.90 +/- 0.1). Both bio- and immunoactive FSH rose after TRH injection, resulting in maintenance of the B/I (mean +/- SEM; pre-TRH: bio-FSH, 63.7 +/- 22.4; immuno-FSH, 28.0 +/- 14.1; B/I ratio, 2.8 +/- 1.2; post-TRH: bio-FSH, 125.6 +/- 42.7; immuno-FSH, 45.8 +/- 21.8; B/I ratio, 3.5 +/- 1.6). When gonadotroph adenoma cells from three separate patients were cultured and their conditioned media (n = 3) studied, relatively large amounts of both bio- and immuno-FSH were detected. Furthermore, the major isoelectric profile of bio-FSH (pH 4.9-3.0) in the conditioned medium from two such adenomas was shown by chromatofocusing to be comparable to that of purified human pituitary FSH (pH 5.2-3.6). We conclude that gonadotroph adenomas in men secrete FSH that is biologically active, both basally and in response to TRH.
Asunto(s)
Adenoma/metabolismo , Hormona Folículo Estimulante/metabolismo , Neoplasias Hipofisarias/metabolismo , Adulto , Anciano , Disponibilidad Biológica , Hormona Folículo Estimulante/sangre , Humanos , Ensayo Inmunorradiométrico , Focalización Isoeléctrica , Masculino , Persona de Mediana Edad , Hormona Liberadora de Tirotropina , Células Tumorales Cultivadas/metabolismoRESUMEN
As a preliminary step in searching for a pharmacological treatment for gonadotroph adenomas, we administered the GnRH antagonist analog Nal-Glu GnRH to five patients, four men and a woman, with FSH-secreting gonadotroph adenomas in order to determine its effect on FSH secretion. Administration of a single 10-mg dose of Nal-Glu GnRH to four of the patients produced a significant decrease in the serum FSH concentration in two patients and returned the FSH level to normal in only one. Administration of 5 mg Nal-Glu every 12 h for 7 days, however, produced a significant (P less than 0.001) decrease, and to within the normal range, in four of the five patients (mean +/- SEM, 32.7 +/- 5.6 IU/L during the 3 days before treatment and 9.8 +/- 1.4 IU/L during the last 3 days of treatment). Also, in response to the 7-day treatment, LH fell significantly in all five patients, alpha-subunit fell in three, and testosterone fell in all four men. Administration for 6 weeks of the GnRH agonist analog leuprolide did not decrease the serum FSH concentration of one of the patients whose serum FSH did decrease in response to Nal-Glu GnRH. We conclude that repetitive administration of Nal-Glu GnRH may often inhibit FSH secretion by gonadotroph adenomas and that FSH secretion by gonadotroph adenomas may be dependent on endogenous GnRH secretion.
Asunto(s)
Adenoma/metabolismo , Hormona Folículo Estimulante/metabolismo , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Síndromes Paraneoplásicos Endocrinos/tratamiento farmacológico , Neoplasias Hipofisarias/metabolismo , Adenoma/cirugía , Adulto , Anciano , Secuencia de Aminoácidos , Relación Dosis-Respuesta a Droga , Femenino , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina/administración & dosificación , Hormona Liberadora de Gonadotropina/metabolismo , Hormona Liberadora de Gonadotropina/farmacología , Humanos , Leuprolida , Hormona Luteinizante/sangre , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Neoplasias Hipofisarias/cirugía , Testosterona/metabolismo , Factores de Tiempo , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
We investigated time- and dose-dependent actions of a gonadotropin-releasing hormone antagonist, the "Nal-Glu" peptide [Ac-D2Nal1, 4CIDPhe2, D3Pal3, Arg5, DGlu6(AA), DAla10], in nine healthy estrogen-withdrawn postmenopausal women. Gonadotropin-releasing hormone antagonist was administered subcutaneously at doses of 10, 30, 100, and 300 micrograms/kg. Suppression of immunoactive luteinizing hormone concentrations was achieved with a 30 micrograms/kg dose of antagonist. Suppression of immunoactive follicle-stimulating hormone levels was less (40%) even at the highest antagonist dose (300 micrograms/kg). Bioactive luteinizing hormone concentrations also significantly decreased (greater than 60%) at the two antagonist doses tested (30 and 300 micrograms/kg). However, the lower antagonist dose showed an "escape" of bioactive luteinizing hormone values after 18 hours. No suppressive effects of the antagonist on prolactin secretion occurred at any dose tested. We conclude that this gonadotropin-releasing hormone antagonist can achieve effective, potent, and long-lasting suppression of pituitary secretion of biologically active luteinizing hormone at higher doses, but secretion of biologically active luteinizing hormone may "escape" at lower doses.
Asunto(s)
Estrógenos/deficiencia , Hormona Folículo Estimulante/metabolismo , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Hormona Luteinizante/metabolismo , Menopausia/efectos de los fármacos , Prolactina/metabolismo , Anciano , Análisis de Varianza , Depresión Química , Relación Dosis-Respuesta a Droga , Femenino , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina/sangre , Hormona Liberadora de Gonadotropina/farmacología , Humanos , Hormona Luteinizante/sangre , Menopausia/metabolismo , Persona de Mediana Edad , Prolactina/sangre , Factores de TiempoRESUMEN
LHRH antagonists suppress pituitary and gonadal function by competing with endogenous LHRH for binding to gonadotroph receptors. To determine the mechanism of suppression of gonadotropin secretion we studied the effects of a single dose of a LHRH antagonist on the pulsatile activity of serum bioactive LH (Bio-LH), immunoreactive LH (IR-LH), alpha-subunit, and testosterone for 24 h in normal men. The LHRH antagonist, Nal-Glu [( Ac-D2Nal1,D4ClPhe2,D3Pal3,Arg5,DGlu6-(AA), DAla10]LHRH) was given as a single sc injection of 5 mg to five normal men. Blood samples were collected every 10 min during a 10-h baseline period and for 14 h after administration of the antagonist. IR-LH, alpha-subunit, and testosterone were measured in triplicate, and Bio-LH in duplicate. Pulses were then evaluated using Cluster analysis; all replicates were entered in the pulse analysis. After administration of the Nal-Glu antagonist, IR-LH levels decreased (P less than 0.001) from 2.81 +/- 0.06 at baseline to a nadir of 0.75 +/- 0.02 U/L. Bio-LH levels followed the same pattern, decreasing by 89% (P less than 0.001) from 4.54 +/- 0.13 to a nadir of 0.51 +/- 0.13 U/L 6.8 h after the injection of Nal-Glu. In contrast, serum alpha-subunit levels did not change (P greater than 0.05) during the 14-h period after antagonist administration (0.85 +/- 0.01 and 0.75 +/- 0.01 microgram/L before and after Nal-Glu, respectively). Serum testosterone levels decreased by more than 80%, from 17.6 +/- 0.2 at baseline to a mean nadir of 3.3 +/- 0.7 nmol/L 12.8 h after Nal-Glu administration. Pulse frequency and the number of significant pulses remained the same for all of the measured hormones during the 10-h baseline period and the 14 h after Nal-Glu administration. In contrast, the pulse amplitude of IR-LH, Bio-LH, and testosterone decreased significantly after injection of the antagonist. The pulse amplitude of the alpha-subunit also declined, albeit not significantly. Coincidence analysis revealed that during both the 10-h baseline and the 14-h post-Nal-Glu period there was a highly significant (P less than 10(-5) nonrandom synchrony between peaks of IR-LH, Bio-LH, alpha-subunit, and testosterone. These results suggest that coordinate pulsatile secretion of IR-LH, Bio-LH, and testosterone persists after the administration of 5 mg Nal-Glu LHRH antagonist.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Hormona Luteinizante/sangre , Testosterona/sangre , Adulto , Hormona Folículo Estimulante/sangre , Hormona Folículo Estimulante/metabolismo , Hormona Liberadora de Gonadotropina/farmacología , Hormona Liberadora de Gonadotropina/fisiología , Humanos , Hormona Luteinizante/metabolismo , Masculino , Persona de Mediana Edad , Hipófisis/fisiología , Testículo/fisiología , Testosterona/metabolismoRESUMEN
Pituitary glycoprotein hormones are composed of two different subunits, the alpha- and beta-subunits. The alpha-subunit is common to all FSH, LH, and TSH, while the beta-subunit is specific for each of these hormones. We studied the effects of a potent LHRH antagonist on alpha-subunit and LH secretion in normal men. The LHRH antagonist Nal-Glu, ([Ac-D2Nal1,D4ClPhe2,D3Pal3,Arg5,DGlu6(AA) ,Ala10]LHRH), was given (10 mg daily) as one injection of 5 mg every 12 h. Blood samples were drawn every 24 h, and on days 1 and 7 a day curve was established by drawing hourly blood samples for 26 h. Mean serum alpha-subunit levels decreased progressively (P less than 0.001) from 2.9 +/- 0.49 micrograms/L at baseline to a nadir of 1.4 +/- 0.27 micrograms/L on day 8. In contrast, mean immunoreactive LH (IR-LH) levels decreased rapidly from 3.2 +/- 0.6 U/L at baseline to 0.9 +/- 0.08 U/L on day 2 and remained suppressed (P less than 0.001) throughout the treatment period. On day 1 after the administration of Nal-Glu mean alpha-subunit levels decreased, although not significantly (P = 0.054), from 3.0 +/- 0.6 micrograms/L at baseline to a nadir of 2.0 +/- 0.3 micrograms/L at 17 h. alpha-Subunit remained at this level for the remainder of day 1. On day 7, however, the baseline serum alpha-subunit level was 1.5 +/- 0.3 micrograms/L, significantly suppressed (P less than 0.01) compared to the level on day 1, and no further decrease was seen after administration of Nal-Glu. IR-LH on day 1 before the first injection of 5 mg Nal-Glu was 3.5 +/- 0.8 U/L. Then, IR-LH levels decreased significantly (P less than 0.001) to a nadir of 0.9 +/- 0.1 U/L and remained at this level throughout day 1. IR-LH levels on day 7 were at or below 1.0 U/L throughout the sampling period. These results indicate that alpha-subunit secretion can be partially suppressed after chronic administration of a LHRH antagonist. Furthermore, LH serum levels dissociate from those of pituitary glycoprotein alpha-subunit after administration of LHRH antagonist analogs.
Asunto(s)
Hormonas Glicoproteicas de Subunidad alfa/sangre , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Adulto , Hormonas Glicoproteicas de Subunidad alfa/metabolismo , Hormona Liberadora de Gonadotropina/administración & dosificación , Humanos , Hormona Luteinizante/sangre , Hormona Luteinizante/metabolismo , Masculino , Persona de Mediana Edad , Hipófisis/efectos de los fármacos , Hipófisis/fisiologíaRESUMEN
LHRH antagonists compete with endogenous LHRH for binding to receptors on pituitary gonadotrophs and thereby inhibit gonadotropin secretion and, consequently, gonadal function. We studied the pituitary and gonadal suppression following single doses and short term administration (1-3 weeks) of a recently developed LHRH antagonist in normal men. First, the antagonist Nal-Glu ([Ac-D2Nal1, D4ClPhe2,D3Pal3,Arg5,DGlu6(AA),DAla10]LHRH ), was given as a single sc injection to five normal men at three dose levels of 1, 5, and 20 mg (study I). Serum FSH, immunoreactive LH (IR-LH), bioactive LH (bio-LH), testosterone, and estradiol were measured before and at frequent intervals for 48 h after Nal-Glu administration. Mean serum FSH decreased (P less than 0.001) by 28.9 +/- 5.4% (+/- SE), 38.2 +/- 7.9%, and 44.5 +/- 3.6% after the 1-, 5-, and 20-mg doses, respectively. Mean serum IR-LH decreased (P less than 0.001) by 39.0 +/- 13.8%, 53.2 +/- 10.0%, and 53.1 +/- 14.4% after the three doses. Serum bio-LH levels and the ratio of bio-LH/IR-LH decreased (P less than 0.001) after the 20-mg dose by 87.8% and 78.5%, respectively. Serum testosterone levels decreased (P less than 0.001) more than 78.5% after all Nal-Glu doses. The duration of testosterone suppression, but not the nadir reached, was dose dependent (P = 0.012). Serum estradiol levels also decreased (P less than 0.001), but the rate of decrease was slower than that of serum testosterone. The apparent plasma disappearance half-life of Nal-Glu after administration of 5 mg was 12.8 +/- 2.7 h. The Nal-Glu antagonist also was given daily as a single sc injection of 5 mg to eight normal men for 21 days (study II) or twice daily to five men for 7 days (study III). In study II, serum FSH, IR-LH, bio-LH, testosterone, estradiol, and 17-hydroxy-progesterone were measured daily, immediately before the next injection, and on days 1, 7, and 21 in frequent blood samples drawn for 24 h. The mean serum testosterone level in study II decreased (P less than 0.001) from 17.6 +/- 2.2 to 4.1 +/- 1.0 nmol/L on day 1, increased (P less than 0.05) between days 2 and 8, and then progressively decreased to below 2 nmol/L from day 18 until 24 h after the end of the study. Serum FSH, IR-LH, and bio-LH levels paralleled those of testosterone.(ABSTRACT TRUNCATED AT 400 WORDS)