Lack of effects of recombinant human GH on spermatogenesis in the adult cynomolgus monkey (Macaca fascicularis).
(25/6154)
OBJECTIVE: The effects on male reproductive parameters after 1 year of treatment with recombinant human GH to the cynomolgus monkey were investigated. DESIGN: Twenty-four male cynomolgus monkeys were given daily subcutaneous doses of 0 (vehicle) (n=7), 0.4 (n=5), 2.0 (n=5) and 10.0 (n=7) IU/kg bodyweight for 52 weeks. At completion of the treatment period two control and two high-dose animals were left for a 12-week treatment-free period. METHODS: Before and during the treatment period and during the recovery period, sperm analyses, testicular volume measurements and hormone analyses of prolactin (PRL), LH, FSH, testosterone and IGF-I in serum, and analysis of serum antibodies against human GH were performed. Testicular morphology was monitored by biopsies, predose and on day 15 of the study, and with light microscopy on organ samples collected at time of death, at the end of the treatment, and during recovery periods respectively. RESULTS: Of all studied parameters, alterations were observed only in serum levels of IGF-I and PRL. IGF-I showed a dose-dependent increase throughout the treatment, with a normalisation during the treatment-free period. PRL decreased significantly in animals given 10.0IU/kg per day from week 14 of treatment and throughout the study but with a normalisation upon cessation of treatment. Spermatogenesis, as judged from semen analysis, testicular volume measurements and testicular morphology was not affected. CONCLUSION: This controlled preclinical study demonstrates that high doses of human GH do not alter male reproductive parameters in a non-human primate model. (+info)
Inhibitory effect of plasma obtained from hypophysectomized and control women on the assay of bioactive luteinizing hormone.
(26/6154)
The purpose of this study was to determine the effect of components of female plasma on the value of bioactive luteinizing hormone (LH), especially in the presence of low immunological LH value. Using both an immunoradiometric assay (IRMA) and rat Leydig cell bioassay, immunoreactive (I) and bioactive (B) LH were assessed in plasma collected from women during a gonadotrophin releasing hormone (GnRH) test performed on day 7 of a spontaneous cycle. Two modes of response to an acute administration of GnRH were defined: normal production of gonadotrophins (group I) and excessive secretion (group II) associated with a significant difference in the B/I-LH ratio between the two groups. The B/I-LH ratio did not vary with sampling time during the test in either group. The addition of LH-free plasma collected from hypophysectomized women caused a 30% decrease in testosterone production compared to control values (in the presence or absence of hLH standard). A partial restoration of testosterone production was observed if plasma was first treated with PEG 12%. The inhibitory factor(s) was also present in plasma from ovulatory women, even after treatment by an antibody against the entire LH molecule. The effect of normal (A) or low I-LH plasma (B) on testosterone production varied strongly according to the plasma volume added to the bioassay, as well as to plasma treatments. Diethylether treatment caused a 50% decrease in testosterone secretion for plasma B (but not for A) whereas a diminution of the steroidogenesis is observed after a PEG treatment of plasma A (but not for B), suggesting that different inhibitory factors are present in plasmas A and B. Therefore the LH bioactivity measured in the rat Leydig cell assay, in terms of testosterone output, seems to represent a balance between the LH molecule and the presence of inhibitory factors in the plasma. (+info)
Once-a-month treatment with a combination of mifepristone and the prostaglandin analogue misoprostol.
(27/6154)
In this two centre study, the efficacy of 200 mg mifepristone orally followed 48 h later by 0.4 mg misoprostol orally for menstrual regulation was investigated. The dose of mifepristone was taken the day before the expected day of menstruation. Each volunteer was planned to participate for up to 6 months. A plasma beta human chorionic gonadotrophin (HCG) was measured on the day of mifepristone intake. The study was disrupted prematurely due to low efficacy. In 125 treatment cycles the overall pregnancy rate was 17.6% (22 pregnancies) and the rate of continuing pregnancies (failure) was 4.0%. Eight women discontinued the study due to bleeding irregularities which were seen in 15 cycles (12%). These effects on bleeding pattern made the timing of treatment day difficult. Late luteal phase treatment with a combination of mifepristone and misoprostol is not adequately effective for menstrual regulation. (+info)
Cross-reaction with luteinizing hormone beta-core is responsible for the age-dependent increase of immunoreactive beta-core fragment of human chorionic gonadotropin in women with nonmalignant conditions.
(28/6154)
BACKGROUND: The beta-core fragment of human chorionic gonadotropin (hCGbetacf), also termed "beta-core" and urinary gonadotropin peptide (UGP), has been reported to be present in the urine of healthy women and to increase in concentration after menopause. This could reflect cross-reaction with the equivalent metabolite of luteinizing hormone (LH), the beta-LH-core. METHODS: We measured immunoreactive LH, hCG, free alpha-subunit, and free beta-subunit hCG (hCGbeta), as well as beta-core, using the S504 RIA and Triton UGP enzyme immunoassay in 274 urine samples from women with nonmalignant gynecological conditions. The molar cross-reaction of each assay with purified beta-LH-core was determined. RESULTS: Cross-reaction with beta-LH-core was 100% in the LH and the S504 beta-core assay, 5% in the Triton UGP assay, and <0.1% in the hCG, free alpha-subunit, and free hCGbeta assays. Median urine concentrations of all analytes showed an age-dependent increase. LH and free alpha-subunit concentrations were approximately 10(3) pmol/mol creatinine; hCG and S504 beta-core were approximately 10(2) pmol/mol creatinine; free hCGbeta and Triton UGP beta-core were in the tens of pmol/mol creatinine. The S504 beta-core concentrations were 10% of those of LH. S504 beta-core was strongly correlated with LH, but not with hCG or with free hCGbeta (LH, r2 = 0.45; hCG, r2 = 0.26; free hCGbeta, r2 = 0.03). The concentrations of beta-core detected by the Triton UGP assay, which has a 5% cross-reaction with beta-LH-core, were 2% of LH and 5% of the S504 beta-core concentrations. Triton UGP values correlated strongly with LH concentrations, but less well with S504 beta-core, intact hCG, and free hCGbeta (LH, r2 = 0.44; S504 beta-core, r2 = 0.33; hCG, r2 = 0.32; free hCGbeta, r2 = 0.19). CONCLUSIONS: Immunoreactive beta-core in women free of malignancies reflects cross-reaction with concentrations of the metabolite of LH, beta-LH-core, within the health-related reference interval. (+info)
The effect of calcium ions on testosterone production in Leydig cells from rat testis.
(29/6154)
Leydig-cell suspensions, prepared from rat testes, were incubated with different amounts of Ca2+ with and without added luteinizing hormone. The basal testosterone production in the absence of luteinizing hormone was unaffected by the Ca2+ concentration in the incubation medium. The luteinizing hormone-stimulated testosterone production, however, was progressively decreased in the absence of Ca2+ to one-third of that with 2.50 mM-Ca2+. This decrease in luteinizing hormone-stimulated testosterone production was independent of the different concentrations of luteinizing hormone (0-10mug/ml) used and could be restored by the addition of Ca2+ to the incubation medium. The restoration of the stimulation was achieved within 30 min after the addition of Ca2+ to the medium. Activation of cyclic AMP-dependent protein kinase by luteinizing hormone was not decreased by omission of Ca2+ from the incubation medium, suggesting that Ca2+ may be involved in steroidogenesis at a stage beyond the luteinizing hormone receptor-adenylate cyclase-protein kinase system. (+info)
Many LH peaks are needed to physiologically stimulate testosterone secretion: modulation by fasting and NPY.
(30/6154)
The pulsatile luteinizing hormone (LH) and testosterone secretions were studied during serial blood collections performed at 7-min time intervals in the male rat. In fed rats, a discontinuous pattern of LH secretion was observed. Periods without secretion alternated with active secretory episodes consisting in trains of three to four LH peaks that triggered testosterone secretion usually 1-2 h later. The magnitude of the testosterone response was not correlated with the amplitude of the LH peaks. Isolated, single peaks of LH did not evoke clear testosterone responses. Forty-eight hours after initiation of fasting, testosterone secretion was markedly decreased, but integrated LH secretion was only partly reduced. Chronic infusion of neuropeptide Y (NPY; 18 microgram/day, icv) reduced testosterone secretion to very low levels and abolished pulsatile LH secretion or testosterone response to isolated LH peaks. In conclusion, the stimulation of testosterone secretion by LH necessitates several LH peaks organized in a proper sequence, and the testosterone response is not immediate. Low testosterone secretion in fasting rats appears to result from disappearance of coordinated, multiple LH peaks of sufficient size. Inhibition of the gonadotropic axis achieved by central NPY administration is due to either absence of LH peak "clusters" or occurrence of nonfunctional single LH peaks. (+info)
Androgen receptor messenger ribonucleic acid in brains and pituitaries of male rhesus monkeys: studies on distribution, hormonal control, and relationship to luteinizing hormone secretion.
(31/6154)
Because the distribution and hormonal regulation of the androgen receptor (AR) mRNA in brains and pituitaries of adult rhesus monkeys have not been studied, we cloned and sequenced a 329-base pair segment of the 5' coding region of the rhesus AR cDNA. Monkey AR cDNA was 99% identical with the human sequence and 96% homologous with the rat sequence. Using a ribonuclease protection assay, we studied the distribution and regulation of AR mRNA in brains and anterior pituitary glands of three groups of male rhesus monkeys: intact (n = 3), castrated (Cx, n = 4), and Cx treated with testosterone (n = 6). Serum testosterone levels of Cx males treated with testosterone differed significantly (p < 0.05) in the morning but not in the evening hours from those in intact controls. Serum LH concentrations were significantly suppressed (p < 0.05) in both morning and evening serum samples of testosterone-treated males compared to intact controls. We found the highest concentrations of AR mRNA in the medial basal hypothalamus, the bed nucleus of the stria terminalis, the medial preoptic area-anterior hypothalamus, and the lateral dorsomedial hypothalamus. Intermediate amounts were found in the septum and amygdala. Low amounts were found in the hippocampus, cingulate cortex, parietal cortex, and cerebellum. The anterior pituitary gland also contained a large amount of AR mRNA. Surprisingly, neither Cx for 3 wk nor Cx plus testosterone replacement for 3 wk significantly affected AR mRNA in any brain area or in the pituitary gland. The present study demonstrates that the effectiveness of testosterone as a regulator of LH secretion in male monkeys is not related to changes of AR mRNA in the brain or pituitary gland. It appears that AR mRNA in the monkey brain and pituitary gland is not regulated at the transcriptional level by androgen. (+info)
Effects of luteinizing hormone-releasing hormone on plasma cocaine levels in rhesus monkeys.
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No effective pharmacotherapy for the treatment of cocaine abuse is currently available. In addition to pharmacological approaches, immunologic methods that use specific antibodies to bind cocaine in blood and prevent it from reaching the central nervous system are also being evaluated. There is considerable evidence that cocaine binds to the dopamine transporter, and there are structural similarities between the dopamine transporter and an anterior pituitary hormone, luteinizing hormone (LH). These structural similarities led us to hypothesize that LH may bind cocaine and decrease plasma levels of free cocaine. Synthetic LH-releasing hormone (LHRH) was used to stimulate LH release from pituitary gonadotropes before i.v. cocaine administration to male and female rhesus monkeys. The effects of placebo-LHRH and 15 and 30 micrograms/kg LHRH on levels of free cocaine in plasma after i.v. administration of 0.8 mg/kg cocaine were studied. LHRH (15 and 30 micrograms/kg) significantly increased LH secretion in both males (P <.01-.001) and females (P <.01-.05). Peak plasma cocaine levels were significantly lower after both doses of LHRH than after placebo-LHRH in males and in females (P <.05). There was an inverse relationship between peak plasma cocaine levels and LHRH-stimulated LH levels in males (P <. 01) but not in females. Pharmacokinetic analyses showed that the time to reach peak plasma cocaine levels, the elimination half-life, and the area under the plasma cocaine curve did not differ as a function of the LHRH dose compared with placebo LHRH. Moreover, there were no gender differences in any cocaine-related, pharmacokinetic parameter after placebo-LHRH administration. These data suggest the feasibility of reducing peak levels of free cocaine in plasma by stimulating secretion of LH. The functional consequences and underlying mechanisms of LHRH-induced decreases in peak plasma cocaine levels remain to be determined. (+info)