Plasma Luteinizing Hormone-releasing Hormone Research Articles

Establishment and clinical application of enzyme immunoassays for determination of luteinizing hormone releasing hormone and metastin

Metastin, a 54-residue peptide, was identified as the cognate ligand of human G-protein-coupled receptor GPR54. Since metastin is a gene product of the human metastasis suppressor gene 'KiSS-1', early studies on metastin were focused on its activity as a tumor metastasis suppressor. Recently, there have been some reports that metastin is found in human plasma and is particularly abundant in the plasma of pregnant women. Dysfunction of the GPR54 receptor causes diseases that are characterized by an insufficient release of gonadotropin and lack or delay of pubertal maturation. This information strongly suggests that metastin is involved in the regulation of reproductive endocrine functions. In order to determine the plasma levels of metastin and luteinizing hormone releasing hormone (LHRH) in an isolated hypogonadotropic hypogonadism (IHH) patient, who received intermittent administrations of LHRH, we tried to establish a sensitive and specific enzyme immunoassay. The plasma LHRH levels of the patient were very high, while plasma metastin levels were at almost the same levels as circadian rhythms of healthy male humans. In the central nervous system, metastin stimulates the neuroendocrine reproductive axis. However, the effects of peripheral metastin are not known. Our result suggested that peripheral metastin had a genesis and activity different from central metastin.

Hypothalamic Control of Mitogen-Induced Proliferative Responses and Luteinizing Hormone-Releasing Hormone Levels in Thymus and Peripheral Blood of Rat Fetuses

The role of endogenous luteinizing hormone-releasing hormone (LHRH) in the development of concanavalin A (ConA)-induced proliferative responses was studied in rat fetuses. Preliminary treatment of fetuses in utero with either the LHRH receptor antagonist or anti-LHRH antibodies resulted in the suppression of ConA-induced proliferative responses of thymocytes. LHRH and LHRH-immunopositive cells, morphologically similar to thymocytes, were detected in intact fetal thymus. A significant content of LHRH was also found in the peripheral blood of fetuses. The LHRH content in thymus and plasma was similar in males and females. Surgical ablation of the hypothalamus resulted in 2-fold decreases in thymus and plasma levels of LHRH in 21-day-old fetuses compared to sham-operated fetuses. It was concluded that LHRH regulates mitogen-induced proliferative responses of thymocytes during prenatal ontogenesis in the rat. The main source of plasma LHRH at that period is the hypothalamus. Moreover, LHRH is synthesized in the fetal thymus. Thus, LHRH is suggested to have not only a central effect but also to be involved in autocrine or paracrine regulation of proliferative immune responses.

Effect of human chorionic gonadotropin on luteal luteinizing hormone concentrations in natural cycles

Effect of human chorionic gonadotropin on luteal luteinizing hormone concentrations in natural cycles

Luteinizing hormone and luteinizing hormone-releasing hormone secretion is under locus coeruleus control in female rats

It has been suggested that norepinephrine (NE) from the locus coeruleus (LC) plays an important role in triggering the preovulatory surge of gonadotropins. This work intended to study the role of LC in luteinizing hormone (LH) secretion during the estrous cycle and in ovariectomized rats treated with estradiol and progesterone (OVXE 2P) and to correlate it with LH releasing hormone (LHRH) content in the medial preoptic area (MPOA) and median eminence (ME). Female rats on each day of the estrous cycle and OVXE 2P were submitted to jugular cannulation and LC electrolytic lesion or sham-operation, at 09:00 h. Blood samples were collected hourly from 11:00 to 18:00 h, when animals were decapitated and their brains removed to analyze LC lesion and punch out the MPOA and ME. Plasma LH levels and LHRH content of MPOA and ME were determined by radioimmunoassay. During metestrus, diestrus and estrus, LC lesion did not modify either LH plasma concentrations or LHRH content, but completely abolished the preovulatory LH surge during proestrus and the surge of OVXE 2P. These blockades were accompanied by an increased content of LHRH in the MPOA and ME. The results suggest that: (1) LC does not participate in the control of basal LH secretion but its activation is essential to trigger spontaneous or induced LH surges, and (2) the increased content of LHRH in the MPOA and ME may be due to a decreased NE input to these areas. Thus, LC activation may be required for depolarization of LHRH neurons and consequent LH surges.

Oramucosal delivery of LHRH: pharmacokinetic studies of controlled and enhanced transmucosal permeation.

Several transmucosal therapeutic systems (TmTs) were developed to study the enhanced/controlled delivery of luteinizing hormone-releasing hormone (LHRH) through oral mucosae for prolonged periods. TmTs is a track field-shaped bilayer mucoadhesive device consisting of fast-release and sustained-release layers. In vivo evaluations were performed in beagle dogs, and pharmacokinetic profiles were monitored to characterize the transmucosal permeation kinetics of LHRH delivered by the various TmTs formulations containing a stabilizer, cetylpyridinium chloride, and a permeation enhancer, such as bile salts, to enhance the stability and permeability of LHRH. The plasma LHRH concentrations were observed to reach the plateau level within 30 min and were maintained for 2 hr following application of TmTs, in contrast to a rapid elimination profile observed after IV administration. Addition of 5% bile salt into the fast-release layer was observed to produce an enhancement in the absorption rate, higher plateau plasma levels, and greater systemic bioavailability. Addition of pH modifiers was noted to affect the bile salt enhanced transmucosal delivery of LHRH. To prolong the plasma LHRH level, several loading doses of LHRH were incorporated into the sustained-release layer. The plasma levels were sustained and the area under the curve (AUC) values were found to be linearly dependent upon the combined loading doses of LHRH in the fast-release and sustained-release layers. Mucosal irritation was also measured, using buccal mucosa, and results were observed to be low and reversible for the single application. The results indicated that TmTs is relatively safe and capable of achieving enhanced and controlled transmucosal delivery of peptide drugs.

Induction of Feline Acquired Immune Deficiency Syndrome by Feline Leukemia Virus: Immuno- and Neuroendocrine Dysfunctions

Young cats, when chronically infected with feline leukemia virus (FeLV), developed feline acquired immune deficiency syndrome (FAIDS). The syndrome was associated with a sequence of dysfunctions in the hypothalamic-pituitary-gonadal (HPG) and the immune system, manifested in the reduction of luteinizing hormone-releasing hormone (LHRH), follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone in blood plasma. The average FSH and LH (in plasma or lymphocyte), testosterone, and LHRH concentrations in the 20 FeLV-infected cats were measured by radioimmunoassay. The results were compared with those of the 12 control cats that were not FeLV-infected. Four weeks after infection, the plasma LHRH concentration in the infected cats showed a 43% reduction. Five to six weeks after infection, the content of FSH and LH in lymphocyte was reduced by 50% and 28%, respectively, whereas, the plasma FSH and LH was reduced by 52% and 42%, respectively. A significant reduction in testosterone content was detected at Week 11 of infection. The onset of the immuno- and neuroendocrine dysfunctions in FAIDs cats followed this sequence: hypothalamus, lymphocyte, pituitary, adrenal gland, and gonads. Indirect immunofluorescence assay showed the presence of FeLV cytoplasmic antigens in the fibers of the hypothalamic preoptic region and the Leydig cells. The possible causal relationship between the dysfunction of the lymphocyte and HPG systems and the presence of FeLV was discussed.

Acute ethanol treatment lowers hypophyseal portal plasma luteinizing hormone-releasing hormone (LH-RH) and systemic plasma LH levels in orchidectomized rats

Acute ethanol (EtOH) treatment resulted in a significant decline in hypophyseal portal plasma levels of luteinizing hormone-releasing hormone (LH-RH) in orchidectomized rats. This was accompanied by a similar decrement in circulating luteinizing hormone (LH) without, however, modifying plasma follicle-stimulating hormone (FSH) levels at a time when peak blood alcohol concentrations occurred. Thus, acute alcohol intoxication lowers circulating LH levels primarily by impairing hypothalamic neuronal secretion of LH-RH into the portal blood.

Immunoreactive LHRH in cerebrospinal fluid: the clinical significance in intracranial diseases.

Cerebrospinal fluid (CSF) and plasma levels of luteinizing hormone-releasing hormone (LHRH) were measured by RIA in 46 patients with acute intracranial diseases, ie, cerebral bleeding (group A), cerebral thrombosis (B), head injury (C) and meningitis (D), and the results were compared to those obtained in 21 patients with non-intracranial diseases (group E; control). Immunoreactive LHRH concentrations in CSF (CSF IR-LHRH) of 8 postmenopausal women in group E ranged 1.3 to 6.1 (mean +/- SE: 3.1 +/- 0.6) pg/ml, and those of 5 other women and 8 men with group E ranged 1.0 to 5.6 (3.6 +/- 0.4)pg/ml. In 7 out of 15 patients in group A(7/15), CSF IR-LHRH were above the levels seen in group E. In group B, C and D, CSF IR-LHRH were above the control levels in 9/15, 1/9, 3/7, respectively. The changes in plasma LHRH were not clear in postmenopausal patients in groups A and B. Plasma IR-LHRH in other women and men in group A were above the control levels in 2 out of 9 patients (2/9). Those in groups B, C and D were above the control levels in 3/8, 1/9, 2/7, respectively. Moreover, both plasma and CSF IR-LHRH of 13 patients in group A or B in chronic stage were within the control ranges. In cases observed following the time course, the occasionally increased IR-LHRH in plasma and CSF tended to decrease following the abatement of the diseases.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of estrogen on episodic secretory patterns of luteinizing hormone-releasing hormone (LHRH) and luteinizing hormone (LH) in hypergonadotropic hypogonadism

The secretory dynamics of plasma luteinizing hormone-releasing hormone (LHRH) and serum luteinizing hormone (LH) were studied in three hypogonadal women before and after chronic administration of mestranol. Blood samples were obtained through an indwelling iv line every 15 min over 3 hours, and plasma levels of LHRH and LH were measured by radioimmunoassay. LHRH and LH pulses were defined as rising from nadir to peak that exceed 2 times the intraassay coefficient of variation. All patients showed pulsatile LHRH and LH release before mestranol administration. The mean LH levels (89 +/- 20 mIU/ml) and pulse amplitude (33 +/- 14 mIU/ml) were significantly reduced after mestranol administration. On the other hand, the mean LHRH levels (1.87 +/- 0.49 pg/ml) and pulse amplitude (0.92 +/- 0.41 pg/ml) did not change significantly after mestranol administration. Pulse frequency (2 approximately 3 times/3 hrs) of LHRH and LH did not change after mestranol administration. These data show that the chronic administration of estrogen to such patients cause a decrease in mean LH levels and amplitude of LH pulse without a decrease of pulsatile LHRH secretions. These results suggest that the chronic negative feedback action of estrogen on episodic LH release in women may be at the level of the pituitary gland and estrogen may change the pituitary sensitivity to LHRH.

Suppression by LRH of the stimulatory effect of oestradiol on the secretion of LH by the rat pituitary gland.

Ovariectomized rats were infused with varying doses of luteinizing hormone-releasing-hormone (LRH). Some of the rats were also treated with oestradiol benzoate (EB). The effects of these pre-treatments on the in vitro release of luteinizing hormone (LH) were studied. The following parameters of in vitro LH release were measured: the autonomous secretion rate; the secretion rate following maximum stimulation with LRH, and the total quantity of LH released during the 6-hour experiment. The in vivo pre-treatments with LRH and EB dose-dependently decreased the pituitary LH content as well as all three of the above parameters of in vitro LH secretion. There was a linear relationship between the pituitary LH content and the three parameters of in vitro LH release. These parameters were therefore expressed as percentage of the pituitary LH content to give the relative LH secretion rates. The three parameters were thereby corrected for LRH/EB-induced changes in the pituitary LH content. In this way we obtained information on the effects of LRH and EB on the state of the LH release mechanisms of the gonadotropes. EB potentiated the LRH-induced depletion of the pituitary LH stores at all in vivo LRH infusion rates. The effect of EB on the quantity of LH released during perifusion in vitro, however, varied with the previous LRH infusion rates. After LRH infusion rates lower than about 120 ng/h (which establishes plasma concentrations of about 70 ng/l) EB enhanced the stimulated quantity of LH released. After higher rates of LRH infusion, EB lowered the amount of LH released.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dopaminergic agonists on plasma luteinizing hormone-releasing hormone (LRH) and gonadotropins in man.

To try to determine the site and mode of action of dopamine (DA) on the secretion of gonadotropins in humans, 4 series of studies were performed in 19 healthy volunteers (7 healthy males, 5 females in follicular phase and 7 postmenopausal females). The intravenous infusion of DA at the rate of 4 micrograms/kg/min decreased plasma LH levels to 75.9 +/- 3.7 (mean +/- SE)% of the initial levels. The oral administration of 500 mg of levodopa (Dopa) also suppressed the concentration of plasma LH to 73.0 +/- 3.5%, but the pretreatment with two doses of 100 mg each of carbidopa (CD), a peripheral dopa decarboxylase inhibitor, attenuated this suppressing effect of Dopa on LH levels (nadir 82.4 +/- 4.1). Plasma FSH were not significantly altered by these drugs. On the other hand, the concentration of endogenous LRH in peripheral blood remained unchanged throughout the studies. The administration of CD alone had no effect on any of these 3 parameters. These results would suggest the direct suppressing effect of DA on pituitary gonadotrophs, although the modulation at the level of the hypothalamus also cannot be ruled out.

Changes in LHRH in human maternal plasma during pregnancy.

AbstractThe changes in luteinizing hormone‐releasing hormone (LHRH) and human chorionic gonadotropin (hCG) concentrations in the maternal plasma during pregnanc‐ were determined b‐ radioimmunoassa‐. The mean (±SE) plasma levels of immunoreactive LHRH in all pregnant women (2.4±0.5 pg/ml) were significantl‐ lower than those in normal c‐cling women (4.2±0.3 pg/ml). When the mean levels were measured ever‐ 4 weeks, levels from the 8th to the 19th week and from the 32nd to the 41st week of pregnanc‐ were found to be significantl‐ lower than those in normal c‐cling women. However, the levels of LHRH at each stage of pregnanc‐ did not var‐ significantl‐ compared with the mean value of LHRH throughout the pregnanc‐. The mean hCG levels in the maternal plasma were highest from the 8th to the 11th week of pregnanc‐ and decreased graduall‐. These data suggest that: i) the plasma LHRH levels during pregnanc‐ are not related to those of hCG, ii) the LHRH secretion from maternal h‐pothalamus ma‐ be suppressed, and iii) LHRH s‐nthesized in the placenta ma‐ be degraded when it enters the maternal circulation

Episodic secretory patterns of immunoreactive luteinizing hormone-releasing hormone (IR-LH-RH) in the systemic circulation of normal women throughout the menstrual cycle

Using established radioimmunoassays for measuring plasma luteinizing hormone-releasing hormone (LH-RH) and serum gonadotropins, we studied the secretory dynamics of these hormones in eight normal ovulatory women during different phases of their menstrual cycle. All of the women demonstrated evidence of pulsatile immunoreactive LH-RH (IR-LH-RH) release throughout the cycle, with IR-LH-RH concentrations fluctuating between 0.5 and 35 pg/ml in the systemic circulation. Analysis of IR-LH-RH episodic secretions revealed a significant increase of both mean IR-LH-RH concentrations (P less than 0.001) and pulse frequency (P less than 0.05) during the periovulatory period. Furthermore, plasma IR-LH-RH titers in five normal women studied during the morning and night at mid-menstrual cycle fluctuated markedly, with slightly greater episodic discharges observed during the night than in the morning (P less than 0.05) and no significant change in pulse frequency.

Plasma LRH levels in chronic renal failure before and during haemodialysis.

Endogenous immunoreactive luteinizing hormone - releasing hormone (LRH) in plasma was determined in 6 male and 7 female patients with chronic renal failure before and during haemodialysis. Basal plasma LRH levels ranged from 5.8 to 23.0 pg/ml and, in 11 out of 13 patients, were above the levels seen in healthy subjects (less than 7 pg/ml for men and less than 8 pg/ml for women). This immunoreactivity was eluted iun identical fractions with synthetic LRH and plasma extracts from climacteric women on Sephadex G-25 chromatography, and the dilution gave a displacement curve parallel to the standard. Within 5 h of haemodialysis, these high LRH levels declined into the normal range. The concentrations of LH in plasma in these patients were also elevated, but those of testosterone in male patients were decreased. These results suggest 1) that elevated plasma LRH reflects decreased feedback inhibition by primary gonadal failure and might in turn be responsible at least in part for high concentrations of plasma LH in chronic renal failure, and 2) that plasma LRH is mainly not bound to plasma proteins.

Suppression of Plasma Luteinizing Hormone-releasing Hormone by Administration of Human Chorionic Gonadotropin in Castrated Women

Suppression of Plasma Luteinizing Hormone-releasing Hormone by Administration of Human Chorionic Gonadotropin in Castrated Women

Suppression of plasma luteinizing hormone-releasing hormone by administration of human chorionic gonadotropin in castrated women

Suppression of plasma luteinizing hormone-releasing hormone by administration of human chorionic gonadotropin in castrated women

Differential effect of althesin versus chloralose-urethane anesthesia on in vivo LHRH and LH release in the proestrous rat.

Anesthetic doses of Althesin and chloralose-urethane were compared as to their effects on neuroendocrine reproductive processes in diestrous and proestrous rats. Proestrous rats treated with Althesin experienced a 5-fold increase in immuno-reactive luteinizing hormone releasing hormone (LHRH) concentration in methanolic extracts of pituitary stalk plasma. This LHRH increase was 67% greater than that of proestrous rats administered chloralose-urethane. Moreover, Althesin given before the onset of the critical period did not suppress the proestrous surge of LHRH in stalk plasma. The Duncan's multiple range test indicated stalk plasma LHRH activity was significantly elevated in proestrous rats anesthetized with Althesin (p less than 0.05) but not with chloralose-urethane. However, the luteinizing hormone (LH) concentration in peripheral plasma increased 14 to 18-fold in all proestrous rats, including those anesthetized with chloralose-urethane. Evidently, in chloralose-urethane-treated rats, the smaller LHRH surge during proestrus is sufficient to elicit maximum release of LH from the anterior pituitary gland. This suggest that under normal conditions the amount of LHRH secreted into portal blood during proestrus is approximately 2-fold greater than that necessary to elicit maximum secretion of LH. The results also show that picogram concentrations of LH in the stalk plasma will stimulate the release of nanogram quantities of LH into the peripheral plasma of the same rats. Moreover, the sensitivity of the pituitary gland to LHRH stimulation via the portal circulation increases nearly 3-fold between diestrus and proestrus.

Plasma Luteinizing Hormone-Releasing Hormone Levels in Normal Women and Patients with Amenorrhea

Plasma levels of immunoreactive luteinizing hormone-releasing hormone (LH-RH) in 89 women with normal menstrual cycles and 109 patients with amenorrhea of various etiologies were determined by specific radioimmunoassay after methanol extraction. The LH-RH levels in patients with hypergonadotropism and Sheehan's syndrome were more than 10 pg/ml, and were significantly higher than basal levels during normal cycles (4.2 +/- 0.3 pg/ml). The mean levels of LH-RH were low in all hypogonadotropic patients with amenorrhea, with the exception of a few patients who showed high LH-RH levels suggestive of a pituitary lesion. The LH-RH levels in patients with polycystic ovary syndrome were comparable with basal levels during normal cycles. It is concluded that, although there is considerable overlap of the plasma LH-RH levels in each group of amenorrheic patients divided according to gonadotropin level, determination of LH-RH levels may be useful for the differentiation of hypothalamic amenorrhea from pituitary amenorrhea.

Changes in Plasma Luteinizing Hormone-Releasing Hormone During Clomiphene-Induced Ovulatory Cycles

Changes in Plasma Luteinizing Hormone-Releasing Hormone During Clomiphene-Induced Ovulatory Cycles

Luteinizing hormone-releasing hormone in cerebrospinal fluid of women.

The concentration of luteinizing hormone-releasing hormone (LH-RH) in both cerebrospinal fluid (CSF) and plasma in 36 women with various conditions were determined, and the correlation of LH-RH concentrations between plasma and CSF was studied. Paired samples of plasma and CSF were obtained just before operation and were extracted with methanol for LH-RH radioimmunoassay. LH and FSH were also measured by radioimmunoassay. The mean plasma LH-RH levels were 3.79 pg/ml in the follicular phase, 4.15 pg/ml in the luteal phase, 12.73 pg/ml in postmenopausal women and 2.31 pg/ml in pregnant women at term. No immunoreactive LH-RH in the CSF was found in 29 out of 36 subjects, and the remaining 7 subjects showed very low levels (less than 0.95 pg/ml). The LH-RH levels in the CSF of post-menopausal women were not higher their those in the remaining 3 groups, although their plasma levels of LH-RH were significantly (p less than 0.001) elevated. The mean plasma levels of LH and FSH in post-menopausal women were significantly higher than those in normal cyclic women and in pregnant women. The present results suggest that little or no LH-RH is present in the CSF, and it is not clear that there is any correlation between the LH-RH level of plasma and those of CSF.