Administration Of Luteinizing Hormone-releasing Hormone Research Articles

Effects of Antiestrogens on Ovarian Aldo-Keto Reductase in Relation to Ovulation in Rats.

The pharmacological effects of antiestrogens on ovarian aldo-keto reductase and ovulation were investigated in rats. The activities of reduction of 13,14-dihydro-15-keto-PGF2 alpha, 4-benzoylpyridine and menadione in ovarian cytosol were significantly decreased by antiestrogen treatments, and the ovulation was completely inhibited. However, administration of luteinizing hormone-releasing hormone at 3:00 p.m. on the day of proestrus restored both enzyme activities and ovulation, which were inhibited by antiestrogens, to control levels. These results indicate that nonsteroidal antiestrogen inhibits the luteinizing hormone surge on the day of proestrus in 4-day cycling rats and that ovarian aldo-keto reductase may be closely involved in the ovulatory process in rats.

Stress induced changes in testis function

The mechanism through which chronic stress inhibits the hypothalamic-pituitary-testicular axis has been investigated. Chronic restraint stress decreases testosterone secretion, an effect that is associated with a decrease in plasma gonadotropin levels. In chronically stressed rats there was a decrease in hypothalamic luteinizing hormone-releasing hormone (LHRH) content and the response on plasma gonadotropins to LHRH administration was enhanced. Thus the inhibitory effect of chronic stress on plasma LH and FSH levels seems not to be due to a reduction in pituitary responsiveness to LHRH, but rather to a modification in LHRH secretion. It has been suggested that β-endorphin might interfere with hypothalamic LHRH secretion during stress. Chronic immobilization did not modify hypothalamic β-endorphin, while an increase in pituitary β-endorphin secretion was observed. Since we cannot exclude that changes in β-endorphin secreted by the pituitary or other opioids may play some role in the stress-induced decrease in LHRH secretion, the effect of naltrexone administration on plasma gonadotropin was studied in chronically stressed rats. Naltrexone treatment did not modify the decrease in plasma concentrations of LH or FSH. These findings suggest that the inhibitory effect of restraint on the testicular axis is exerted at hypothalamic level by some mechanism other than opioids.

In vivo studies on paracrine actions of pituitary angiotensin II in stimulating prolactin release in rats

The present experiments were performed to test the hypothesis that, in vivo, intrapituitary angiotensin II (ANG II) mediates the effect of luteinizing hormone-releasing hormone (LHRH) on prolactin release. After intravenous administration of LHRH (100 ng/100 microliters saline), plasma levels of both luteinizing hormone (LH) and prolactin were increased in ovariectomized rats pretreated with estradiol and progesterone. Intravenous administration of saralasin or sarthran (ANG II receptor blockers) reduced or abolished, respectively, the LHRH-induced increase in prolactin without affecting the rise in LH. In other ovariectomized steroid-treated rats, saralasin did not affect the increase in LH or prolactin induced by 10 min of restraint stress. Finally, in intact female rats on the day of proestrus, neither saralasin nor sarthran affected the mid-cycle prolactin surge. Taken together, these results show that in vivo exogenous LHRH stimulates prolactin release via a paracrine action of pituitary ANG II. However, under other conditions in which both LH and prolactin (and presumably endogenous LHRH) are elevated, pituitary ANG II does not appear to be involved in the prolactin rise.

Traitement des pubertes precoces par un agoniste du LH-RH (D-Trp6-LH-RH)

Chronic administration of luteinizing hormone-releasing hormone (LH-RH) is currently considered as the most appropriate therapy of precocious puberty. A delayed release preparation of D-Trp-6-LH-RH (Décapeptyl ® in microcapsules) designed to release the agonist for 28 days after intramuscular injection of 60 μg/kg body wt was given to 12 boys and 26 girls with precocious puberty. Plasma levels of gonadotropins and sex steroids were suppressed to prepubertal levels within 3 weeks, whilst pituitary responses to LH-RH test were almost abolished within 7 weeks. A significant improvement of secondary sex characteristics, as well as gonadal size, was observed within 6 months. Growth velocity (cm/yr, mean ± SD) was reduced in boys and girls from 9.9 ± 3.4 and 9.6 ± 3.3 respectively before treatment to 5.2 ± 1.0 and 5.3 ± 1.3 respectively during the third year of treatment. The mean ratio height age/bone age was just before treatment 0.91 in boys and 0.88 in girls and increased to 1 after 3 yr of treatment. This study shows that Decapeptyl in microcapsules induced a prolonged suppression of gonadal function and a relative blockade of bone maturation. A significant improvement of adult height relative to the effect of conventional treatments should be expected.

Naloxone does not Affect the Luteinizing Hormone‐Releasing Hormone‐Induced Inhibition of Luteinizing Hormone Secretion in Sheep

Abstract Injection of luteinizing hormone-releasing hormone (21 pmol) into the third cerebral ventricle of long-term ovariectomized ewes caused a marked inhibition of luteinizing hormone secretion. Mean luteinizing hormone levels and luteinizing hormone pulse frequency were reduced significantly when compared with the control responses to saline (50 mul). A notable characteristic of the response was the delayed and sustained nature of the luteinizing hormone-releasing hormone-induced inhibition. In the presence of the opioid antagonist naloxone (4 +/- 25 mg iv), the central administration of luteinizing hormone-releasing hormone still produced a marked inhibition of luteinizing hormone secretion. Again, mean luteinizing hormone levels and luteinizing hormone pulse frequency were reduced significantly. When naloxone was injected iv, there was a significant rise in mean luteinizing hormone levels as a consequence of an increase in pulse frequency (in four out of five ewes) and a significant increase in luteinizing hormone pulse amplitude. In conclusion, these data suggest that central opioid pathways sensitive to blockade by naloxone are not involved in the luteinizing hormone-releasing hormone-induced inhibition of luteinizing hormone release. Furthermore, in the long-term ovariectomized ewe, endogenous opioid peptides exert a tonic inhibitory influence on luteinizing hormone-releasing hormone/luteinizing hormone secretion.

Cluster headache in the male: sex steroid pattern and gonadotropic response to luteinizing hormone releasing hormone.

Serum testosterone, dihydrotestosterone, delta 4-androstendione and 17 beta-estradiol, sex hormone binding globulin (SHBG) and gonadotropic response to luteinizing hormone releasing hormone (LHRH) were studied in 34 male subjects with episodic or chronic cluster headache (CH). The sex steroid free fractions and those bound to SHBG and albumin were determined by a simulatory computerized method based on the mass action law. Individual steroid values were dispersed over a wide range in CH patients. Total, free and carrier protein-bound testosterone levels were significantly diminished only in chronic CH, where luteinizing hormone (LH) peak values after intravenous administration of LHRH were also decreased. Basal and peak follicle stimulating hormone (FSH) levels were significantly increased in episodic and in chronic CH groups, in comparison to healthy controls.

Luteinizing hormone releasing hormone (LHRH) in the periaqueductal gray substance increases some subcategories of grooming behavior in male rats

Locomotion, holeboard exploration and grooming behavior were measured in male rats after injection of LHRH or cerebrospinal fluid (CSF) into the mesencephalic periaqueductal gray substance (PGS). LHRH injection at doses of 75 ng did not alter locomotion and rearing but decreased significantly the scores of head dipping and defecation. Several subcategories of grooming responses were evaluated in a home cage-like environment. Head, body and genital grooming increased significantly after injection of 75 ng LHRH. The frequency of gnawing and head shakes increased as well. Lower doses (50 ng) also raised the scores of head and body grooming and produced a tendency for genital grooming increase. Higher doses (100 ng) did not affect genital grooming responses and produced drowsiness in most of animals. These results demonstrate that some motor activities are selectively modified by the localized administration of LHRH in the PGS.

Effect of des-Gly 10-(im-Bzl- d-his 6)LHRH-ethylamide on hypophysial gonadotrophs and ovary of the juvenile frog Rana cyanophlyctis (Schn.)

The effects of synthetic luteinizing hormone-releasing hormone (LHRH) (0.01 and 0.1 μg) agonist on pituitary and ovary were studied in the juvenile frog Rana cyanophlyctis with respect to their body weights. Injections (ip) were given 6 days a week for 30 days and frogs were sacrificed on the 31st day. The pituitary sections were stained with AB-PAS-OG technique. The staining intensity, cytoplasmic granulations, and length of hypophysial gonadotrophs (B 2 cells) were increased ( P < 0.05) due to LHRH treatment. In controls, the B 2 cells were small and faintly stained. Treatment with LHRH (0.01 or 0.1 μg) once a day or twice a day (0.01 μg) to frogs weighing less than 6 g body weight had no effect on gonadosomatic index (GSI) or size frequency distribution of oocytes even though gonadotrophs were hypertrophied and hyperactive. Whereas administration of LHRH (0.01 or 0.1 μg) once a day to frogs weighing around 8 g caused a significant (p < 0.05) increase in ovary weight, GSI, and diameter of the largest oocytes. Further, oocytes were recruited to second growth phase (i.e., incorporation of yolk in oocytes) due to LHRH treatment. The above findings suggest that synthetic LHRH agonist has the stimulatory effect on oocyte growth and recruitment of vitellogenic oocytes in juvenile frogs weighing around 8 g. The LHRH induces precocious maturity by incorporating yolk in oocytes. The pituitary responsiveness to LHRH agonist is also evident in juvenile frogs. The ovarian receptivity/responsiveness to endogenous gonadotrophins seems to progressively increase with the increase in the body weight of the juvenile frogs.

Anterior Pituitary Function in the Vegetative State

Anterior pituitary function tests were performed in 33 patients in the vegetative state, and the results were assessed for correlation with various clinical factors. Radioimmunoassays were employed to measure the secretion of growth hormone and cortisol during insulin tolerance testing (regular insulin, 0.15 to 0.20 U/kg), luteinizing hormone and follicle stimulating hormone under administration of luteinizing hormone-releasing hormone (100 micrograms), and thyroid stimulating hormone and prolactin under administration of thyroid-releasing hormone (500 micrograms). Impairment rate, defined as number of abnormal hormone secretions divided by number of hormones examined, was calculated for each patient. The data were statistically assessed by analysis of variance in terms of disease, sex, age, site of lesion, etiology of vegetative state, duration of illness, brain atrophy as demonstrated by computed tomography, and Hockaday's electroencephalographic (EEG) grade. The results were as follows. 1) The levels of growth hormone, luteinizing hormone, follicle stimulating hormone, cortisol, thyroid stimulating hormone, and prolactin were abnormal in 70%, 67%, 45%, 39%, 36%, and 15% of cases, respectively. 2) Anterior pituitary hormone secretion was impaired in all 33 patients, severely in 52%. 3) The impairement rate was significantly increased in patients with ruptured cerebral aneurysms, primary coma, severe brain atrophy, and abnormal EEGs. 4) The impairment rate tended to be higher in long-term vegetative patients. These results suggest that, in the vegetative state, impairment of anterior pituitary function frequently occurs at the onset of disease and worsens over time.

Inhibitory effect of central LHRH on LH secretion in the ovariectomized ewe.

The role of central luteinizing hormone releasing hormone (LHRH) in the control of pulsatile LHRH and luteinizing hormone (LH) secretion was investigated in ovariectomized adult ewes. Injection of LHRH (2.1-21 pmol) into the third cerebral ventricle caused a delayed but sustained inhibition of LH secretion. Pulse frequency, pulse amplitude and mean LH levels were reduced significantly when compared with the responses to the control injection of saline (50 microliters). The inhibitory effect of centrally administered LHRH was not accompanied by a reduction in the pituitary responsiveness to intravenous LHRH. In contrast to the effect on LH, plasma levels of follicle-stimulating hormone (FSH) and prolactin were unaffected by central LHRH. The inhibitory action of LHRH was antagonized by prior injection of an LHRH antagonist ([N-Ac-D-Nal(2)1, D-p-Cl-Phe2, D-Trp3, D-hArg (Et2)6, D-Ala10] LHRH, 69 pmol) into the third ventricle. Central injection of the LHRH antagonist alone (at the same concentration) did not influence any characteristic of pulsatile LH secretion. In conclusion, these data indicate that exogenous administration of LHRH into the brain exerts a dose-related and receptor-mediated inhibition of LHRH pulse generator activity. However, the physiological significance of endogenous LHRH in the regulation of the LHRH pulse generator remains unresolved.

Luteinizing hormone releasing hormone and human behavior.

Sir .—The effects of luteinizing hormone releasing hormone (LHRH) on the sexual behavior of rats are well documented. 1-3 The data on adult humans are limited, and the data on children are nonexistent. We report the sexual and aggressive responses of children and adults after administration of LHRH. Patient Reports.—Patients and Methods .—Three males and two females, 11, 15, 18, 26, and 28 years old, suffering from Kallman's syndrome (one patient), delayed puberty (one patient), prepuberty (one patient), and infertility of undetermined cause (two patients) were studied. None manifested pathologic personality problems. No organic or intracranial lesion was detected. Each subject received intramuscular injections of 100 μg/m 2 of LHRH daily as a diagnostic agent for three consecutive days. All subjects were informed of the use of LHRH as a diagnostic agent; we did not discuss whether LHRH affects thoughts or behavior. A Rorschach Test and Thematic Apperception Test

Endogenous opioid blockade and gonadotropin secretion: role of pulsatile luteinizing hormone-releasing hormone administration in anorexia nervosa and weight loss amenorrhea

In anorexia nervosa alterations in the hypothalamic-pituitary-gonadal unit were previously thought to have been connected to an increase of endogenous opiate tone. The authors tried to prove that the replacement of normal endogenous steroid levels could restore the functional coupling between opiatergic and luteinizing hormone-releasing hormone (LH-RH) neurons in patients with anorexia nervosa. Pulsatile LH-RH therapy has been used to achieve normal ovarian activity. The authors studied gonadotropin levels before and during intravenously (IV) pulsatile LH-RH therapy (50 to 100 ng/kg body weight/90 to 120 minutes) in three anorexia nervosa and two weight loss amenorrhea patients, during both placebo and naloxone administration (2 mg IV bolus plus 4 mg infusion lasting 120 minutes). Before therapy, naloxone administration did not significantly change gonadotropin levels in three out of five patients, while a decrease in gonadotropin levels was observed in the other two subjects. During LH-RH therapy, normal pituitary-gonadal activity was demonstrated and ovulatory cycles were found in all patients. Naloxone administration did not change gonadotropin release during LH-RH therapy. Data could support the hypothesis of either a primitive impairment of LH-RH neurons, or an alteration in central regulation of LH-RH pulsar in anorexia nervosa.

Hypothalamic-pituitary function in chronically cystic and regularly cycling dairy cows.

Studies were conducted to characterize, in detail, serum luteinizing hormone (LH) profiles 1) before and at various times after ovariectomy (OVX) in chronically cystic (CC) and regularly cycling (control) cows and 2) after injection of luteinizing hormone-releasing hormone (LHRH) and estradiol-17 beta (E2) to OVX CC and control cows. Blood samples were drawn from follicular-phase control cows and CC cows (pre-OVX) for 8 h at 15-min intervals. Cows were bilaterally OVX, and blood samples were collected for 8 h at 15-min intervals at 1, 2, and 4 wk after OVX. Five weeks after OVX, cows were challenged with 20 micrograms LHRH i.m. Six weeks after OVX, cows were challenged with 1 mg E2 i.m. Pulse frequency, pulse amplitude, and interpulse interval were not different (p less than 0.05) before or after OVX in CC and control cows. Peak LH, time to the peak, and area under the curves were not different (p greater than 0.05) after LHRH administration in CC and control cows. After injection of E2, peak LH levels were higher (p less than 0.05) in CC cows than in control cows. However, the time to the peak or the area under the curves were not different (p greater than 0.05) between groups. It appears that the feedback regulation of the hypothalamic-pituitary axis to circulating estrogen levels is altered as a result of the cystic condition.

A Patient with Hypogonadotropic Hypogonadism Successfully Treated by Long-Term Pulsatile Administration of Luteinizing Hormone-Releasing Hormone.

A male patient with hypogonadotropic hypogonadism has been treated by pulsatile administration lf luteinizing hormone-releasing hormone (LHRH) (20-25 micrograms, every 2 hours, sc) for 4 years 6 months. His plasma testosterone (T) concentration began to increase after 4 weeks of treatment and reached the normal range in week 5. He showed complete secondary sexual development after 1 year of treatment. His sperm count was normalized after 1 year of treatment. He was married after 29 months of therapy, and has a healthy male child. Blood type tests showed his paternity of the child. During the long duration of pulsatile LHRH therapy, his gonadotropin secretion has been stimulated by LHRH and his T level has been maintained with no observable side effects. There are no other reports of patients treated by pulsatile LHRH injection for such a long duration, but finding in this patient indicated that long-term pulsatile LHRH therapy is a useful and safe method for treatment of hypothalamic hypogonadotropic hypogonadism.

Inappropriate growth hormone response to luteinizing hormone-releasing hormone in diabetes mellitus

We randomly administered luteinizing hormone-releasing hormone (LHRH) or thyrotropin releasing hormone (TRH) (25 μg and 200 μg, respectively, as a bolus), to 16 diabetic male subjects (9 type I, 7 type II) and to 9 healthy male controls in two different mornings. While GH in the basal state was similar in type I, type II, and normal subjects, LHRH administration surprisingly evoked a significant GH release in 7 (5 type I, 2 type II) diabetic patients. GH-responders had higher glycated hemoglobin than non-responders (11 ± 1 v 8.3 ± 0.5%) but superimposable fasting and intratest average glucose levels. Only one patient among the GH-responders to LHRH showed a GH release also after TRH. These data support the hypothesis that GH secretion in diabetes, especially when poorly controlled, is abnormal.

The response of the anterior pituitary and testes to synthetic luteinizing hormone-releasing hormone (LHRH) and the effect of castration on pituitary responsiveness in the maturing chicken fed aflatoxin.

The responsiveness of the anterior pituitary to exogenous luteinizing hormone-releasing hormone (LHRH; 20 micrograms/kg body weight) and the subsequent stimulation of testosterone secretion by the testes was studied after administration of dietary aflatoxin (10 ppm) to 9-wk-old male chickens. In both control and aflatoxin-treated males, there were significant (p less than 0.05) increases in plasma luteinizing hormone (LH) concentrations following LHRH administration, which peaked at 5 min post injection and declined thereafter. Plasma testosterone levels increased soon after the LHRH injection in control males, secondary to elevated LH levels in the peripheral circulation, and continued to increase throughout the experimental period. In contrast, this LH-induced elevation in plasma testosterone was delayed in aflatoxin-treated males, with no substantial increase until 20 min post-LHRH injection. In a subsequent experiment, castration of aflatoxin-fed males resulted in an altered response to exogenous LHRH, as compared to their intact counterparts. Based on these data, it appeared that while the LH-secretory capacity of the anterior pituitary was not diminished in birds receiving aflatoxin, the testicular response to exogenous LHRH was altered during aflatoxicosis. Additionally, the effect of castration on plasma LH profiles after LHRH administration provides preliminary evidence for extra-testicular effects of dietary aflatoxin on reproduction in the avian male.

Failure of luteinizing hormone-releasing hormone (LHRH) to affect the differentiation of LH cells in the rat hypophysial primordium in serum-free culture.

The aims of this study were to investigate the differentiating capacity of adenohypophysial LH cells in a serum-free culture medium and to test whether cytogenesis is affected by synthetic LHRH. The adenohypophysial primordia of fetal rats were isolated on days 11.5 and 12.5 of gestation and cultured without serum for 10 and 9 days, respectively, in synthetic Medium 199 or alpha MEM. Immunohistochemical examination using the PAP method revealed that most culture explants, apart from a few degenerate ones, contained LH cells. In comparison with Medium 199, which has been widely used as a culture medium for hypophysial explants, alpha MEM gave far better results and the primordia cultured in this medium showed better tissue growth and contained a greater number of LH cells. Administration of synthetic LHRH (10 ng/ml) on the first day of culturing had no effect on the number of LH cells, no matter whether or not the culture medium was supplemented with insulin, transferrin or thyroxine. These results suggest that at the early developmental stage LHRH is not essential for the differentiation and/or proliferation of LH cells.

Effect of exogenous luteinizing hormone-releasing hormone on hypothalamic pituitary function in women with ovarian failure

Pituitary luteinizing hormone (LH) pulse frequency and amplitude were assessed as an indirect indicator of hypothalamic luteinizing hormone-releasing hormone (LH-RH) release in women with evidence of ovarian failure. Exogenous LH-RH (20 micrograms) was administered intravenously every 2 hours for 48 hours to determine the effect on pituitary LH release and the hypothalamic pulse generator for LH-RH secretion. This study design was used to investigate the possibility of an ultrashort negative feedback of LH-RH upon the synthesis and release of endogenous LH-RH. A wide range of LH pulse frequencies (8 to 28 pulses/24 hours) was present in these women. There was no discernible inhibition of hypothalamic LH-RH pulse frequency during or following exogenous LH-RH administration. Mean peripheral LH levels were significantly increased during exogenous LH-RH administration (P = 0.0038), reflecting both an increased baseline and an augmented pituitary LH response to the exogenous LH-RH. There were no differences found in LH pulse amplitude before and after LH-RH treatment. These data indicate that pituitary LH secretion in women with ovarian failure can be further stimulated by exogenous LH-RH. However, there was no evidence for inhibition of either pituitary LH secretion or hypothalamic LH-RH release using this administration schedule of exogenous LH-RH.

Exaggerated gonadotropin response to luteinizing hormone-releasing hormone in amenorrheic runners

Most studies of exercise-induced amenorrhea have compared amenorrheic athletes (usually runners) with sedentary control subjects. Such comparisons will identify hormonal changes that develop as a result of exercise training but cannot determine which of these changes play a role in causing amenorrhea. To obviate this problem, we assessed reproductive hormone status in a group of five amenorrheic runners and compared them to a group of six eumenorrheic runners matched for body fatness, training intensity, and exercise performance. Compared to the eumenorrheic runners, the amenorrheic runners had lower serum estradiol concentrations, similar basal serum luteinizing hormone and follicle-stimulating hormone concentrations, and exaggerated responses of serum gonadotropins after administration of luteinizing hormone-releasing hormone (100 μg intravenous bolus). Serum prolactin levels, both basally and after thyrotropin-releasing hormone administration (500 μg intravenous bolus) or treadmill exercise, was similar in the two groups, as were serum thyroid function tests (including thyrotropin response to thyrotropin-releasing hormone). Changes in serum cortisol levels after short-term treadmill exercise were simiiar in both groups, and serum testosterone levels increased after exercise only in the eumenorrheic group. In neither group did such exercise change serum luteinizing hormone, follicle-stimulating hormone, or thyrotropin levels. We conclude that exercise-induced amenorrhea is not solely related to the development of increased prolactin output after exercise training. The exaggerated gonadotropin response to luteinizing hormone-releasing hormone seen in amenorrheic runners in comparison with matched eumenorrheic runners is consistent with a hypothalamic etiology for the menstrual dysfunction, analogous to that previously described in “stress-induced” or “psychogenic” amenorrhea.

Abnormal growth hormone release following luteinizing hormone releasing hormone in anorexia nervosa.

We studied the luteinizing hormone (LH), follicle stimulating hormone (FSH) and growth hormone (GH) secretion following an i.v. injection of 0.1 mg of luteinizing hormone releasing hormone (LHRH) in patients with anorexia nervosa, who showed the GH secretion after thyrotropin releasing hormone (TRH). Five out of 11 patients had an elevated plasma GH level in a fasting state. The administration of LHRH resulted in a significant increase in the plasma GH concentrations in 3 of the 11 patients. Three other patients also showed an elevation of the plasma GH concentration to 7.0, 18.4 and 29.6 ng/ml, which were 212, 175 and 191% of the preinjection levels, respectively. There is a positive correlation between the basal and peak plasma GH levels after LHRH. These increases, however, were related to neither the plasma gonadotropin responses to LHRH nor the plasma GH responses to TRH. The basal levels of plasma LH were reduced in 8 patients and normal responses to LHRH were observed in only one patient. Although plasma FSH was undetectable in 5 patients, the FSH response to LHRH appeared normal in 9 patients. These results indicate that an elevation of the plasma GH level after LHRH is not confined to patients with a GH secreting pituitary tumor but observed in subjects with anorexia nervosa and further suggest that the GH responsiveness to non-specific hypothalamic releasing hormones may be due to the impaired hypothalamic control in anorexia nervosa.