Luteinizing Hormone Releasing Factor Research Articles

JAK/STAT signaling pathway gene expression is reduced following Nelf knockdown in GnRH neurons.

Hypothalamic gonadotropin releasing hormone (GnRH) is crucial for the proper function of the hypothalamic-pituitary-gonadal (HPG) axis, subsequent puberty, and reproduction. When GnRH neuron migration or GnRH regulation is impaired, hypogonadotropic hypogonadism results. Mutations in the gene for nasal embryonic luteinizing hormone-releasing factor (NELF) have been identified in GnRH-deficient humans. NELF is a predominantly nuclear protein that may participate in gene transcription, but the genes NELF regulates are unknown. To address this question, RNA was extracted from NLT GnRH neuronal cells following either stable Nelf knockdown or scrambled control and subjected to cDNA arrays. Transcription factors and cell migration gene expression was altered most commonly. Members of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, including Stat1, Stat2, Stat5a, Jak2, Irf7 and Irf9, were significantly down regulated as assessed by RT-qPCR. Protein levels of STAT1, phospho-STAT1, and JAK2 were reduced, but the protein level of phospho-JAK2 was not. These findings suggest a role for NELF in the regulation of the JAK/STAT signaling pathway, which have important functions in GnRH neurons.

NELF knockout is associated with impaired pubertal development and subfertility

Puberty and reproduction require proper signaling of the hypothalamic–pituitary–gonadal axis controlled by gonadotropin-releasing hormone (GnRH) neurons, which arise in the olfactory placode region and migrate along olfactory axons to the hypothalamus. Factors adversely affecting GnRH neuron specification, migration, and function lead to delayed puberty and infertility. Nasal embryonic luteinizing hormone-releasing factor (NELF) is a predominantly nuclear protein. NELF mutations have been demonstrated in patients with hypogonadotropic hypogonadism, but biallelic mutations are rare and heterozygous NELF mutations typically co-exist with mutations in another gene. Our previous studies in immortalized GnRH neurons supported a role for NELF in GnRH neuron migration. To better understand the physiology of NELF, a homozygous Nelf knockout (KO) mouse model was generated. Our findings indicate that female Nelf KO mice have delayed vaginal opening but no delay in time to first estrus, decreased uterine weight, and reduced GnRH neuron number. In contrast, male mice were normal at puberty. Both sexes of mice had impaired fertility manifested as reduced mean litter size. These data support that NELF has important reproductive functions. The milder than expected phenotype of KO mice also recapitulates the human phenotype since heterozygous NELF mutations usually require an additional mutation in a second gene to result in hypogonadotropic hypogonadism.

The spatiotemporal regulation of activity-dependent genes in post-mitotic neurons

Puberty and reproduction require proper signaling of the hypothalamic–pituitary–gonadal axis controlled by gonadotropin-releasing hormone (GnRH) neurons, which arise in the olfactory placode region and migrate along olfactory axons to the hypothalamus. Factors adversely affecting GnRH neuron specification, migration, and function lead to delayed puberty and infertility. Nasal embryonic luteinizing hormone-releasing factor (NELF) is a predominantly nuclear protein. NELF mutations have been demonstrated in patients with hypogonadotropic hypogonadism, but biallelic mutations are rare and heterozygous NELF mutations typically co-exist with mutations in another gene. Our previous studies in immortalized GnRH neurons supported a role for NELF in GnRH neuron migration. To better understand the physiology of NELF, a homozygous Nelf knockout (KO) mouse model was generated. Our findings indicate that female Nelf KO mice have delayed vaginal opening but no delay in time to first estrus, decreased uterine weight, and reduced GnRH neuron number. In contrast, male mice were normal at puberty. Both sexes of mice had impaired fertility manifested as reduced mean litter size. These data support that NELF has important reproductive functions. The milder than expected phenotype of KO mice also recapitulates the human phenotype since heterozygous NELF mutations usually require an additional mutation in a second gene to result in hypogonadotropic hypogonadism.

Hot flashes: behavioral treatments, mechanisms, and relation to sleep

Hot flashes are the most common symptom of the climacteric and occur in about 75% of perimenopausal and postmenopausal women in Western societies. Although hot flashes accompany the withdrawal of estrogen at menopause, the decline in estrogen levels is not sufficient to explain their occurrence. Elevated sympathetic activation acting through central alpha(2)-adrenergic receptors contributes to the initiation of hot flashes, possibly by narrowing the thermoneutral zone in symptomatic women. Hot flashes are then triggered by small elevations in core body temperature acting within this narrowed zone. A relaxation-based method, paced respiration, has been shown in 3 controlled investigations to significantly reduce objectively measured hot flash occurrence by about 50% with no adverse effects. In 6 studies of physical exercise, however, investigators did not find positive effects on hot flashes, possibly because exercise raises core body temperature, thereby triggering hot flashes. Although many epidemiologic studies have found increased reports of sleep disturbance during the menopausal transition, recent laboratory investigations have not found this effect, nor have they found that hot flashes produce disturbed sleep. Therefore, sleep complaints in women at midlife should not routinely be attributed to hot flashes or to menopause.

Successful gonadal development and maturation of tench (Tinca tinca L.) in small concrete ponds

Summary The experiments were performed in a tench farm from autumn until the spawning season (June–July). Tench broodstocks from natural habitats were maintained in 25 × 6 × 1 m concrete ponds and fed on commercial trout pellets. Females and males were separated and maintained under natural photoperiod and temperature conditions at densities around 2 kg m−2. Water flow throughout was supplied at the rate of 15 L s−1. When females showed external signs of advanced gonadal development, induction of spawning was made by luteinizing hormone releasing factor (LH-RH) synthetic analogue administration at three different periods of the reproductive season (June–July). A single intramuscular injection (20 μg kg−1 body weight) was administered to 110 mature females selected from a total of 150. The females were stripped 42 h (22°C) after hormone administration. The mean rate of stripped females to the number injected was 77%. Mean relative egg weight in relation to the weight of the stripped females was 5.61%. More than 90% of the males provided semen without hormonal induction. Differences in egg production and external egg quality were observed at different times of the spawning period. It was proven that tench maintained in small concrete tanks and fed on artificial diets were able to reach gonadal maturation.

Testicular function in men treated in childhood for undescended testes

Purpose: The aim of the study was to evaluate testicular hormones and sperm counts of young men treated in childhood for cryptorchidism Methods: Testicular volume, serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone as well as semen specimens were evaluated in 57 men (mean age, 19 years; range, 18 to 27 years) treated in childhood for unilateral (n = 47) and bilateral (n = 10) cryptorchidism. In 3 unilateral cases monorchidism was found. Thirty-seven patients underwent orchiopexy after hormonal treatment (luteinizing hormone releasing factor, 1.2 mg/d for 28 days followed by human chorionic gonadotropin, 500 IU intramuscularly 3 times a week for 3 weeks). The remainder underwent surgery. Mean age at surgical treatment was 5.4 years (range, 2 to 12 years). These patients were examinated again after a mean period of 13.3 years (range, 10 to 19 years). Results: Reduced testicular volume (<12 mL) was found in 6 of 64 testes (9.3%). LH, FSH, and testosterone levels were found within the normal range in all patients. With linear regression, inverse relations were found between FSH and, respectively, testicular volume (P =.002), sperm concentration (P =.013), sperm motility (P =.023), and normally shaped sperms (P =.019). There were direct relations between testicular volume and sperm concentration (P =.02), sperm motility (P =.000), and normally shaped sperms (P =.001). We did not find any statistical correlation between age at surgery and semen quality. Significantly better results in terms of sperm counts were found in patients directly operated on in comparison to those treated with hormones before orchiopexy. Conclusions: Presented data indicate tubular impairment in young men operated on in childhood for cryptorchidism; FSH values increase and testicular volume decrease are related to sperm deterioration. Studies on children treated in the first 2 years of life are required to clarify the usefulness of early treatment of cryptorchidism. J Pediatr Surg 36:385-388. Copyright © 2001 by W.B. Saunders Company.

Experimental and Clinical Aspects of using luteinizing hormone-releasing factor and its analogs

This literature review briefly summarizes the methods of application and the conditions necessary from the physiological point of view to activate the secretion of gonadotropins by the pituitary gland by stimulating the luteinizing hormone-releasing hormone (LH-RH) in a pulsating mode, and we compare the effect of the pituitary stimulating LH-RH- agonists. The structure of LT-RG was explained in 1971 by Matsuo, Baba, in 1972 by F. Burgus, J. Butcher and confirmed in 1971 by the synthesis of Geiger, Konigi Wissmann. Studies conducted over 10 years showed that LG-RG , as well as its analogs are important for clinical practice. There are 2 active groups of agonist analogs. The 1st includes LH-RH analogs with an altered amino acid sequence and is abbreviated Trp "LH-RH. These peptides have a structure very similar to the natural LH-RH. The 2nd group combines LH-RH of 1-9-nano-peptidethylamide agonists. These peptides differ from LH-RG in their C-terminal sequence, Pro9-ethylamide, Leu6 is introduced - LH-RH (l-9-ethylamide), which is abbreviated as Leu6-EA- (1-Trp6), LH-RH (1-9 -ethylamide) - abbreviated as Trp-EA-Z-Ser (Bu +) 6, LH-RH 1-9-ethylamide - l-Ser- (Bu +) 6-EA.

Hormonal function of sexual glands and adrenals in monkeys of different age

The levels of bioactive LH, major sex and adrenal steroid hormones and their precursors in the system of biosynthesis were measured in the peripheral blood of 37 male Papio hamadryas of different age under baseline conditions and after injection of ACTH, LH releasing hormone, and human chorionic gonadotropin. The measurements were carried out in adult animals with the optimal reproductive characteristics (group 1, aged 6 to 9, and group 2, aged 10 to 15 years) and in aging males (group 3, aged 20 to 26 years). The levels of hydrocortisone and its immediate precursor in the biosynthesis chain of 11-deoxyhydrocortisone virtually did not change with age, whereas the concentrations of ∆5-precursors (pregnenolone and 17-hydroxypregnenolone) gradually reduced with aging. The levels of the major adrenal androgens dehydroepiandrosterone and dehydroepiandrosterone sulfate also appreciably decreased with age. The levels of sex hormones did not change between 6 and 15 years of age; but in animals aged 20 to 26 the concentration of testosterone showed a trend to reduction, and that of LH to increase. In group 3 the peaks of LH and testosterone secretion in response to LH releasing factor were delayed. On the other hand, the amplitude and duration of the increment of both LH and testosterone in response to LH releasing factor was virtually unchanged at all ages and was largely determined by the basal level of LH. The detected age-specific changes in the hormonal function of adrenals and sex glands of Papio hamadryas are much similar to those in humans.

Hormonal function of the adrenal cortex in «medical castration» induced by prolonged infusion of LH releasing factor agonists

Time course of the major corticosteroid hormones and the precursors in the biosynthesis chain was studied, as was the type of corticosteroid complex formation with transcortin in the peripheral blood plasma in male papua hamadryas exposed to a 4-16 week infusions of LH releasing factor agonists (busereline, Hoechst A. G., Germany, and surfagon, Cardiology Research Center of the Russian Academy of Medical Sciences) with the use of osmotic mini-pumps (Alza Corp., Palo Alto, USA). Suppression of the gonadal function resultant from prolonged infusion of LH releasing factor agonists was not associated with essential shifts in the adrenal steroidogenesis and in the specific corticosteroid transport. Such exposure induced a somewhat more marked activation of glucocorticoid and adrenal androgen secretion in response to acute stressor exposure (a single injection of insulin in'a dose of 0.2 U/kg b. m.). One should bear in mind this fact when prescribing therapy with LH releasing factor agonists to patients with prostatic carcinoma, for the adrenal androgens are transformed into active androgens in the prostatic tissue.

LH-releasing activity of hypothalamic extracts not attributable to GnRH.

LH secretion is under hypothalamic control, mostly through GnRH. Hypothalamic extracts stimulate LH release in vitro, an action usually attributed to the presence of GnRH. However, the presence of other LH-releasing factors cannot be ruled out since there are other neuromediators endowed with the capacity to influence LH release. We analyzed the presence of an LH-releasing activity in bovine median eminence extracts (ME extracts) different from GnRH using cultured rat pituitary cells. Both, GnRH and ME extracts caused a dose-dependent stimulation of LH release. The maximum response obtained with ME extracts (up to 10-fold the respective baseline) was significantly greater than the maximum response obtained with GnRH (up to 5-fold the respective baseline). Monoclonal or polyclonal GnRH antibodies in the solid phase completely eliminated the LH-releasing activity of 10(-7) M GnRH; in contrast, they only partially removed the activity present in ME extracts. The GnRH receptor blocker, Nal-Glu, 10(-7) M, which completely blocked the effect of GnRH could not totally suppress the LH-releasing activity of ME extracts. These findings indicate that ME extracts contain, in addition to GnRH, an LH-releasing activity not attributable to GnRH because it differs in its immunoreactivity and in its ability to stimulate LH release when GnRH receptors are blocked.

Will GNRH antagonists be worth the wait?

Gonadotropin-releasing hormone (GnRH) is also known as luteinizing hormone-releasing hormone (LHRH), formerly luteinizing hormone releasing factor (LRF). Since this hormone regulates the secretion of both FSH and LH, we prefer to call it GnRH. GnRH antagonists, as the name implies, are a class of compounds that actively compete with GnRH for the GnRH receptor, thereby neutralizing the effects of GnRH by competitive receptor occupancy. In order to fully appreciate their potential clinical utility, it is first important to comprehend the critical role of GnRH in the regulation of the pituitary-gonadal axis and secondly to familiarize ourselves with the mechanisms of action of GnRH, GnRH agonists and GnRH antagonists.

Incidence of liver toxicity associated with the use of flutamide in prostate cancer patients

purpose: The incidence of flutamide-related liver toxicity was studied in 1,091 consecutive patients treated for stage C or D prostate cancer with the antiandrogen flutamide and the luteinizing hormone-releasing factor (LHRH) agonist [D-Trp 6, des-Gly-NH 2 10] LHRH ethylamide. patients and methods: Liver function tests, namely measurement of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, γglutamyl transpeptidase (γ-GT), and prothrombin and thromboplastin times, were performed at 4, 8, and 12 weeks and every 3 months thereafter. Clinical signs and symptoms of liver dysfunction were also sought. The causal link between the antiandrogen used and liver injury was assessed on the basis of the temporal relationship with the use of the drug in the absence of other possible causes and, in two patients, through rechallenge of the putative causative drug after a period of normalization of liver function. results: An increase in AST and ALT at fourfold or more above upper normal limits was observed in only four patients (0.36%). Total serum bilirubin and alkaline phosphatase were elevated in only one patient at 126 mmol/L and 640 IU/L, respectively. Among the four patients, only two developed clinical manifestations of liver disease (0.18%). Biopsy was performed in one patient, and the histopathologic findings showed a mixed pattern of cytotoxic and cholestatic changes. All clinical and biologic manifestations of liver toxicity rapidly disappeared upon discontinuation of flutamide alone. No sequelae were observed in the long-term follow-up at 18, 22, 31, and 62 months. The 1,087 remaining patients experienced no or mild (less than fourfold upper normal limit) and transient elevation in aminotransferase serum levels during the first 6 months of treatment, with normalization at later time intervals. conclusion: Despite the fact that the cases reported so far, along with our large series, indicate that the incidence of flutamide-induced liver toxicity is very low, we recommend serial blood aminotransferase measurements at 2 and 4 weeks of treatment in order to detect early signs of possible flutamide-induced hepatic injury, thus avoiding the low potential risk of clinically significant liver toxicity.

Hormone Ontogeny in the Ovine Fetus XXVI. A Sex Difference in the Effect of Castration on the Hypothalamic-Pituitary Gonadotropin Unit in the Ovine Fetus*

The detection of pulsatile ovine LH (oLH) secretion in the sheep fetus by 81 days gestation (term 147 days), the suppression of fetal gonadotropin secretion by chronic administration of an LH-releasing factor agonist or antagonist, and the capacity of N-methyl; D-aspartate (a neuroexcitatory amino acid analog) to evoke a fetal oLH pulse strongly support a functional LH-releasing factor pulse-generator in the ovine fetus. In light of the sex difference in fetal gonadal function and gonadotropin secretion before day 114, we postulated that fetal castration would have a discordant effect on the pattern of gonadotropin secretion in males and females. Fetal sheep were either castrated (male = 11; female = 9) or sham operated (male = 9; female = 6) at 110-115 days gestation. Chronic indwelling arterial and venous catheters were implanted, and animals were studied for up to 30 days. During each study period fetal arterial blood samples were drawn every 15 min for 5 h and the plasma assayed for oFSH and oLH by specific RIAs. Multiple studies were performed on each fetus. In all fetuses (both intact and castrated) a decrease in oLH pulse frequency occurred after day 130. In female fetuses before day 130, castration had no effect on mean oLH pulse frequency (sham, 0.72 +/- 0.19 pulses/5 h; castrate, 0.50 +/- 0.13 pulses/5 h; P greater than 0.05). After day 130, pulsatile oLH secretion decreased in both intact and castrated female fetuses to undetectable levels during the sampling period. In contrast, castration significantly (P less than 0.001) increased mean oLH pulsatility in males before and after day 130 (less than 130 days, sham, 1.06 +/- 0.24 pulse/5 h; castrate, 2.70 +/- 0.22 pulse/5 h; greater than 130 days, sham, 0.18 +/- 0.12 pulses/5 h; castrate, 1.65 +/- 0.26 pulses/5 h). Mean oLH pulse amplitude was increased by castration only in the male fetuses (sham, 3.89 +/- 0.87 ng/ml; castrate, 6.02 +/- 0.39 ng/ml; P less than 0.05). oFSH pulses were infrequent in both sexes and not influenced by castration. The mean plasma concentration of oFSH was greater in intact female fetuses than in intact males (female, 5.65 +/- 1.15 ng/ml vs. male, 2.07 +/- 0.45 ng/ml; P less than 0.01). Castration increased the mean value for plasma oFSH in males (4.40 +/- 0.43 ng/ml; P less than 0.001) but had no effect in females (3.83 +/- 0.64 ng/ml; P greater than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of reversible androgen deprivation on hemoglobin and serum immunoreactive erythropoietin in men

To examine the role of testosterone in the maintenance of hemoglobin levels, we studied the effect of reversible androgen deprivation on hemoglobin, serum immunoreactive erythropoietin, and serum testosterone in seven men treated with a luteinizing hormone-releasing factor (LHRH) agonist for 6 months and then followed for an additional 6 months. The mean serum testosterone level was 4.35 +/- 1.05 ng/ml initially and it decreased to castrate levels in all patients by 6 months. After stopping therapy, there was a rapid increase in serum testosterone such that by 12 months the mean concentration was normal. The pretreatment hemoglobin was 15.2 +/- 0.9 g/dl (mean +/- SD); after 6 months of androgen deprivation it had fallen to 14.1 +/- 0.4 g/dl (P less than 0.05). Six months after stopping therapy, the hemoglobin rose to pre-treatment levels. Before treatment, serum immunoreactive erythropoietin was 9.5 +/- 4.6 mu/ml (mean +/- SD) and did not change significantly during or after the 6 month period of androgen deprivation. No significant inhibition of burst-forming unit-erythroid (BFU-E) or colony-forming unit-granulocyte macrophage (CFU-GM) was observed at the serum level of nafarelin acetate obtainable in vivo. These data suggest that, within the normal range of hemoglobin in men, androgens are a determinant of the red cell mass.

Growth factor-mediated regulation of aromatase activity in human skin fibroblasts.

We investigated the effects of various hormones and growth factors on aromatase activity in cultured human skin fibroblasts. Several potential trophic factors were tested for their ability to modify basal aromatase activity or the response to dibutyryladenosine 3',5'-cyclic monophosphate and dexamethasone because (i) no endogenous ligand has been identified that is responsible for stimulating aromatase activity in the periphery, and (ii) dexamethasone and cAMP analogs can increase this enzyme's activity in fibroblasts. The effect of insulin and insulin-like growth factors were examined in closer detail because of the clinical association between insulin and hyperandrogenism. Pituitary hormones and hypothalamic releasing factors, such as human ACTH (10 nM), beta-endorphin (10 nM), beta-lipotropin (10 nM), alpha-MSH (10 nM), gamma 3-MSH (10 nM), ovine luteinizing hormone (10 ng/ml), ovine follicle-stimulating hormone (10 ng/ml), ovine thyroid-stimulating hormone (10 ng/ml), rat growth hormone (10 ng/ml), rat prolactin (10 ng/ml), rat corticotropin-releasing factor (10 nM), luteinizing hormone-releasing factor (10 nM), thyrotropin-releasing factor (10 nM), human growth hormone-releasing factor (10 nM), and somatostatin (10 nM), have no significant effects on aromatase activity. Porcine inhibin A (10 ng/ml) and porcine activin AB (10 ng/ml), two ovarian hormones with structural transforming homology to transforming growth factor-beta, also have no effect on aromatase activity. Although basic fibroblast growth factor (1-100 ng/ml), acidic fibroblast growth factor (1 ng/ml), epidermal growth factor (1 ng/ml), platelet-derived growth factor (1 ng/ml), tumor necrosis factor (1 ng/ml), and transforming growth factor-beta 1 (1 ng/ml) have no effect on basal aromatase activity in human skin fibroblasts, all of these growth factors inhibited the ability of dibutyryladenosine 3',5'-cyclic monophosphate to stimulate aromatase activity. In contrast, both insulin (100 pg/ml-10 ng/ml) and insulin-like growth factor-1 (1-100 ng/ml) had no effect on cAMP-stimulated aromatase but potentiated the action of dexamethasone (100 nM). Thus, there is a clear distinction between the effects of dexamethasone and cAMP on peripheral aromatase. On the basis of the results presented here, it is interesting to speculate that the hyperandrogenism that is often associated with insulin resistance may be due to a combination of growth factor-mediated inhibition of aromatase activity and the failure of peripheral tissues to respond to insulin and metabolize androgens to estrogens.

Hormone Ontogeny in the Ovine Fetus: XIX: The Effect of a Potent Luteinizing Hormone-Releasing Factor Agonist on Gonadotropin and Testosterone Release in the Fetus and Neonate'

To investigate further the role of the hypothalamic luteinizing hormone releasing factor (LRF) pulse generator and the pituitary LRF receptor in the regulation of gonadotropin secretion and gonadal steroidogenesis in the ovine (O) fetus and neonatal lamb, we measured the increment (the difference between the concentration of plasma LH at time 0 and peak LH) in oLH (delta oLH) and oFSH (delta oFSH) responses to a potent LRF agonist, D-Trp6Pro9NEt-LRF (LRF-A), after consecutive daily doses in 17 ovine fetuses (six females, 11 males) and in 15 neonatal lambs (six females, nine males). Seven of the lambs had been studied as fetuses. In addition, plasma concentrations of testosterone (T) and androstenedione (delta 4A) were measured in nine male fetuses. After a stimulatory response to the first dose of LRF-A, the mean delta oLH and delta oFSH responses in the 106- to 118-d gestation fetuses of both sexes were significantly suppressed by the fourth dose and in the neonatal lamb by the second dose. Suppression was sustained throughout the duration of LRF-A therapy which included the gestational interval when the fetal pituitary exhibits its greatest responsiveness to an acute dose of synthetic LRF. The duration of oLH and oFSH suppression after cessation of LRF-A therapy was studied by measuring the delta oLH and delta oFSH responses to LRF before and at intervals after LRF-A therapy. In the fetus, the delta oLH and delta oFSH responses remained significantly decreased 7-8 d after the agonist was discontinued.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of sex steroids and their suppression on skeletal growth and maturation

Forty girls with central precocious puberty (CPP) were studied before and during 1-3 yr of luteinizing hormone-releasing factor (LHRH) agonist (LHRHa) administration to examine the impact of gonadal steroid secretion and its suppression on skeletal growth and maturation. Pubertal growth velocity (GV) was 10.1 +/- 0.7 (SE) cm/yr and, when normalized for chronological age (CA) and bone age (BA), demonstrated that the effects of sex steroids were most profound in patients with the youngest CA and BA. GV decreased significantly to 5.8 +/- 0.3 (n = 40), 4.6 +/- 0.3 (n = 30), and 3.2 +/- 0.6 cm/yr (n = 12) during 3 yr of gonadal suppression and correlated negatively with starting BA. Skeletal maturation was markedly accelerated by premature sex steroid secretion (BA/CA = 1.8 +/- 0.1), was slowed significantly with gonadal suppression (mean delta BA/delta CA less than 1), and also was negatively correlated with the starting BA. Cumulative increases in predicted adult height were observed regardless of starting BA and averaged +2.0 +/- 0.4, +5.2 +/- 0.5, and +6.7 +/- 1.2 cm after 1, 2, and 3 yr of gonadal suppression. The comparable changes in height predictions across all BAs despite highly variable GVs underscore the need for use of developmental (i.e., BA-based) rather than CA-based standards in the analysis of growth during gonadal steroid exposure and suppression in childhood.

Regulation of neuropeptide gene expression by steroid hormones.

Steroid hormones modify several brain functions, at least in part by altering expression of particular genes. Of interest are those genes that are involved in cell-cell communication in the brain, for instance neuropeptide genes and genes that code for enzymes involved in synthesis of neurotransmitters. Steroid regulation of mRNA levels for several genes has been reported, including the genes coding for the neuropeptides vasopressin, corticotropin releasing factor, luteinizing hormone-releasing factor, pro-opiomelanocortin; somatostatin, preproenkephalin, and the enzyme tyrosine hydroxylase. Steroid control of releasing factor genes is consistent with classical neuroendocrine concepts of negative feedback. Steroid-induced plasticity of gene expression is sometimes in evidence, with the presence or absence of a particular steroid inducing expression of a neuropeptide gene in neurons that under other conditions do not express the gene. As a means of gaining some insight into the mechanism of action of steroid hormones, several groups have determined some of the neuropeptide profiles of neurons that contain receptors for steroid hormones. Marked heterogeneity is found, in that often only a subpopulation of phenotypically-similar neurons, even within a single brain area, contains receptors for a given steroid.

Central nervous system actions of atrial natriuretic factor

The recently discovered cardiac peptides, called atrial natriuretic factors (ANF), act peripherally as hormones which control fluid and electrolyte homeostasis. Their renal, adrenal and vascular effects are complemented by central nervous system (CNS) actions to inhibit vasopressin secretion, salt preference, and water intake, and to inhibit the CNS component of the hypothalamo-pituitary-adrenal axis. These central actions of ANF are thought to mirror physiological roles played by endogenous, neuronally derived ANF within the brain. ANF immunoreactivity and binding sites in the anterior pituitary gland and median eminence suggest, as well, neuroendocrine actions of the peptide. We have failed to observe direct pituitary effects of ANF on basal or stimulated pituitary hormone secretion, however, specific hypothalamic actions have been discovered. ANF infusions (IV or cerebroventricular) inhibit luteinizing hormone (LH) secretion via, at least in part, an opioid mechanism since naloxone pretreatment blocks the effect. Additionally ANF inhibits catecholamine stimulation of the release of LH-releasing factor in the median eminence. Direct effects of ANF on tuberoinfundibular dopamine neurons are suggested by the observation that the prolactin-inhibiting action of ANF is prevented by domperidone treatment and is absent following alpha methyl-p-tyrosine inhibition of tyrosine hydroxlyase activity. These recent results imply neuromodulatory actions of ANF within the CNS that are expressed via interaction with brain peptide and catecholamine systems.

Tryptophan reduction and histidine racemization during deprotection by catalytic transfer hydrogenation of an analog of the luteinizing hormone releasing factor.

(D-Trp)6-LHRH:pGlu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-GlyNH2 was prepared by solid-phase peptide synthesis using the nitro group to protect the guanidine side chain of the arginyl residue. Removal of the side-chain protecting groups was carried out by catalytic transfer hydrogenation (CTH) using palladium acetate/ammonium formate or palladium on charcoal/formic acid. We show in this paper that this deprotection method induces i) reduction of the tryptophan residue and ii) epimerization at the histidine level (with palladium acetate/ammonium formate). Despite the formation of significant amounts of reduced peptide, CTH enabled us to obtain (D-Trp)6-LHRH in relatively good yield.