Fetal hemoglobin regulating genetic variants identified in homozygous (HbSS) and heterozygous (HbSA) subjects from South Mexico.

Hemoglobin S is caused by a nucleotide change in HBB gene (HBB:c.20A>T, p.Glu6Val), is presented in diverse forms: simple carriers (HbSA), homozygotes (HbSS) also known as sickle cell anemia, and compound heterozygotes with other ß-hemoglobinopathies. It is worldwide distributed, in Mexico, is frequently observed in the southern states Guerrero, Oaxaca and Chiapas. Elevated fetal hemoglobin (HbF) is associated with mild phenotype; single-nucleotide variants (SNVs) in modifier genes, such as BCL11A, HBG2, HBBP1 pseudogene and HBS1L-MYB intergenic region, upregulate HbF synthesis. The aim of this study was to identify HbF regulating genetic variants in HbSS and HbSA Mexican subjects. We studied 39 individuals (HbSS = 24, 61%, HbSA = 15, 39%) from Chiapas (67%) and Guerrero (33%), peripheral blood was collected in ethylenediamine tetraacetic acid (EDTA) for molecular and hematological studies, DNA was isolated by salting-out technic and genotyping was performed through allelic discrimination by real time polymerase chain reaction (RT-PCR) using Taqman® probes for 15 SNV (in BCL11A: rs6706648, rs7557939, rs4671393, rs11886868, rs766432, rs7599488, rs1427407; HBS1L-MYB: rs28384513, rs7776054, rs9399137, rs4895441, rs9402686, rs1320963; HBG2: rs7482144; and HBBP1: rs10128556). The obtained data were analyzed using IMB SPSS v.22.0 software. All minor alleles were observed in frequencies over 0.05, the most frequent was rs9402686 (0.82), while the less frequent was rs101028556 (0.08). In HbSS group, the mean fetal hemoglobin was 11.9 ± 5.9% and was significantly elevated in BCL11A rs11886868 wildtype homozygotes and in carriers of HBS1L-MYB intergenic region rs7776054 (p = 0.04 and p = 0.03, respectively). In conclusion, in HbSS Mexican patients, two SNVs were observed related to increased HbF; BCL11A rs11886868 and HBS1L-MYB rs7776054.

Sickle cell anemia (SCA) is one of the most common types of hemoglobinopathies in people of African ancestry, it is caused by homozygosity of HbS mutation (HBB:c.20A>T). It is known that fetal hemoglobin plays a key role in decreasing HbS polymerization which damages the erythrocyte structure and is responsible for the characteristic hemolytic crises endured by these patients. Single-nucleotide variant (SNV) in genes that regulate fetal hemoglobin (HbF) after birth have been associated with its increment, thus ameliorating the hematologic phenotype of this pathology and other ß-hemoglobinopathies. Therefore, in this study, we identified, for the first time in Mexican patients with SCA (HbSS) and HbS carriers (HbSA), the presence of 15 SNVs on BCL11A, HBS1L-MYB and HBG2; all HbSS patients had anemia and elevated HbF; 2 variants were related to increased HbF rs11688888C of BCL11A and rs7776054G of HBSIL-MYB; and finally, all minor alleles were found at a frequency higher than 0.05.

Genotype × region and genotype × production level interactions in Holstein cows.

The identification of the presence of genotype by environment interaction effects on important traits in Holstein cattle allows for the use of international genetic evaluations and a more efficient design of regional genetic evaluation programmes. The aim of this study was to determine the genotype × environment interaction effects in Chilean Holstein dairy cattle through the analysis of records corresponding to calvings between 1998 and 2015. Herds were classified in the central and southern regions of Chile based on herd location as well as by high and low levels of production environments based on the fat plus protein yield averages per herd within each region. The central region has a Mediterranean climate and a confined production system while the southern region has a humid temperate climate and a production system based on grazing with supplementation. Traits studied were milk yield (MY), fat yield (FY), protein yield (PY), fat content (FC) and protein content (PC) by lactation, age at first calving (AFC) and calving interval (CI). Several four-trait mixed animal models were applied to environmental category data as different traits, which included herd-year-calving season (herd-year-birth season for AFC) and lactation number as fixed effects, and animal additive genetic, sire-herd, permanent environment and residual effects as random effects. Genetic correlations (rg) for MY, FY, FC, PC and CI were found to decrease as differences between environmental categories increased. The rg between the most extreme environmental categories considered in this study for AFC (0.26) was the only one found statistically lower than 0.60. Genetic correlation values statistically lower than 0.80 (P < 0.05) were observed for AFC, CI, MY, FY and PY between some environmental categories. If separate genetic evaluations are adopted as practical criteria when the value of rg is lower than 0.60, the consequence of improving a multi-trait economic breeding objective in this population is likely to be small unless extreme environmental categories are considered. However, a moderate decrease in selection response and re-ranking of selection candidates is expected for AFC, CI and yield traits when selection is performed in different environmental conditions. Genotype × environment interaction effects involving production systems in a Mediterranean climate and confinement vs. Temperate Oceanic climate and grazing with supplementation, and between two fat plus protein yield level categories within each environment, were at most moderate for the studied traits.

[Teledermatology in the Health Center West Area of Granada: From primary to specialized care]. / Teledermatología en el Área Sanitaria Centro Oeste de Granada: desde atención primaria a especializada.

INTRODUCTION: Teledermatology (TD) is a health tool based on the application of information and communication technologies (ICT) for the care of skin diseases at a distance, allowing a better connection between primary care professionals (PCP) and specialized care. The objective of this study was to analyze the characteristics of the teleconsultations made to our service in a period of 2years (January 1, 2018 to December 31, 2019). MATERIAL AND METHODS: The data was obtained from a TD system with dermoscopy that allows teleconsultations to be carried out asynchronously. Data were analyzed over 24months. The variables studied were the health centre of origin, the diagnostic suspicion of the PCP, the time and type of response, and the clinical judgment issued by the dermatologist. RESULTS: Between January 1, 2018 and December 31, 2019, a total of 3,294 teleconsultations were received. 24.76% were referred to the dermatology consultation, while 25.63% required subsequent follow-up electronically. The most frequent diagnostic suspicion by the PCP was that of benign pathology (54.71%). The most frequent dermatological clinical judgment was that of seborrheic keratosis (20.19%), followed by actinic keratosis (14.02%), acquired common melanocytic nevi (13.24%) and basal cell carcinoma (8.98%). CONCLUSIONS: The TD system is a useful tool that allowed a quick response to a high percentage of consultations, helping to avoid unnecessary referrals and easy communication between primary and specialized care. It also allows prioritizing those patients with malignant tumour pathology.

Development and validation of the patient history COVID-19 (PH-Covid19) scoring system: a multivariable prediction model of death in Mexican patients with COVID-19.

Most of the existing prediction models for COVID-19 lack validation, are inadequately reported or are at high risk of bias, a reason which has led to discourage their use. Few existing models have the potential to be extensively used by healthcare providers in low-resource settings since many require laboratory and imaging predictors. Therefore, we sought to develop and validate a multivariable prediction model of death in Mexican patients with COVID-19, by using demographic and patient history predictors. We conducted a national retrospective cohort study in two different sets of patients from the Mexican COVID-19 Epidemiologic Surveillance Study. Patients with a positive reverse transcription-polymerase chain reaction for SARS-CoV-2 and complete unduplicated data were eligible. In total, 83 779 patients were included to develop the scoring system through a multivariable Cox regression model; 100 000, to validate the model. Eight predictors (age, sex, diabetes, chronic obstructive pulmonary disease, immunosuppression, hypertension, obesity and chronic kidney disease) were included in the scoring system called PH-Covid19 (range of values: -2 to 25 points). The predictive model has a discrimination of death of 0.8 (95% confidence interval (CI) 0.796-0.804). The PH-Covid19 scoring system was developed and validated in Mexican patients to aid clinicians to stratify patients with COVID-19 at risk of fatal outcomes, allowing for better and efficient use of resources.

Effect of calving age on genetic evaluation of milk yield in Holstein cattle.

The aim of this study was to evaluate the effect of including calving age (CA) on genetic evaluation models for Holstein cattle. The evaluated models included the permanent environment, the sire-herd interactions, and the animals and residual effects as random. The fixed effects included the average production of milk, fat, and protein and the herd-year-season effect. The analyzed data included 603,521 records of milk production (in kg) corresponding to 438,098 animals from 527 herds. Additionally, there were 179,122 records of fat and protein components, corresponding to 148,930 animals from 137 herds. The records were classified by first lactation only (FL) and all available lactations (AL) for validation test (VT). The FL records corresponded to 275,487 milk production records with a mean of 10,874.1 ± 2773.9 kg at a mean CA of 25.6 ± 4.2 months. For FL, the milk components consisted of 78,955 records with a mean fat production of 392.86 ± 89.9 kg, a mean protein production of 362.8 ± 74.9 kg and a mean CA of 25.2 ± 4.1 months. For AL, the number of records was 603,521 for milk production with a mean of 10,802.8 ± 2905.9 kg and a mean CA of 35.6 ± 11.5 months. For the milk components, there were 179,122 records with a mean of 36.1 ± 9.5 months for CA and 388.3 ± 98.4 kg and 356.7 ± 82.6 kg for fat and protein, respectively. Three models were compared: the base model (M0) described above, and two alternative models that included CA in a linear and quadratic form (M1 and M2, respectively). Estimations of the variance components (VC) and breeding value (BV) were obtained using a repeatability animal model, with the same phenotypic and pedigree information used for all models. To select the best fit model for the data, a likelihood ratio test (LRtest) was used. A validation test (VT) was also applied to each model to evaluate the consistency of the genetic trends for females with information on AL and FL. The inclusion of CA in its linear form (M1) was the model that achieved the best results in the LRtest and an acceptable value for the VT. These results show that CA improves the model fit for BV prediction and reliability.

Genome-Wide Association Studies for Methane Production in Dairy Cattle.

Genomic selection has been proposed for the mitigation of methane (CH4) emissions by cattle because there is considerable variability in CH4 emissions between individuals fed on the same diet. The genome-wide association study (GWAS) represents an important tool for the detection of candidate genes, haplotypes or single nucleotide polymorphisms (SNP) markers related to characteristics of economic interest. The present study included information for 280 cows in three dairy production systems in Mexico: 1) Dual Purpose (n = 100), 2) Specialized Tropical Dairy (n = 76), 3) Familiar Production System (n = 104). Concentrations of CH4 in a breath of individual cows at the time of milking (MEIm) were estimated through a system of infrared sensors. After quality control analyses, 21,958 SNPs were included. Associations of markers were made using a linear regression model, corrected with principal component analyses. In total, 46 SNPs were identified as significant for CH4 production. Several SNPs associated with CH4 production were found at regions previously described for quantitative trait loci of composition characteristics of meat, milk fatty acids and characteristics related to feed intake. It was concluded that the SNPs identified could be used in genomic selection programs in developing countries and combined with other datasets for global selection.

Pedigree verification and parentage assignment using genomic information in the Mexican Holstein population.

Genealogical information is an essential tool for carrying out any genetic improvement program. The objective of this study was to determine the accuracy of pedigree information in the Mexican registered Holstein population using genomic data available in Mexico and for the US Holstein population. The study included 7,508 animals (158 sires and 7,350 cows) that were born from 2002 through 2014, registered with Holstein de México, and genotyped with single nucleotide polymorphism arrays of different densities. Parentage could not be validated for 17% of sires of cows and 12% of sires of bulls. Most (79%) of the dams of cows and the dams of bulls had no genotype available and could not be validated. A parentage test was possible for only 6,104 sires of cows, 139 sires of bulls, 1,519 dams of cows, and 33 dams of bulls. Of the animals with a parentage test, parent assignment was confirmed for 89% of sires of cows, 92% of dams of cows, 95% of sires of bulls, and 97% of dams of bulls. Parent discovery was possible for some animals without confirmed parents: 17% for sires of cows, 2.5% for dams of cows, 43% for sires of bulls, and 0% for dams of bulls. Of the 7,795 progeny tests, 777 had parent conflicts, which is an error rate of 9.97% for parental recording in the population, a rate that is similar to those recently reported for other populations. True parents for some progeny conflicts (15%) were discovered for the Mexican population, and the remaining parents were assigned as unknown. Expected effects of misidentification on rate of genetic gain could be decreased by half if genealogical errors were decreased to 5%. This study indicates that genotyping and genealogy recovery may help in increasing rates of genetic improvement in the Mexican registered Holstein population.

Looking at genetic structure and selection signatures of the Mexican chicken population using single nucleotide polymorphism markers.

Genetic variation enables both adaptive evolutionary changes and artificial selection. Genetic makeup of populations is the result of a long-term process of selection and adaptation to specific environments and ecosystems. The aim of this study was to characterize the genetic variability of México's chicken population to reveal any underlying population structure. A total of 213 chickens were sampled in different rural production units located in 25 states of México. Genotypes were obtained using the Affymetrix Axiom® 600 K Chicken Genotyping Array. The Identity by Descent (IBD) and the principal components analysis (PCA) were performed by SVS software on pruned single nucleotide polymorphisms (SNPs).ADMIXTURE analyses identified 3 ancestors and the proportion of the genetic contribution of each of them has been determined in each individual. The results of the Neighbor-Joining (NJ) analysis resulted consistent with those obtained by the PCA. All methods utilized in this study did not allow a classification of Mexican chicken in distinct clusters or groups. A total of 3,059 run of homozygosity (ROH) were identified and, being mainly short in length (<4 Mb), these regions are indicative of a low inbreeding level in the population. Finally, findings from the ROH analysis indicated the presence of natural selective pressure in the population of Mexican chicken.The study indicates that the Mexican chicken clearly appear to be a unique creole chicken population that was not subjected to a specific artificial selection. Results provide a genetic knowledge that can be used as a basis for the genetic management of a unique and very large creole population, especially in the view of using it in production of hybrids to increase the productivity and economic revenue of family farming agriculture, which is widely present in México.

Genomic variability in Mexican chicken population using copy number variants.

BACKGROUND: Copy number variations are genome polymorphism that influence phenotypic variation and are an important source of genetic variation in populations. The aim of this study was to investigate genetic variability in the Mexican Creole chicken population using CNVs. RESULTS: The Hidden Markov Model of the PennCNV software detected a total of 1924 CNVs in the genome of the 256 samples processed with Axiom® Genome-Wide Chicken Genotyping Array (Affymetrix). The mapped CNVs comprised 1538 gains and 386 losses, resulting at population level in 1216 CNV regions (CNVRs), of which 959 gains, 226 losses and 31 complex (i.e. containing both losses and gains). The CNVRs covered a total of 47 Mb of the whole genome sequence length, corresponding to 5.12% of the chicken galGal4 autosome assembly. CONCLUSIONS: This study allowed a deep insight into the structural variation in the genome of unselected Mexican chicken population, which up to now has not been genetically characterized. The genomic study disclosed that the population, even if presenting extreme morphological variation, cannot be organized in differentiated genetic subpopulations. Finally this study provides a chicken CNV map based on the 600 K SNP chip array jointly with a genome-wide gene copy number estimates in a native unselected for more than 500 years chicken population.

Effect of reference population size and available ancestor genotypes on imputation of Mexican Holstein genotypes.

The effects of reference population size and the availability of information from genotyped ancestors on the accuracy of imputation of single nucleotide polymorphisms (SNP) were investigated for Mexican Holstein cattle. Three scenarios for reference population size were examined: (1) a local population of 2,011 genotyped Mexican Holsteins, (2) animals in scenario 1 plus 866 Holsteins in the US genotype database (GDB) with genotyped Mexican daughters, and (3) animals in scenario 1 and all US GDB Holsteins (338,073). Genotypes from 4 chip densities (2 low density, 1 mid density, and 1 high density) were imputed using findhap (version 3) to the 45,195 markers on the mid-density chip. Imputation success was determined by comparing the numbers of SNP with 1 or 2 alleles missing and the numbers of differently predicted SNP (conflicts) among the 3 scenarios. Imputation accuracy improved as chip density and numbers of genotyped ancestors increased, and the percentage of SNP with 1 missing allele was greater than that for 2 missing alleles for all scenarios. The largest numbers of conflicts were found between scenarios 1 and 3. The inclusion of information from direct ancestors (dam or sire) with US GDB genotypes in the imputation of Mexican Holstein genotypes increased imputation accuracy by 1 percentage point for low-density genotypes and by 0.5 percentage points for high-density genotypes, which was about half the gain found with information from all US GDB Holsteins. A larger reference population and the availability of genotyped ancestors improved imputation; animals with genotyped parents in a large reference population had higher imputation accuracy than those with no or few genotyped relatives in a small reference population. For small local populations, including genotypes from other related populations can aid in improving imputation accuracy.

Genetic and environmental parameters for milk production, udder health, and fertility traits in Mexican Holstein cows.

Genetic and phenotypic parameters for Mexican Holstein cows were estimated for first- to third-parity cows with records from 1998 to 2003 (n=2,971-15,927) for 305-d mature equivalent milk production (MEM), fat production (MEF), and protein production (MEP), somatic cell score (SCS), subsequent calving interval (CAI), and age at first calving (AFC). Genetic parameters were obtained by average information matrix-REML methodology using 6-trait (first-parity data) and 5-trait (second- and third-parity data) animal models. Heritability estimates for production traits were between 0.17+/-0.02 and 0.23+/-0.02 for first- and second-parity cows and between 0.12+/-0.03 and 0.13+/-0.03 for third-parity cows. Heritability estimates for SCS were similar for all parities (0.10+/-0.02 to 0.11+/-0.03). For CAI, estimates of heritability were 0.01+/-0.05 for third-parity cows and 0.02+/-0.02 for second-parity cows. The heritability for AFC was moderate (0.28+/-0.03). No unfavorable estimates of correlations were found among MEM, MEF, MEP, CAI, and SCS. Estimates of environmental and phenotypic correlations were large and positive among production traits; favorable between SCS and CAI; slightly favorable between MEM, MEF, and MEP and SCS, between AFC and SCS, and between SCS and CAI; and small but unfavorable between production traits and CAI. Estimates of genetic variation and heritability indicate that selection would result in genetic improvement of production traits, AFC, and SCS. Estimates of both heritability and genetic variation for CAI were small, which indicates that genetic improvement would be difficult.

Development of digestive enzyme activity in larvae of spotted sand bass Paralabrax maculatofasciatus II: Electrophoretic analysis.

The activities of several digestive enzymes during larval development of the spotted sand bass (Paralabrax maculatofasciatus) were evaluated using electrophoretic techniques. The results show the presence of three isoforms of alkaline protease from day 2 after hatching (ah) and the early appearance of one pepsin-like band from day 12 ah onwards. In addition, two lipase bands first appeared on day 2 ah, and there was a change in the molecular weight of one band from day 15 ah onwards. Several alpha-amylase isoforms were observed from hatching up to day 5 ah. These results indicate that the important digestive enzymes develop rapidly in these larvae, supporting the possibility of early weaning at day 12 ah using artificial diets.

Selection response for milk production in conventional production systems in Mexico, using genetic evaluations of Holstein sires from Canada and the United States.

Polynomial regression models of the first, second, and third order were used to fit milk production deviations of daughters in Mexico on Canadian and US predicted transmitting ability values for 305-d mature-equivalent milk production (kg). For the pairs Canada-Mexico and Mexico-United States, 40 and 73 bulls with a minimum reliability of 0.75 were analyzed, respectively. Genetic correlations between pairs of countries were also estimated. The parameters were evaluated for all data, and for sires grouped according to the mean of the average phenotypic milk production (high and low) of their daughters' herd mates. Quadratic and cubic effects were not significant in any analysis. From linear regression models, slopes of Mexican daughter deviations on US and Canadian predicted transmitting abilities were 1.01 and 0.93, respectively. Slopes were greater but intercepts were smaller for the high versus low level of production of the sires' herd mates in Mexico. A greater difference between the genetic correlations was found for the high versus low environmental level than for the low level (0.79 vs. 0.70) for Mexico-US data compared with Canada-Mexico data (0.81 vs. 0.78). Genetic correlations between Mexico and the United States (0.74), and between Mexico and Canada (0.77), were smaller than the genetic correlation between the same Canadian and US sires (0.92), suggesting the presence of a moderate degree of genotype-environment interaction for milk production between Canada and the United States, and Mexico.

Development of digestive enzyme activity in larvae of spotted sand bass Paralabrax maculatofasciatus. 1. Biochemical analysis.

Spotted sand bass Paralabrax maculatofasciatus is a potential aquaculture species in Northwest Mexico. In the last few years it has been possible to close its life cycle and to develop larviculture technology at on pilot scale using live food, however survival values are low (11%) and improvements in growth and survival requires the study of the morpho-physiological development during the initial ontogeny. In this research digestive activity of several enzymes were evaluated in larvae, from hatching to 30 days after hatching (dah), and in live prey (rotifers and Artemia), by use of biochemical and electrophoretic techniques. This paper, is the first of two parts, and covers only the biochemical analysis. All digestive enzyme activities were detected from mouth opening; however the, maximum activities varied among different digestive enzymes. For alkaline protease and trypsin the maximum activities were detected from 12 to 18 dah. Acid protease activity was observed from day 12 onwards. The other digestive enzymes appear between days 4 and 18 after hatching, with marked fluctuations. These activities indicate the beginning of the juvenile stage and the maturation of the digestive system, in agreement with changes that occur during morpho-physiological development and food changes from rotifers to Artemia. All enzymatic activities were detected in rotifers and Artemia, and their contribution to enhancement the digestion capacity of the larvae appears to be low, but cannot be minimised. We concluded that the enzymatic equipment of P. maculatofasciatus larvae is similar to that of other marine fish species, that it becomes complete between days 12 and 18 after hatching, and that it is totally efficient up to 25 dah.

A novel rotometer based on a RISC microcontroller.

A new, low-cost rotometer, based on a reduced instruction set computer (RISC) microcontroller, is presented. Like earlier devices, it counts the number and direction of full turns for predetermined time periods during the evaluation of turning behavior induced by drug administration in rats. The present stand-alone system includes a nonvolatile memory for long-term data storage and a serial port for data transmission. It also contains a display for monitoring the experiments and has battery backup to avoid interruptions owing to power failures. A high correlation was found (r > .988, p < 2 x 10(-14)) between the counts of the rotometer and those of two trained observers. The system reflects quantitative differences in turning behavior owing to pharmacological manipulations. It provides the most common counting parameters and is inexpensive, flexible, highly reliable, and completely portable (weight including batteries, 159 g).

Estrogen activity and novel tissue selectivity of delta8,9-dehydroestrone sulfate in postmenopausal women.

Recent basic and clinical advances have consolidated the concept of tissue-selective estrogens, i.e. molecules that express different degrees of partial agonist, full agonist or antagonist activity in different tissues or cells. Delta8,9-Dehydroestrone sulfate (delta8,9-DHES) is a conjugated estrogen and a component of conjugated equine estrogens (CEE). It is metabolized in the human in at least a 1:1 ratio to its 17beta form, 17beta-delta8,9-DHES. To evaluate its activity in different clinical and biochemical parameters, a clinical research study was conducted with delta8,9-DHES and estrone sulfate as a comparator in postmenopausal women. Delta8,9-DHES was given orally at a daily dose of 0.125 mg for 12 weeks in a group of 10 women. Two additional groups of women received either estrone sulfate alone (1.25 mg/day) or the combination of delta8,9-DHES and estrone sulfate at the previously specified doses. A significant and consistent suppression of hot flushes (number, severity, and total score) was observed with delta8,9-DHES, reaching more than 95% suppression in all parameters of vasomotor symptoms. This level of activity was equal to that obtained with the much higher dose of estrone sulfate, and it was sustained for the duration of the treatment period (12 weeks). Measurements of a bone resorption marker, i.e. urinary excretion of N-telopeptide, demonstrated that delta8,9-DHES at 8 weeks produced a degree of suppression (40%) similar to that observed with the higher dose of estrone sulfate. Gonadotropin secretion (FSH and LH) was significantly suppressed in women receiving delta8,9-DHES, similar to that observed with estrone sulfate alone or with the combination of the two. Other parameters, such as total cholesterol, low density lipoprotein cholesterol and high density lipoprotein cholesterol were not modified significantly, whereas serum globulins (sex hormone-binding globulin and corticosteroid-binding globulin) showed only marginal increases after delta8,9-DHES administration. Taken together with preclinical data, it is found that delta8,9-DHES is an active estrogen with a distinct pharmacological profile that results in significant clinical activity in vasomotor, neuroendocrine (gonadotropin and PRL) and bone preservation parameters, whereas displaying little or no efficacy, at the dose tested, on other peripheral parameters normally affected by estrogens. Collectively, this information supports the concept that delta8,9-DHES is an integral component of CEE, with distinct tissue selectivity contributing to the CEE's overall clinical activity, and places this estrogen as a distinct member of a novel class of centrally active molecules with unique peripheral tissue selectivity.

Regulation of luteinizing hormone-releasing hormone and luteinizing hormone secretion by hypothalamic amino acids.

1. The present review discusses the proposed roles of the amino acids glutamate and GABA in the central regulation of luteinizing hormone-releasing hormone (LHRH) and in luteinizing hormone (LH) secretion. 2. Descriptions of the mechanisms of action of these neurotransmitters have focused on two diencephalic areas, namely, the preoptic-anterior hypothalamic area where the cell bodies of LHRH neurons are located, and the medial basal hypothalamus which contains the nerve endings of the LHRH system. Increasing endogenous GABA concentration by drugs, GABA agonists, or blockade of glutamatergic neurotransmission by selective antagonists in rats and non-human primates prevents ovulation and pulsatile LH release, and blunts the LH surges induced by estrogen or an estrogen-progesterone combination. In contrast, glutamate and different glutamate agonists such as NMDA, AMPA and kainate, can increase LHRH/LH secretion. 3. The simultaneous enhancement of glutamatergic activity and a decrease of GABAergic tone may positively influence the maturation of the pituitary-gonadal system in rats and non-human primates. Administration of glutamate receptor agonists has been shown to significantly advance the onset of puberty. Conversely, glutamate antagonists or increased endogenous GABA levels may delay the onset of puberty. The physiological regulation of LHRH/LH secretion may thus involve a GABA-glutamate interaction and a cooperative action of the various types of ionotropic glutamate receptors. 4. The inhibitory actions of GABA on LH release and ovulation may be exerted at the level of afferent nerve terminals that regulate LHRH secretion. A likely candidate is noradrenaline, as suggested by the synaptic connections between noradrenergic nerve terminals and GABAergic interneurons in the preoptic area. Recent experiments have provided complementary evidence for the physiological balance between inhibitory and excitatory transmission resulting in modulation of the action of noradrenaline to evoke LHRH release.