Interaction between epidermal growth factor receptor and C-C motif chemokine receptor 2 in the ovulatory cascade.

The epidermal growth factor receptor (EGFR) signaling pathway is one of the main pathways responsible for propagating the luteinizing hormone (LH) signal throughout the cumulus cells and the oocyte. Recently, we have proposed the C-C motif chemokine receptor 2 (CCR2) and its main ligand (monocyte chemoattractant protein-1, MCP1) as novel mediators of the ovulatory cascade. Our previous results demonstrate that the gonadotropins (GNT), amphiregulin (AREG), and prostaglandin E2 (PGE2) stimulation of periovulatory gene mRNA levels occurs, at least in part, through the CCR2/MCP1 pathway, proposing the CCR2 receptor as a novel mediator of the ovulatory cascade in a feline model. For that purpose, feline cumulus-oocyte complexes (COCs) were cultured in the presence or absence of an EGFR inhibitor, recombinant chemokine MCP1, and gonadotropins [as an inducer of cumulus-oocyte expansion (C-OE), and oocyte maturation] to further assess the mRNA expression of periovulatory key genes, C-OE, oocyte nuclear maturation, and steroid hormone production. We observed that MCP1 was able to revert the inhibition of AREG mRNA expression by an EGFR inhibitor within the feline COC. In accordance, the confocal analysis showed that the GNT-stimulated hyaluronic acid (HA) synthesis, blocked by the EGFR inhibitor, was recovered by the addition of recombinant MCP1 in the C-OE culture media. Also, MCP1 was able to revert the inhibition of progesterone (P4) production by EGFR inhibitor in the C-OE culture media. Regarding oocyte nuclear maturation, recombinant MCP1 could also revert the inhibition triggered by the EGFR inhibitor, leading to a recovery in the percentage of metaphase II (MII)-stage oocytes. In conclusion, our results confirm the chemokine receptor CCR2 as a novel intermediate in the ovulatory cascade and demonstrate that the EGFR/AREG and the CCR2/MCP1 signaling pathways play critical roles in regulating feline C-OE and oocyte nuclear maturation, with CCR2/MCP1 signaling pathway being downstream EGFR/AREG pathway within the ovulatory cascade.

Body mass index in girls with idiopathic central precocious puberty during and after treatment with GnRH analogues.

BACKGROUND: In girls with Idiopathic Central Precocious Puberty (ICPP) concern has been raised by the potential impact of GnRH-analogues (GnRHa) treatment on body weight. We evaluated the effect of GnRHa on Body Mass Index (BMI) in girls with ICPP according to weight status at diagnosis. METHODS: One hundred seventeen ICPP girls were divided according to pretreatment weight status in: normal weight (NW), overweight (OW) and obese (OB). BMI at one and two years of treatment was assessed. BMI-SDS of 60 patients who reached adult height (AH) was compared to that of 33 ICPP untreated girls. RESULTS: NW girls significantly increased their baseline BMI-SDS at 1 and 2 years of treatment. OW girls only had a significant increment at one year of treatment while OB girls showed no BMI-SDS change. Patients evaluated at AH (at least four years after GnRHa withdrawal) showed a significant decrease on BMI compared to baseline and a significantly lower BMI than the untreated group. CONCLUSION: In ICPP girls the BMI increase under GnRHa was inversely related to the pretreatment weight status. In the long term follow-up, no detrimental effect of GnRHa on body weight was observed. BMI-SDS was lower in treated than in untreated girls.

Early onset of primary hypogonadism revealed by serum anti-Müllerian hormone determination during infancy and childhood in trisomy 21.

Male patients with an extra sex chromosome or autosome are expected to present primary hypogonadism at puberty owing to meiotic germ-cell failure. Scarce information is available on trisomy 21, a frequent autosomal aneuploidy. Our objective was to assess whether trisomy 21 presents with pubertal-onset, germ-cell specific, primary hypogonadism in males, or whether the hypogonadism is established earlier and affects other testicular cell populations. We assessed the functional status of the pituitary-testicular axis, especially Sertoli cell function, in 117 boys with trisomy 21 (ages: 2months-20year). To compare with an adequate control population, we established reference levels for serum anti-Müllerian hormone (AMH) in 421 normal males, from birth to adulthood, using a recently developed ultrasensitive assay. In trisomy 21, AMH was lower than normal, indicating Sertoli cell dysfunction, from early infancy, independently of the existence of cryptorchidism. The overall prevalence rate of AMH below the 3rd percentile was 64.3% in infants with trisomy 21. Follicle-stimulating hormone was elevated in patients <6months and after pubertal onset. Testosterone was within the normal range, but luteinizing hormone was elevated in most patients <6months and after pubertal onset, indicating a mild Leydig cell dysfunction. We conclude that in trisomy 21, primary hypogonadism involves a combined dysfunction of Sertoli and Leydig cells, which can be observed independently of cryptorchidism soon after birth, thus prompting the search for new hypotheses to explain the pathophysiology of gonadal dysfunction in autosomal trisomy.

La determinación de PTH intraquirúrgica o posquirúrgica por quimioluminiscencia predice la hipocalcemia en el posoperatorio de la tiroidectomía en niños / Determination of PTH during or post surgery for quimioluminiscency can predict hypocalcemy in the post surgery children´s thyroidectomy

Objetivo: Evaluar la eficacia diagnóstica de la determinación de PTH en muestras de plasma tomadas durante la cirugía (intra) y posquirúrgica inmediata para predecir el riesgo de desarrollar hipocalcemia en el postoperatorio de la tiroidectomía total en pacientes pediátricos. Métodos: Se llevó a cabo un estudio de cohortes,prospectivo, longitudinal con 20 pacientes pediátricos en los que se practicó tiroidectomía total. Se determinaron los niveles de PTH preoperatorios, intraoperatorios y en el período posquirúrgico inmediato (basal, 5 y 60 minutos de la remoción de la glándula tiroides) utilizando un ensayo automatizado quimioluminiscente (IMMULITE, Siemens), límite de cuantificación 8 pg/mL, CV intra e interensayos < 5,4%. Para este estudio, la concentración de PTH de cada paciente no fue conocida por el equipo tratante hasta el final del mismo. Además se determinó la concentración en suero de Calcio total (Ca T) y/o Calcio iónico (Cai) regularmente durante las 48 hs posquirúrgicas y se controló la presencia de síntomas o signos de hipocalcemia. Se consideró hipocalcemia Ca T < 8 mg/dl y/o Cai < 0,8 nmol/L. Se realizó un análisis por curva ROC para determinar el nivel de PTH que fuera más eficaz en predecir la aparición de hipocalcemia según su sensibilidad (S), especificidad (E), eficiencia diagnóstica (ED) y Valor Predictivo Positivo (VPP). Resultados: Diez de los 20 pacientes (50%) desarrollaron hipocalcemia y 3 de ellos presentaron síntomas. La presentación de hipocalcemia sucedió: 40% en las primeras 6 hs y 40% a las 24 hs.vel de PTH en la muestra intraoperatoria < 14 pg/ml mostró S: 80%, E: 100%, ED: 90% (IC95%: 73-100) y VPP: 100% para predecir hipocalcemia posquirúrgica. En la muestra posquirúrgica inmediata, la concentración de PTH < 14 pg/ml presentó S: 80%, E: 90%, ED 82% (IC95% 63-100) y VPP 90% para predecir hipocalcemia posquirúrgica. Cuando la PTH intraquirúrgica o posquirúrgica es <14 pg/ml el riesgo relativo de presentar hipocalcemia postiroidectomía es de 9. Conclusiones: La medición de PTH intraquirúrgica y posquirúrgica es una herramienta eficiente para predecir hipocalcemia posquirúrgica por tiroidectomía total en la población pediátrica. Esta detección permite la inmediata decisión sobre el tratamiento suplementario con calcio en los pacientes de riesgo mejorando su evolución y evitando la presentación de tetania y otros síntomas de hipocalcemia. Además, permitiría disminuir los controles en los pacientes que evolucionarán con normocalcemia, reduciendo en ambos grupos de pacientes los costos de internación.

Características clínicas, endocrinas y metabólicas de una población argentina de niñas con pubarca prematura / Clinical, hormonal and metabolic findings in argentinean girls with premature pubarche

La pubarca prematura se ha asociado con alteraciones hormonales y metabólicas. Se estudiaron 40 niñas con pubarca prematura de 7,23 ± 0,29 años (media ± ESM). Se evaluó grado de desarrollo, talla, edad ósea, IMC y peso al nacimiento (PN). Se dosaron andrógenos, gonadotrofinas, lípidos, glucemia e insulina, HOMA e índice glucemia/insulina (G/I) y se compararon con un grupo control normal de 25 niñas. Las pacientes se dividieron según el nivel de sulfato de dehidroepiandrosterona (SDHEA) en dos grupos, Pre A (Pre adrenarca), < 400 ng/ml, n= 17 y Post A (Post adrenarca) < 400 ng/ml , n= 23. El grupo Post A tuvo mayor edad cronológica, edad ósea y grado de vello pubiano que el Pre A, sin diferencias en IMC ni en peso de nacimiento (PN). Insulina y HOMA fueron mayores y G/I menor en Post A que en Pre A y grupo control. Dos niñas en Post A tuvieron franca resistencia a la insulina. 64 % de las niñas en Pre A y 59 % en Post A tuvieron valores elevados o limítrofes de colesterol total (CT). Conclusiones: el grupo Post A presentó menor sensibilidad insulínica y ambos grupos de pacientes tuvieron valores de CT elevados, alteraciones que podrían favorecer el riesgo de futuras complicaciones. Se recomienda el seguimiento a largo plazo de todas las niñas con pubarca prematura.

Precocious pubarche in girls is caused by premature adrenarche in most cases. Less frequently it occurs in absence of biochemical markers of adrenarche being ascribed to increased target tissue sensitivity. Premature pubarche with pronounced adrenarche has been associated with insulin resistance and dyslipemia, especially in girls with history of low birth weight. Most studies have been conducted in hispanic and affrican-american patients. We studied a total of 40 argentinean girls with isolated premature pubarche, aged 7.23 ± 0.29 years (mean ± SEM) at the moment of diagnosis. Grade of sexual development, height, weight, BMI and birth weight (BW) were recorded. Dehidroepiandrosterone sulphate (DHEAS), androstenedione (A), testosterone (T), 17OH progesterone (17 OHP), SHBG, LH, FSH, PRL and estradiol were measured. Total cholesterol (TC), LDL cholesterol (LDL- C), triglycerides (TGC), glucose, insulin, HOMA and fasting glucose/ insulin index (G/I) were evaluated and compared with those in a control group of 25 normal girls. Patients were divided into two groups: Pre A (Pre adrenarche), with DHEAS < 400 ng/ml, and Post A (Post adrenarche), with DHEAS > 400 ng/ml. Post A girls had higher chronological age, bone age advancement and grade of pubic hair development than Pre A girls. No difference was found regarding BMI or BW. Besides higher DHEAS levels, Post A girls showed elevated A and 17OHP levels than Pre A girls (86 ± 8 vs 35 ± 4 ng/dl, p<0. 0001 and 1.1 ± 0.09 vs 0.75 ± 0.07 ng/ml, p< 0.01, respectively). Insulin levels (µUI/ml) were 4.51 ± 0.75 in Pre A, 6.53 ± 1.11 in Post A and 4.05 ± 0.45 in control group. Fasting G/I was 24.07 ± 3.75 in Pre A , 18.4 ± 2.34 in Post A and 25.41 ± 2.31 in controls. HOMA was 0.90 ± 0.12 in Pre A, 1.35 ± 0.22 in Post A and 0.89 ± 0.11 in control group. Post A girls had higher insulin and HOMA and lower G/I than control group girls (p<0.05) while those parameters in Pre A girls were not different than in normal control subjects. Only two patients in Post A group had HOMA and G/I consistent with insulin resistance. TC was higher in Pre A than in control group (182.2 ± 4.9 vs156.7 ± 8.5 mg/dl, p<0.05). According to The National Cholesterol Education Program definition, 64 % of Pre A girls and 59 % of Post A girls had elevated or borderline TC levels. TGC values were not different among Pre A, Post A and control group (81.1 ±7.1, 77.6 ± 6.1 and 71.9 ± 4.7 mg/dl, respectively. Summary and Conclusions: In this cohort of argentinean girls with premature pubarche, we did not find a significant history of intrauterine growth retardation. Patients with biochemical pattern of adrenarche showed clinical signs of androgen exposure (accelerated bone age, more advanced degree of pubic hair development) and a serum profile suggestive of reduced insulin sensitivity compared with those without biochemical adrenarche. Both groups of patients had undesirable total cholesterol levels. These findings support the recommendation of long-term follow-up for all girls with premature pubarche.

Serum levels of dimeric and monomeric inhibins and the degree of seminal alteration in infertile men with varicocele.

The aim of the present study was to establish the serum levels of inhibins and their relationship with the degree of seminal alteration in infertile men. Thirty-six patients with varicocele (Va) and seven non-obstructive azoospermic men (Az) were included. The Va group was divided into two subgroups: Va I (sperm concentration: >20 x 106; n = 21) and Va II (sperm concentration: < 20 x 106; n = 15). Twelve fertile men were included as a control group (Co). Semen analysis and serum follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), inhibin B and Pro-alphaC levels were determined. Serum inhibin B and T levels were significantly lower and FSH and LH significantly higher in group Az when compared with the Co. Inhibin B was unable to differentiate Va I from Va II groups. However, in Va II an increase in FSH levels was observed. An inverse correlation between inhibin B and FSH, a direct correlation between inhibin B and testosterone, sperm concentration, motility and morphology were found. No such correlations were seen when only the Va group was analysed. The lack of correlation between serum levels of inhibin B, gonadotrophins, sperm concentration and seminal parameters observed in Va, adds other factor to the complex pathophysiology of varicocele. Finally, further studies are needed to elucidate if oligozoospermic patients with varicocele have also an impaired negative feed-back mechanism that regulates FSH synthesis and secretion.