Male-female differences in 6-sulfatoxymelatonin excretion in hypopituitary patients

ABSTRACT Objective To evaluate melatonin secretion in adult hypopituitary patients with Growth Hormone deficiency (AGHD) on and off replacement therapy. Subjects and methods We studied 48 subjects: 12 (6 males) untreated AGHD (AGHDnt), 20 (10 males) treated AGHD (AGHDt) and 16 healthy subjects (8 males) as control group (CG). We measured urinary 6-sulfatoxymelatonin (6-SM) in total (24 h samples), nocturnal (6-SMn): 1800-0800 and diurnal samples (6-SMd): 0800-1800. Results Significant differences were observed among the 3 groups of male subjects, in total 6-SM (p < 0.05), nocturnal 6-SM (p < 0.02) and nighttime-daytime delta values (p < 0.003). CG had significantly higher values than the AGHDnt in total 6-SM (p < 0.01), nocturnal 6-SM (p < 0.05) and nighttime-daytime delta values (p < 0.01). AGHDt patients showed significantly higher levels in nighttime-daytime delta values than AGHDnt patients (p < 0.05). In females, no significant differences were found among the 3 groups studied in total, nocturnal, diurnal or nighttime-daytime delta values. In males, significant correlations were found among total 6-SM (r = 0.58; p = 0.029), nocturnal 6-SM (r = 0.70; p = 0.006) and nighttime-daytime delta values (r = 0.71; p = 0.004) vs. serum IGF-1 levels in subjects evaluated. In females, significant correlations were found among total 6-SM (r = 0.57; p = 0.02) vs. serum IGF-1 levels in subjects evaluated. A tendency towards a significant correlation was found in diurnal 6-SM (r = 0.48; p = 0.07). Conclusions Our findings show a sexual dimorphism in 6-SM excretion in AGHD patients and provide an interesting approach to a further understanding of some chronobiological disorders involved in GH deficiency.

Screening for acromegaly in adult patients not reporting enlargement of the extremities, but with arterial hypertension associated with another comorbidity of the disease / Rastreamento de acromegalia em pacientes adultos não relatando crescimento de extremidades, mas com hipertensão arterial associada a outra comorbidade da doença

Objective To determine the value of acromegaly screening in adult patients not reporting enlargement of the extremities, but who present arterial hypertension associated with at least one other comorbidity of the disease. Subjects and methods Patients seen by general practitioners at primary health care units were evaluated. Among the patients without extremity enlargement, those with recently diagnosed arterial hypertension associated with at least one other comorbidity were selected. Results A total of 1,209 patients were submitted to laboratory investigation. Elevated IGF‐1 was observed in 22 patients. Eighteen patients had adequate suppression of growth hormone (GH). No GH suppression was observed in four women with confirmed elevated IGF‐1. In the latter, IGF‐1 and nadir GH were only slightly elevated, magnetic resonance showed a normal pituitary, and chest and abdominal computed tomography revealed no tumor, and no intervention was performed. Conclusion In patients with arterial hypertension without known pituitary disease, acromegaly is unlikely in the absence of enlargement of the extremities. .

Objetivo Determinar o valor do rastreamento de acromegalia em pacientes adultos sem aumento de extremidades, mas com hipertensão arterial associada a pelo menos uma outra comorbidade da doença. Sujeitos e métodos Pacientes vistos por clínicos em unidades primárias de saúde foram avaliados. Entre pacientes sem aumento de extremidades, aqueles com hipertensão arterial diagnosticada recentemente e associada a pelo menos uma outra comorbidade foram selecionados. Resultados Um total de 1.209 pacientes foi submetido à investigação laboratorial. IGF‐1 foi elevado em 22 pacientes. Dezoito pacientes apresentavam supressão adequada do hormônio do crescimento (GH). Ausência de supressão do GH foi vista em quatro mulheres com IGF‐1 repetidamente elevado. Nestas, IGF‐1 e nadir do GH foram apenas discretamente aumentados, ressonância magnética revelou hipófise normal, tomografia computadorizada de tórax e abdome não revelaram tumor, e nenhuma intervenção foi realizada. Conclusão Em pacientes com hipertensão arterial sem doença hipofisária conhecida, acromegalia é improvável na ausência de aumento de extremidades. .

Avances en el diagnóstico de las alteraciones del eje somatotrófico que causan retardo del crecimiento / An update on the diagnosis of growth hormone axis disturbances that cause stunting

Human growth is a complex process regulated by several genes, most of which are unknown. Recently, our knowledge regarding the etiology of genetically determined causes of short stature has greatly increased, so molecular analysis is becoming essential for the diagnosis of growth retardation. The advances in our understanding of the molecular mechanisms involved in the function of the somatotrophic axis have resulted in a dramatic enhancement of our ability to diagnose and treat growth disorders. We hope that in the next few years improved methods for identifying specific abnormalities which cause short stature will expand our ability to diagnose other causes of growth retardation, and reduce the proportion of patients with "idiopathic" short stature.

Impacto do traumatismo cranioencefálico nas funções adeno e neuroipofisárias / Impact of traumatic brain injury in anterior and posterior pituitary functions

Chama a atenção que, apesar da freqüência com que ocorrem os traumatismos cranioencefálicos (TCE), haja tão poucos estudos a respeito das complicações neuroendócrinas deles decorrentes. Tanto deficiência neuroipofisária, com diabetes insípidus, como deficiências adenoipofisárias podem fazer-se presentes e o tempo decorrente entre o traumatismo e as manifestações neuroendócrinas pode ser muito variável, chegando a ocorrer décadas após o evento. A possibilidade de tais complicações nunca deve passar despercebida ao profissional que atende o paciente, pois, muitas vezes, nem o paciente se recorda mais do evento traumático prévio e cuidadosa anamnese pode recuperar esta importante informação. Não devemos esquecer, também, que acidentes esportivos ou hemorragias subaracnóideas podem também gerar seqüelas neurológicas e, eventualmente, neuroendócrinas.

Histological seasonal changes in ovaries of Spotted tinamous (Nothura maculosa Tinamidae, Temminck, 1815) related to gonadotrope population / Cambios histológicos estacionales en ovarios de perdiz común (Nothura maculosa Tinamidae, Temminck, 1815)) y su relación con la población de gonadotropas

Nothura maculosa is a South American Tinamidae with a marked seasonal reproductive pattern. This work describes ovarian seasonal changes in this species related to gonadotrope (GTHs) population. Ovary and pituitary samples were collected monthly from adult birds during four annual periods. They were fixed in Bouin's solution and processed for light microscopy. The data of post-fixation gonadal weight were analysed using STATISTIX 4.0. Histological sections of the ovaries were stained with H/E, PAS and Goldner-Masson trichrome. Single and double immunostaining were applied on pituitary sections with anti-chicken-FSH and anti-chicken-LH antibodies. The samples were analysed in quarterly periods of the year, Pl: March-May (resting stage); P2: June-August (developing stage); P3: September-November (reproductive stage); P4: December-February (involutive stage). Ovary weight (ow) significantly varied among periods (p<0.001). During Pl, only primordial and previtellogenic follicles were observed, ow 0.09±0.01 g (n=25); during P2, developing follicles with signs of vitellogenesis were detected, ow 0.13+0.01 g (n=14); during P3, maximum follicular development was found, ow 0.9 +/- 0.15 g (n=39); P4 exhibited great variability in follicular stages, ow 0.18+0.18 g (n=19). Involutive atresia was observed in all the periods, while bursting atresia and post-ovulatory follicles were only characterized at P3 and P4. The GTHs containing few LH and FSH immunoreactive (ir) granules were predominant during P1-P2. The GTHs with LH ir granules were abundant in intermediate zone and caudal lobe in P3 and P4 while few cells contained both types of granules. The number of FSH cells was increased during P3 and P4. The histological ovarían changes were narrowly correlated with the variations in the gonadotrope population.

Nothura maculosa es un tinámido sudamericano que presenta marcada estacionalidad reproductiva. Este trabajo describe los cambios estacionales del ovario de esta especie, en relación con la población de gonadotropas (GTHs). Muestras de ovarios y pituitarias de ejemplares adultos fueron colectadas mensualmente durante cuatro años; se fijaron en solución de Bouin y procesadas para M.O. Los datos del peso gonadal posfijación fueron analizados usando STATISTIX 4.0. Los cortes de ovarios fueron coloreados con H/E, P.A.S. y Tricrómico de Goldner-Masson. En cortes de adenohipófisis se aplicó inmunocitoquímica simple y doble (sistema ABC, Vector Lab.), empleando anticuerpos anti-pollo FSH y anti-pollo LH. Las muestras se analizaron en períodos trimestrales de cada año (P): Pl: Marzo-Abril-Mayo (etapa de reposo), P2: Junio-Julio-Agosto (etapa de desarrollo), P3: Septiembre-Octubre-Noviembre (etapa reproductiva), P4: Diciembre-Enero-Febrero (etapa involutiva). El peso de los ovarios (PO) varió significativamente entre los periodos (p< 0.001). Durante Pl, sólo se observaron folículos primordiales y pre-vitelogénicos, PO 0.09 +/- 0.01 g (n=25); durante P2, se detectaron folículos en desarrollo con signos de vitelogénesis, PO 0.13+0.01 g (n=14); durante P3, se encontró máximo desarrollo folicular, PO 0.90+0.15 g (n=39); P4 exhibió gran variabilidad folicular, PO 0.18+0.18 g (n=19). La atresia involutiva se observó en todos los períodos, mientras que la atresia explosiva y los folículos postovulatorios caracterizaron a P3 y P4. Las GTHs conteniendo escasos granulos LH y FSH inmunoreactivos (ir) predominaron durante Pl y P2. Las GTHs con granulos LH¡> eran abundantes en la zona intermedia y en el lóbulo caudal en P3 y P4 mientras que escasas células contenían ambos tipos de granulos. El número de células FSH¡> se incrementó durante P3 y P4. Los cambios histológicos del ovario se correlacionaron estrechamente con las variaciones en la población de gonadotropas.

Effects of prenatal stress on male offspring sexual maturity

Prenatal stimulations have been shown to have long-term effects on at reproductive activity. We evaluated the influence of the prenatal stress on the hypothalamic-pituitary-gonad (HPG) axis in male offsprings from mothers with high number of offsprings per litter (HNL) and low number of offsprings per litter (LNL) after hypothesizing that the number of offsprings per litter may modify the effect of the prenatal stress on the HPG of adult offsprings. Pregnant Wistar rats were used for this study. Immobilization (IMO) stress was used, 30 min, 3 times per week, from the 5th to 21st day of pregnancy. The weight of adrenal and gonads, and the corticosterone (COR), testosterone (TES) and luteinizing hormone (LH) plasmatic levels were analyzed in the male offspring at 30, 45 and 70 days of age. The offspring males coming from LNL showed a decrease in testicle weight and TES levels, without changes in the plasmatic LH levels. However, the offspring of HNL showed a decrease of LH levels. It is possible to conclude that in LNL prenatal stress would produce alterations to gonadal level, while in HNL the effect of stress would be evident at pituitary level.

Estudo longitudinal do eixo hipófise-tireóide durante a gravidez / Longitudinal study of pituitary-thyroid axis in pregnancy

A tireóide sofre importantes modificações durante a gravidez. Visando mostrar as modificações no eixo hipófise-tireóide ao longo deste período, estudamos a função tireoidiana de 587 mulheres, com dosagens de TSH, T4 livre, anti-TPO, betahCG no 1°. trimestre e TSH, T4 livre e anti-TPO no 2°. e 3°. trimestres. Observamos aumento progressivo do TSH no 2°. (média: 2,14mU/L) e 3°. (média: 2,76mU/L) trimestres, em relação ao 1°. (média: 1,39mU/L). No grupo com TSH abaixo do valor de referência (0,4mU/L) no 1°. trimestre, a média de bhCG foi de 129.200UI/L, enquanto no grupo que apresentou níveis normais de TSH, a média foi de 34.200UI/L. Observamos, também, uma ligeira diminuição do T4 livre no 2°. e 3°. trimestres em relação ao 1°. (médias: 1°: 1,15; 2°: 0,99; 3°: 0,94ng/dl). A presença de anti-TPO positivo ocorreu em 13,9 por cento das mulheres. Não foram observadas alterações significativas nos valores médios de TSH e T4 livres naquelas com ou sem auto-imunidade. Entretanto, proporções significativamente maiores de gestantes apresentaram valores hormonais fora da faixa da normalidade em todos os trimestres da gestação. Concluímos que a função tireoidiana é afetada pela gravidez, com tendência ao declínio durante seu progresso, sendo este fenômeno mais marcante no grupo de gestantes anti-TPO positivas.

Growth hormone and future medical applications

Trials for gene therapy were conducted on dwarf mice by using germ cells and transgenic techniques. However; the integration of the growth gene within mice genomes have led to permanent expression and mice gigantism. With the move toward the using of somatic cells instead of germ cells, two approaches were available: 1-Ex vivo gene therapy. 2- In vivo gene therapy. This article is an overview on growth gene, growth hormone and future medical applications

Macroadenoma prolactinosecretante y tratamiento con cabergolina: caso clínico / Prolactin-secreting macroadenoma and cabergoline treatment: clinical case

Presentamos la primera experiencia nacional con el uso de cabergolina en el tratamiento de los macroadenomas hipofisarios.

Bases genéticas dos distúrbios de crescimento / Genetic bases of growth disorders

A integridade do eixo GHRH-GH-IGF-I é fundamental para o crescimento normal de um indivíduo. Mutações nos genes responsáveis por cada uma das etapas deste eixo resultam em baixa estatura grave. Podemos dividir os distúrbios de crescimento em: 1. Deficiência de GH associada a deficiências de outros hormônios hipofisários por alterações em fatores de transcriçäo envolvidos na organogênese hipofisária (HESX1/RPX, LHX3 e LHX4, PROP-1, PIT-1); 2. Deficiência isolada de GH (receptor do GHRH:GHRHR, GH-1, GH bioinativo); e 3. Insensibilidade ao GH (receptor de GH:GHR, gene da IGF-I e receptor da IGF-I:IGFR). Seräo discutidos também os genes implicados na baixa estatura da Síndrome de Turner (SHOX) e Síndrome de Noonan (PTPN11). Atualmente estamos analisando no Laboratório de Hormónios e Genética Molecular da Disciplina de Endocrinologia da FMUSP - LIM 42 os genes HESX-1, LHX3, LHX4, PROP-1, GHRHR, GH-1, GHR, SHOX e PTPN11 em pacientes com baixa estatura e características clínicas e laboratoriais que sugerem o envolvimento destes genes.

The neuroimmune-endocrine axis: pathophysiological implications for the central nervous system cytokines and hypothalamus-pituitary-adrenal hormone dynamics

Cytokines are molecules that were initially discovered in the immune system as mediators of communication between various types of immune cells. However, it soon became evident that cytokines exert profound effects on key functions of the central nervous system, such as food intake, fever, neuroendocrine regulation, long-term potentiation, and behavior. In the 80's and 90's our group and others discovered that the genes encoding various cytokines and their receptors are expressed in vascular, glial, and neuronal structures of the adult brain. Most cytokines act through cell surface receptors that have one transmembrane domain and which transduce a signal through the JAK/STAT pathway. Of particular physiological and pathophysiological relevance is the fact that cytokines are potent regulators of hypothalamic neuropeptidergic systems that maintain neuroendocrine homeostasis and which regulate the body's response to stress. The mechanisms by which cytokine signaling affects the function of stress-related neuroendocrine systems are reviewed in this article.

Atrial natriuretic peptide and feeding activity patterns in rats

This review presents historical data about atrial natriuretic peptide (ANP) from its discovery as an atrial natriuretic factor (ANF) to its role as an atrial natriuretic hormone (ANH). As a hormone, ANP can interact with the hypothalamic-pituitary-adrenal axis (HPA-A) and is related to feeding activity patterns in the rat. Food restriction proved to be an interesting model to investigate this relationship. The role of ANP must be understood within a context of peripheral and central interactions involving different peptides and pathways.

Participación de los factores de crecimiento en la reproducción humana / Growth factors participation in human reproduction

Los factores de crecimiento (FC) incluyen un grupo de moléculas peptídicas, con importantes efectos tróficos, mitóticos y de diferenciación celular sobre prácticamente todos los tejidos humanos. Se hace una revisión acerca de los diferentes FC, así como de sus efectos biológicos sobre los tejidos involucrados en el proceso reproductivo humano. Del mismo modo, se comenta la importancia de los FC en el desarrollo embrionario, así como en el proceso de la implantación. Finalmente, se valora la participación de los FC en la fisiopatología del síndrome de ovarios poliquísticos y de la endometriosis, a la luz de recientes investigaciones en estos campos. Se puede apreciar la importancia que los FC tienen como mediadores de diferentes hormonas (tanto en su secreción como en sus efectos biológicos), así como en la regulación de varios procesos celulares. Queda por establecer la utilidad de estos FC en la práctica cotidiana, por las limitantes tecnológicas inherentes a su identificación y cuantificación así como por la falta de más investigaciones clínicas en humanos. Sin embargo, parece tener un interesante potencial de aplicación en el manejo de problemas de esterilidad humana, así como en las diferentes técnicas de reproducción asistida, ya se in vivo o in vitro

Effects of bromocriptine on serum prolactin levels, pituitary weight and immunoreactive prolactin cells in estradiol-treated ovariectomized rats: an experimental model of estrogen-dependent hyperprolactinemia

The present study was designed to assess the effects of bromocriptine, a dopamine agonist, on pituitary wet weight, number of immunoreactive prolactin cells and serum prolactin concentrations in estradioltreated rats. Ovariectomized Wistar rats were injected subcutaneously with sunflower oil vehicle or estradiol valerate (50 or 300 mug rat-1 week-l) for 2, 4 or 10 weeks. Bromocriptine (0.2 or 0.6 mg rat-1 day-l) was injected daily during the last 5 or 12 days of estrogen treatment. Data were compared with those obtained for intact control rats. Administration of both doses of estrogen increased serum prolactin levels. No difference in the number of prolactin cells in rats treated with 50 mug estradiol valerate was observed compared to intact adult animals. In contrast, rats treated with 300 mug estradiol valerate showed a significant increase in the number of prolactin cells (P<0.05). Therefore, the increase in serum prolactin levels observed in rats treated with 50 mug estradiol valerate, in the absence of morphological changes in the pituitary cells, suggests a "functional" estrogen-induced hyperprolactinemia. Bromocriptine decreased prolactin levels in all estrogen-treated rats. The administration of this drug to rats previously treated with 300 mug estradiol valerate also resulted in a significant decrease in pituitary weight and number of prolactin cells when compared to the group treated with estradiol alone. The general antiprolactinemic and antiproliferative pituitary effects of bromocriptine treatment reported here validate the experimental model of estrogen-induced hyperprolactinemic rats.

LHRH induced changes in the interrenal gland of the frog Rana cyanophlyctis (Schn.).

Administration (i.m.) of synthetic mammalian LHRH (40 ng/frog, alternate day for 30 days) to adult male intact frogs R. cyanophlyctis resulted in activation of the interrenal cells as shown by increases in nuclear diameters of the interrenal cells, activity (histochemical demonstration) of delta 5-3 beta-hydroxysteroid dehydrogenase and glucose-6-phosphate dehydrogenase and concomitant decrease in sudanophilic lipid droplets in the interrenal gland when compared to those of controls. These changes were not observed in the interrenal gland of LHRH treated hypophysectomized frogs. The results indicate that LHRH stimulates secretory activity of the interrenal cells and action may not be directly on the adrenal gland.

Inhibin binding sites in bovine pituitary membranes

Membranes derived from bovine pituitary glands free of the neural lobe were used to investigate the presence of binding sites for inhibin, a glycoprotein produced by the ovarian granulosa cells capable of selectively suppressing FSH secretion from the pituitary gland. Optimal concentration of membranes (400 micrograms prot) and 125I-bovine inhibin (2 nM) were incubated in a medium containing 50 mM Tris-HCl pH 7.4, 0.01 M MgCl2 and BSA 0.01 percent in a final assay volume of 200 microliters at 37 degrees C for different time intervals. Non-specific binding was estimated using unlabelled inhibin in excess. The time course of specific 125I-bovine inhibin (2 nM) binding to bovine pituitary membranes is slow with 50 percent binding at approximately 20 min of incubation and reaching equilibrium at 90 min of incubation. The kinetic analysis shows an apparent pseudo first order association rate constant (Kob) equivalent to 4 x 10(-2) min-1. Following equilibrium with the tracer, a large excess of unlabelled inhibin (1.27 microM) was able to displace 84 percent of the specific binding within 120 min of incubation and 50 percent of the binding at approximately 40 min. The analysis under displacing conditions showed an apparent dissociation rate constant (K2) equals to 1.5 x 10(-2) min-1 and an apparent association rate constant (K1) equals to 1.3 x 10(9) M min-1. Thus, the estimation of the apparent kinetic equilibrium dissociation constant (Kd = K2/K2) of the binding of inhibin to bovine pituitary membranes was 1.2 nM. These results show for the first time the existence of bovine inhibin specific binding sites in bovine pituitary, and also that such a binding can take place in the absence of either gonadal and/or hypothalamic influences. They also contribute to the better understanding of the role of non-steroidal hormones such as inhibin, in the regulation of gonadotrophin secretion

La piel durante el embarazo / Skin in pregnancy

La embarazada experimenta en su piel, durante los 280 días que dura su estado de gravidez, una serie de cambios muy notorios, que por su alta incidencia se consideran normales. En este trabajo se hace un análisis de los cambios fisiológicos que se presentan en los tegumentos durante la gestación; se revisan somerante las alteraciones endocrinológicas y se describen los padecimientos y lesiones dermatológicas que se observan en las embarazadas, exceptuando las erupciones pruriginosas específicas del embarazo

pituitary ovarian axis in the late phase of breast-feeding

This study was performed to evaluate the changes in the pituitary ovarian axis during the stage of escape from the inhibitory effect when breast feeding is prolonged. Also, to investigate the probability of occurrence of subclinical abortion during this stage. Volunteers from the attendee of the postpartum and well-baby clinic of Assiut University Hospital, were studied. Women who had been breast feeding for more than 6 months were frequently examined during one complete menstrual cycle or one month if still amenorrheic. They were having regular marital sexual relation. Examinations included sonographic scanning of the ovary and measurement of FSH, LH, prolactin, estradiol, progesterone and hCG. 7 patients out of the 8 who were amenorrheic showed either quiescent ovaries or partial follicular activity. 8 patients got pregnant during the period of observation. Out of 21 menstrual cycles studied 14 were ovulatory. Ovulation occurred in spite of persistence of hyperprolactinemia in most of them. These ovulatory cycles showed relatively high FSH values in the early and mid-follicular phases but the mid-cycle peak of FSH was occasionally absent. The mid-cycle peaks of E and LH, were lower than normal. The preovulatory rise in P was absent in most of the cycles. P and E production during luteal phase tended to be subnormal [LPD]. Prolongation of breast feeding is associated with resumption of folliculogenesis in spite of hyperprolactinemia. But it seems that the negative feed-back effect of E is exaggerated while the positive feed-back is subnormal. These findings may contribute to LPD which is common during this phase of breast feeding