Rol de los fitoestrógenos en la calcificación vascular e interacciones óseo-vasculares / Role of phytoestrogens in vascular calcification and bonevascular interactions

La osteoporosis y las enfermedades cardiovasculares son patologías prevalentes en mujeres posmenopáusicas. La calcificación vascular es un proceso en el que se produce una distorsión de la arquitectura natural del tejido arterial con una transformación símil osteogénica. La fisiología vascular y la osteogénesis (formación y remodelación ósea) comparten una complejidad metabólica y funcional crítica, que ha sido poco explorada en forma conjunta, lo que ha impulsado la concepción del Eje Óseo-Vascular como nueva área de investigación, con una visión de estudio integradora con la finalidad de identificar vínculos entre ambos sistemas. En virtud de la controversia planteada sobre los riesgos/beneficios de la terapia de reemplazo hormonal para prevenir enfermedades asociadas a la menopausia, se ha incentivado la búsqueda de nuevas opciones de tratamiento. Los fitoestrógenos, como compuestos nutracéuticos, surgen como una potencial alternativa terapéutica. En particular, las isoflavonas presentan gran analogía estructural con el estrógeno humano 17ß-estradiol, lo que les permite unirse al receptor de estrógenos e inducir acciones estrogénicas tanto en células animales como humanas. Basado en la experiencia propia como en lo reportado en la bibliografía, este artículo analiza la información disponible sobre las acciones vasculares y óseas de los fitoestrógenos (específicamente la isoflavona genisteína), con una visión de ciencia traslacional. Es de esperar que los avances en el conocimiento derivado de la ciencia básica, en un futuro cercano, pueda contribuir a decisiones clínicas a favor de promover terapias naturales de potencial acción dual, para la prevención de enfermedades de alta prevalencia y significativo costo social y económico para la población. (AU)

Osteoporosis and cardiovascular diseases are prevalent diseases in postmenopausal women. Vascular calcification is a cellmediated process that leads to the loss of the natural architecture of the arterial vessels due to osteogenic transdifferentiation of smooth muscle cells, and matrix mineralization. Vascular physiology and osteogenesis (bone formation and remodeling) share a critical metabolic and functional complexity. Given the emerging integrative nature of the bonevascular axis, links between both systems are a matter of ongoing interest. In view of the controversy stated about the risks/benefits of hormone replacement therapy to prevent diseases associated with menopause, phytoestrogens arise as a potential natural therapeutic alternative. In particular, isoflavones have a strong structural analogy with the human estrogen 17ß-estradiol, that allows them to bind to the estrogen receptor and induce estrogenic actions in animal and human cells. Based in on our own experience and the information available in the literature, in this paper we provide an overview of the role of phytoestrogens on vascular and bone tissues, with focus on Genistein actions. We wish that the basic knowledge acquired may contribute to guide clinical decisions for the promotion of natural therapies for the treatment of diseases that conspire against human health. (AU)

Influence of male on estrus behavior, estradiol and progesterone release and puberty onset on prepubertal Saanen goats / Influência do reprodutor sobre o comportamento de estro, liberação de estrógeno, progesterona e início da puberdade em cabras Saanen pré-puberes

The present study investigated the male effect on the estrus behaviors, estradiol and progesterone release in prepubertal Saanen goats. Twenty-nine female Saanen goats at 135 ± 10 days old with body weight of 22.8 ± 3.3 Kg were randomly assigned to three treatments: exposure to sexually active male (male treatment), exposure to androgenized females (androgenized female treatment), and prepubertal goats isolated from active male and androgenized females (control treatment). Sexual behaviors associated with estrus were recorded daily, and blood samples were taken weekly to determine estradiol and progesterone concentrations over 24 weeks. The experimental goats subjected to male or androgenized female had significantly higher frequency of estrus (mount acceptance) (P ≤ 0,02), progesterone (P ≤ 0,01), and estradiol (P ≤ 0,01) release than the control goats. Furthermore, goats exposed to a male showed estrus behavior two weeks earlier and maintained this estrus behavior for three weeks more than goats of both female and control treatments. Estrus was observed in 70 % of goats in male and female treatments during the breeding season versus 44 % of the control goats. Finally, significantly more goats subjected to male treatment (60 % of goats) showed progesterone concentrations higher than 1 ng mL-1 (which indicates the presence of a functional corpus luteum) compared to the female and control treatment (40 and 22 % of goats, respectively). These results shows that male treatment significantly increased the number of females showing estrus behavior, estradiol and progesterone release, and the number of animals with a functional corpus luteum, anticipating puberty for experimental goats, suggesting that the male effect could be used to anticipate the onset of puberty in goats.(AU)

O presente estudo investigou o efeito do macho sobre o comportamento do estro, liberação de estradiol e progesterona em cabritas Sannen pré-púberes. Vinte e nove cabritas com 135 ± 10 dias de idade e peso corporal de 22,8 ± 3,3 kg foram submetidas à três tratamentos: macho; fêmeas androgenizadas; controle (mantidas isoladas do efeito macho ou de fêmeas androgenizadas) . Os comportamentos sexuais foram registrados diariamente e as amostras de sangue foram colhidas semanalmente ao longo de 24 semanas. Os tratamentos macho e fêmea androgenizada aumentaram significativamente a ocorrência comportamental do estro (P ≤ 0,02), a concentração de progesterona (P ≤ 0,01) e estradiol (P ≤ 0,01) em comparação ao tratamento controle. As cabritas expostas ao efeito macho anteciparam o comportamento de estro em duas semanas, e o mantiveram por mais três semanas quando comparado às cabritas dos tratamentos fêmea androgenizada e controle. Apenas 44% das cabritas controle foram observadas em estro, sendo que 70% das cabritas submetidas aos tratamentos macho e fêmea androgenizada foram observadas em estro. Além disso, 60% das cabritas expostas ao efeito macho, 40 % das cabritas expostas ao efeito fêmea androgenizada e 22% das cabritas controle apresentaram concentrações de progesterona superiores a 1 ng mL-1, o que indica a presença de corpo lúteo funcional. De fato, o efeito macho aumentou significativamente o número de fêmeas em estro, a concentração de estradiol e progesterona, o número de fêmeas com corpo lúteo funcional, sugerindo que o efeito macho pode ser usado para antecipar o início da puberdade em cabritas Saanen.(AU)

Characterization of quality of sediments from Paranaguá Bay (Brazil) by combined in vitro bioassays and chemical analyses.

The present study characterizes the quality of sediments from the Paranaguá Estuarine Complex (South Brazil). Polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and organochlorine pesticides (OCPs) were determined in sediment samples together with a series of different in vitro bioassays. The fish hepatoma cell line (PLHC-1) was used to determine the presence of cytotoxic compounds and CYP1A- and oxidative stress-inducing agents in sediment extracts. Ovarian microsomal fractions from sea bass (Dicentrarchus labrax) were used to detect the presence of endocrine disrupters that interfered with the synthesis of estrogens (ovarian CYP19). Despite the relatively low levels of pollutants and no evidence of negative effects based on guideline levels, sediments collected close to harbors were enriched with CYP1A-inducing agents and they showed higher cytotoxicity. In contrast, sediments from internal areas inhibited CYP19 activity, which suggests the presence of endocrine disrupters at these sites. Overall, the selected bioassays and the chemistry data led to the identification of potentially impacted areas along the Paranaguá Estuarine Complex that would require further action to improve their environmental quality. Environ Toxicol Chem 2017;36:1811-1819. © 2016 SETAC.

Oestrogens and Progestagens: Synthesis and Action in the Brain.

When steroids, such as pregnenolone, progesterone and oestrogen, are synthesised de novo in neural tissues, they are more specifically referred to as neurosteroids. These neurosteroids bind specific receptors to promote essential brain functions. Pregnenolone supports cognition and protects mouse hippocampal cells against glutamate and amyloid peptide-induced cell death. Progesterone promotes myelination, spinogenesis, synaptogenesis, neuronal survival and dendritic growth. Allopregnanolone increases hippocampal neurogenesis, neuronal survival and cognitive functions. Oestrogens, such as oestradiol, regulate synaptic plasticity, reproductive behaviour, aggressive behaviour and learning. In addition, neurosteroids are neuroprotective in animal models of Alzheimer's disease, Parkinson's disease, brain injury and ageing. Using in situ hybridisation and/or immunohistochemistry, steroidogenic enzymes, including cytochrome P450 side-chain cleavage, 3ß-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase, cytochrome P450arom, steroid 5α-reductase and 3α-hydroxysteroid dehydrogenase, have been detected in numerous brain regions, including the hippocampus, hypothalamus and cerebral cortex. In the present review, we summarise some of the studies related to the synthesis and function of oestrogens and progestagens in the central nervous system.

Expression of aromatase in the embryonic brain of the olive ridley sea turtle (Lepidochelys olivacea), and the effect of bisphenol-A in sexually differentiated embryos.

Brain aromatase participates in several biological processes, such as regulation of the reproductive-endocrine axis, memory, stress, sexual differentiation of the nervous system, male sexual behavior, and brain repair. Here we report the isolation and expression of brain aromatase in olive ridley sea turtle (Lepidochelys olivacea) embryos incubated at male- and female-promoting temperatures (MPT and FPT, respectively), at the thermosensitive period (TSP) and the sex-differentiated period. Also, aromatase expression was assessed in differentiated embryos exposed to bisphenol-A (BPA) during the TSP. BPA is a monomer of polycarbonate plastics and is considered an endocrine-disrupting compound. Normal aromatase expression was measured in both forebrain and hindbrain, showing higher expression levels in the forebrain of differentiated embryos at both incubation temperatures. Although no significant differences were detected in the hindbrain, expression was slightly higher at MPT. BPA did not affect aromatase expression neither in forebrains or hindbrains from embryos incubated at MPT, whereas at FPT an inverted U-shape curve was observed in forebrains with significant differences at lower concentrations, whereas in hindbrains a non-significant increment was observed at higher concentrations. Our data indicate that both incubation temperature and developmental stage are critical factors affecting aromatase expression in the forebrain. Because of the timing and location of aromatase expression in the brain, we suggest that brain aromatase may participate in the imprinting of sexual trends related to reproduction and sexual behavior at the onset of sex differentiation, and BPA exposure may impair aromatase function in the female forebrain.

Adrenarche: postnatal adrenal zonation and hormonal and metabolic regulation.

Adrenarche is the direct consequence of the organogenesis of the zona reticularis (ZR). Proliferation of cortical cells could take place in the outermost layers of the adrenal cortex. Cells could then migrate to differentiate the zona glomerulosa (ZG) and zona fasciculata (ZF) during fetal life, and the ZR during postnatal life. After adrenarche, there are detectable increases in circulating DHEA and DHEA-S. Adrenarche could result from an increase in 17,20-lyase activity of P450c17 secondary to high levels of cytochrome b(5) expression, and from a decrease in 3betaHSD2 expression along with an increase in the expression of SULT2A1 in the ZR. The GH-IGF system and insulin, among other factors, might also modulate adrenal androgen production. Furthermore, high concentrations of estradiol enhance basal and ACTH-stimulated DHEA-S production, while aromatase expression was observed in the human adrenal medulla but not in the ZR, suggesting that estrogens produced in the adrenal medulla might be involved in the regulation of androgen production in the ZR. Premature adrenarche might be associated with ovarian hyperandrogenism and polycystic ovarian syndrome in females, as well as with insulin resistance in both sexes. However, many questions remain, transforming adrenal androgens into markers of diseases important for human health.

[Exon 5 alternative splicing of the cytochrome P450 aromatase could be a regulatory mechanism for estrogen production in humans]. / El splicing alternativo del exón 5 de la citocromo p450 aromatasa podría ser un mecanismo de regulación de la producción de estrógenos en humanos.

P450 aromatase (P450Aro), involved in androgen to estrogen conversion, is encoded by the CYP19 gene. P450Aro c655G>A mutation described in heterozygous form in a girl and in homozygous form in an adult male with P450Aro deficiency results in an aberrant splicing due to disruption of a donor splice site. A truncated inactive protein would be expected if intron5 is retained. Surprisingly, the girl described with this mutation showed spontaneous breast development and pubertal estradiol (E2) levels suggesting residual P450Aro activity (AA). Formerly, we postulate the in frame E5 skipping as a consequence of this mutation generating a protein with some degree of activity. When P450Aro mRNA expression was analysed from patient's lymphocytes, an aberrant spliced mRNA lacking E5 (-E5mRNA) was detected, suggesting an association between E5 skipping and the presence of the mutation. Splicing assays in Y1 cells confirmed this association. -Ex5 cDNA expression in Y1 cells resulted in an inactive protein that could not explain patient's phenotype. Exon 5 might be predicted as a poorly defined exon suggesting a susceptibility to splicing mutations and physiological alternative splicing (AS) events. Therefore, -Ex5mRNA was assessed as a natural occurring alternative transcript in normal human steroidogenic tissues. As P450Aro -E5mRNA expression was detected in human term placenta, prepubertal testis and prepubertal adrenal, we might speculate that AS of P450Aro coding region would occur in humans and would be involved in the complex AA regulation. Furthermore, tissue specific regulation of AS might suggest low expression of +E5mRNA from the c655G>A allele explaining residual AA evidenced in the affected girl.

El splicing alternativo del exón 5 de la citocromo p450 aromatasa podría ser un mecanismo de regulación de la producción de estrógenos en humanos / Exon 5 alternative splicing of the cytochrome P450 aromatase could be a regulatory mechanism for estrogen production in humans

La enzima P450 aromatasa (P450Aro) participa en la síntesis de estrógenos a partir de andrógenos. La mutación c655G>A, descripta en forma heterocigota en una niña y en forma homocigota en un hombre adulto, ambos con déficit de aromatasa, genera la disrupción del sitio dador de splicing exón5-intrón5. Se ha postulado que la retención del intrón5 y la generación de una proteína truncada inactiva serían las consecuencias de esta mutación. Sorpresivamente, la paciente presentó desarrollo espontáneo de mamas y niveles puberales de estradiol, sugiriendo una actividad aromatasa (AA) residual. En principio postulamos que la mutación c655G>A generaría la pérdida del exón5 con conservación del marco de lectura, generándose una proteína con menor actividad que podría explicar el déficit parcial. La expresión del ARNm sin exón5 (ARNm- E5) en linfocitos de la paciente sugiere una asociación entre la pérdida del exón y la presencia de la mutación; posteriormente confirmada realizando ensayos de splicing en células Y1. Sin embargo, la expresión del cDNAE5 en células Y1 presentó una AA nula que no explicaría un déficit parcial. La expresión del ARNm-E5 fue detectada en placenta, testículo y adrenal humanos como una variante de splicing normal. Estos resultados indicarían la ocurrencia de splicing alternativo (SA) en la zona codificante de P450Aro como un posible mecanismo regulador de la producción de estrógenos en tejidos esteroidogénicos humanos. La mutación c655G>A podría alterar los mecanismos fisiológicos reguladores del SA del exón5 favoreciendo su exclusión. De esta forma, bajos niveles de ARNm+E5 podrían expresarse aun en presencia de la mutación explicando el fenotipo de déficit parcial observado en la paciente.

P450 aromatase (P450Aro), involved in androgen to estrogen conversion, is encoded by the CYP19 gene. P450Aro c655G>A mutation described in heterozygous form in a girl and in homozygous form in an adult male with P450Aro deficiency results in an aberrant splicing due to disruption of a donor splice site. A truncated inactive protein would be expected if intron5 is retained. Surprisingly, the girl described with this mutation showed spontaneous breast development and pubertal estradiol (E2) levels suggesting residual P450Aro activity (AA). Formerly, we postulate the in frame E5 skipping as a consequence of this mutation generating a protein with some degree of activity. When P450Aro mRNA expression was analysed from patient's lymphocytes, an aberrant spliced mRNA lacking E5 (-E5mRNA) was detected, suggesting an association between E5 skipping and the presence of the mutation. Splicing assays in Y1 cells confirmed this association. -Ex5 cDNA expression in Y1 cells resulted in an inactive protein that could not explain patient's phenotype. Exon 5 might be predicted as a poorly defined exon suggesting a susceptibility to splicing mutations and physiological alternative splicing (AS) events. Therefore, -Ex5mRNA was assessed as a natural occurring alternative transcript in normal human steroidogenic tissues. As P450Aro -E5mRNA expression was detected in human term placenta, prepubertal testis and prepubertal adrenal, we might speculate that AS of P450Aro coding region would occur in humans and would be involved in the complex AA regulation. Furthermore, tissue specific regulation of AS might suggest low expression of +E5mRNA from the c655G>A allele explaining residual AA evidenced in the affected girl.

El splicing alternativo del exón 5 de la citocromo p450 aromatasa podría ser un mecanismo de regulación de la producción de estrógenos en humanos / Exon 5 alternative splicing of the cytochrome P450 aromatase could be a regulatory mechanism for estrogen production in humans

La enzima P450 aromatasa (P450Aro) participa en la síntesis de estrógenos a partir de andrógenos. La mutación c655G>A, descripta en forma heterocigota en una niña y en forma homocigota en un hombre adulto, ambos con déficit de aromatasa, genera la disrupción del sitio dador de splicing exón5-intrón5. Se ha postulado que la retención del intrón5 y la generación de una proteína truncada inactiva serían las consecuencias de esta mutación. Sorpresivamente, la paciente presentó desarrollo espontáneo de mamas y niveles puberales de estradiol, sugiriendo una actividad aromatasa (AA) residual. En principio postulamos que la mutación c655G>A generaría la pérdida del exón5 con conservación del marco de lectura, generándose una proteína con menor actividad que podría explicar el déficit parcial. La expresión del ARNm sin exón5 (ARNm- E5) en linfocitos de la paciente sugiere una asociación entre la pérdida del exón y la presencia de la mutación; posteriormente confirmada realizando ensayos de splicing en células Y1. Sin embargo, la expresión del cDNAE5 en células Y1 presentó una AA nula que no explicaría un déficit parcial. La expresión del ARNm-E5 fue detectada en placenta, testículo y adrenal humanos como una variante de splicing normal. Estos resultados indicarían la ocurrencia de splicing alternativo (SA) en la zona codificante de P450Aro como un posible mecanismo regulador de la producción de estrógenos en tejidos esteroidogénicos humanos. La mutación c655G>A podría alterar los mecanismos fisiológicos reguladores del SA del exón5 favoreciendo su exclusión. De esta forma, bajos niveles de ARNm+E5 podrían expresarse aun en presencia de la mutación explicando el fenotipo de déficit parcial observado en la paciente.(AU)

P450 aromatase (P450Aro), involved in androgen to estrogen conversion, is encoded by the CYP19 gene. P450Aro c655G>A mutation described in heterozygous form in a girl and in homozygous form in an adult male with P450Aro deficiency results in an aberrant splicing due to disruption of a donor splice site. A truncated inactive protein would be expected if intron5 is retained. Surprisingly, the girl described with this mutation showed spontaneous breast development and pubertal estradiol (E2) levels suggesting residual P450Aro activity (AA). Formerly, we postulate the in frame E5 skipping as a consequence of this mutation generating a protein with some degree of activity. When P450Aro mRNA expression was analysed from patients lymphocytes, an aberrant spliced mRNA lacking E5 (-E5mRNA) was detected, suggesting an association between E5 skipping and the presence of the mutation. Splicing assays in Y1 cells confirmed this association. -Ex5 cDNA expression in Y1 cells resulted in an inactive protein that could not explain patients phenotype. Exon 5 might be predicted as a poorly defined exon suggesting a susceptibility to splicing mutations and physiological alternative splicing (AS) events. Therefore, -Ex5mRNA was assessed as a natural occurring alternative transcript in normal human steroidogenic tissues. As P450Aro -E5mRNA expression was detected in human term placenta, prepubertal testis and prepubertal adrenal, we might speculate that AS of P450Aro coding region would occur in humans and would be involved in the complex AA regulation. Furthermore, tissue specific regulation of AS might suggest low expression of +E5mRNA from the c655G>A allele explaining residual AA evidenced in the affected girl.(AU)

Estrogens and male reproduction: a new concept.

The mammalian testis serves two main functions: production of spermatozoa and synthesis of steroids; among them estrogens are the end products obtained from the irreversible transformation of androgens by a microsomal enzymatic complex named aromatase. The aromatase is encoded by a single gene (cyp19) in humans which contains 18 exons, 9 of them being translated. In rats, the aromatase activity is mainly located in Sertoli cells of immature rats and then in Leydig cells of adult rats. We have demonstrated that germ cells represent an important source of estrogens: the amount of P450arom transcript is 3-fold higher in pachytene spermatocytes compared to gonocytes or round spermatids; conversely, aromatase activity is more intense in haploid cells. Male germ cells of mice, bank voles, bears, and monkeys express aromatase. In humans, we have shown the presence of a biologically active aromatase and of estrogen receptors (alpha and ss) in ejaculated spermatozoa and in immature germ cells in addition to Leydig cells. Moreover, we have demonstrated that the amount of P450arom transcripts is 30% lower in immotile than in motile spermatozoa. Alterations of spermatogenesis in terms of number and motility of spermatozoa have been described in men genetically deficient in aromatase. These last observations, together with our data showing a significant decrease of aromatase in immotile spermatozoa, suggest that aromatase could be involved in the acquisition of sperm motility. Thus, taking into account the widespread localization of aromatase and estrogen receptors in testicular cells, it is obvious that, besides gonadotrophins and androgens, estrogens produced locally should be considered to be physiologically relevant hormones involved in the regulation of spermatogenesis and spermiogenesis.

Estrogens and male reproduction: a new concept

The mammalian testis serves two main functions: production of spermatozoa and synthesis of steroids; among them estrogens are the end products obtained from the irreversible transformation of androgens by a microsomal enzymatic complex named aromatase. The aromatase is encoded by a single gene (cyp19) in humans which contains 18 exons, 9 of them being translated. In rats, the aromatase activity is mainly located in Sertoli cells of immature rats and then in Leydig cells of adult rats. We have demonstrated that germ cells represent an important source of estrogens: the amount of P450arom transcript is 3-fold higher in pachytene spermatocytes compared to gonocytes or round spermatids; conversely, aromatase activity is more intense in haploid cells. Male germ cells of mice, bank voles, bears, and monkeys express aromatase. In humans, we have shown the presence of a biologically active aromatase and of estrogen receptors (alpha and ß) in ejaculated spermatozoa and in immature germ cells in addition to Leydig cells. Moreover, we have demonstrated that the amount of P450arom transcripts is 30 percent lower in immotile than in motile spermatozoa. Alterations of spermatogenesis in terms of number and motility of spermatozoa have been described in men genetically deficient in aromatase. These last observations, together with our data showing a significant decrease of aromatase in immotile spermatozoa, suggest that aromatase could be involved in the acquisition of sperm motility. Thus, taking into account the widespread localization of aromatase and estrogen receptors in testicular cells, it is obvious that, besides gonadotrophins and androgens, estrogens produced locally should be considered to be physiologically relevant hormones involved in the regulation of spermatogenesis and spermiogenesis.

Influência do gênero e da variação dos hormônios femininos (estrógeno e progesterona) na farmacocinética do etanol / Influence of sex female hormone (estrogen and progesterone) on the pharmacokinetics of ethanol

O uso do álcool entre mulheres é uma questão atual e preocupante, face a maior vulnerabilidade destas aos danos hepáticos, cerebrais, entre outros, quando comparadas aos homens com padrões semelhantes de consumo.Sendo assim, investigaram-se as possíveis variações na farmacocinética do etanol em mulheres, considerando duas fases do ciclo menstrual (pré-folicular e lútea), bem como o uso de anticoncepcionais orais (AO). Participaram voluntários dos sexos feminino (n=22) e masculino (n=14), administrando-lhes 0,3 g/kg de etanol, na forma de uísque. Os resultados indicaram: a) os parâmetros farmacocinéticos do etanol não variam em função do ciclo menstrual (fase pré-folicular e lútea); b) as mulheres que tomavam (AO)...

Studies on the relative in-vitro biological potency of the naturally-occurring isoforms of intrapituitary follicle stimulating hormone.

In the present study, we analysed and compared the relative in-vitro biological activity of the various intrapituitary human follicle stimulating hormone (FSH) isoforms employing two different bioassay systems. FSH was fractionated by chromatofocusing (pH range 7.10 to < 3.80) and the several isoforms isolated were quantified at multiple dose levels by three highly specific immunoassay systems: radioimmunoassay (RIA), enzyme-immunoassay (EIA) and immunoradiometric assay (IRMA), as well as by two in-vitro bioassays, one that measures the amount of oestrogen produced by rat granulosa cells in culture and the other that determines the amount of cAMP produced by a human fetal cell line (293) expressing the recombinant human FSH receptor. The relative in-vitro biological activity of each FSH isoform, expressed as the bioassay/ immunoassay (B/I) activity ratio (B/RIA, B/EIA and B/IRMA ratios) varied with its elution pH value. Regardless of the immunoassay or bioassay method employed, less acidic FSH isoforms exhibited higher B/I ratios than their more acidic counterparts [B/RIA, B/EIA and B/IRMA ratios for isoforms with elution pH values > 4.5 = 1.05 +/- 0.13, 0.99 +/- 0.10 and 1.15 +/- 0.08 (rat oestrogen bioassay), and 2.75 +/- 0.34, 2.20 +/- 0.25 and 2.96 +/- 0.35 (human cAMP production bioassay) respectively. Ratios for isoforms with pH values < 4.5 = 0.71 +/- 0.06, 0.47 +/- 0.05 and 0.63 +/- 0.06 (rat oestrogen assay), and 1.80 +/- 0.26, 1.10 +/- 0.09 and 1.44 +/- 0.13 (cAMP assay) respectively (P < 0.05 for isoforms with pH < 4.5 compared with those isoforms with pH > 4.5)]. Furthermore, statistically significant direct relationships between the B/RIA, B/EIA and B/IRMA ratios and elution pH value of each isoform was identified by regression analysis [rat assay: r = 0.844, 0.800 and 0.780 (P < 0.01); human assay: r = 0.730, 0.845 and 0.821 (P < 0.01), for their corresponding B/RIA, B/EIA and B/IRMA ratios respectively]. The finding of significant differences in relative in-vitro biological potency among the various intrapituitary FSH isoforms strongly suggests that the shifts towards the production and secretion of more basic or acidic FSH molecules occurring in certain specific physiological conditions (e.g. puberty and menstrual cycle), may represent an important mechanism through which the anterior pituitary regulates gonadal function.

El sistema lisosomal en los mecanismos hormonales: revisión / Lysosomal system in hormonal mechanisms: review

Los lisosomas no deben considerarse sólo orgánulos que participan en la lisis de diferentes moléculas en proceso de digestión o defensa celular, ya que participan en diversos procesos de metabolismo celular, incluyendo los regulados hormonales. La actividad lisosomal se ve alterada minutos después de la administración de hormonas tanto esteroides como peptídicas incluyendo efectos como: labilización de membranas, cambio en la estructura química de las hidrolasas (latencia estructural) y migración perinuclear de lisosomas. Estas alteraciones demuestran que la actividad lisosomal es hormino-dependiente, y que hidrolasas como fosfatasa ácida pueden esta actuando de alguna manera a nivel de des-represión génica. Por otro lado, los lisosomas pueden propagar efectos hormonales desde la superficie de las células blanco hasta el núcleo. Es muy probable que ésta propagación se efectúe por medio de poblaciones especializadas de lisosomas que bajo el efecto hormonal migran a la región perinuclear. Se ha demostrado que ciertas substancias naturales y sintéticas que estabilizan membranas pueden bloquear esos eventos de distinto grado, de tal manera, que estos restablecen la labilización lisosomal y por consiguiente impiden la liberación enzimática. De una u otra forma, por lo anteriormente descrito, el sistema lisosomal participa en los mecanismos de comunicación autocrina, paracrina y endocrina

Las hormonas esteroides y la etiopatogénesis de padecimientos hepáticos de naturaleza fibrótica / Fibrotic liver disease and steroid hormones

Existen hipótesis en el sentido de que el estatus hormonal está involucrado en la distinta susceptibilidad entre el hombre y la mujer en el desarrollo de enfermedad hepatobiliar, ya que el hígado es órgano blanco para hormonas esteroides. En el desarrollo del fenómeno fibrogénico durante la cirrosis hepática de diversa etiología están involucradas las células de Ito, los miofibroblastos y diversas citocinas como factor transformador de crecimiento-ß, interleucina-6 y factor de necrosis tumoral-alfa. Se sabe que en el organismo existen asas de regulación mutua entre citocinas, glucocorticoides y esteroides sexuales; en el hígado, esta interacción pudiera afectar el proceso fibrogénico a través de diferenciación de células de Ito. El conocimiento del papel preciso de los glucocorticoides y las hormonas esteroides sexuales sobre los mecanismos fibrogénicos, permitiría sustentar racionalmente la viabilidad de la manipulación hormonal en el tratamiento de padecimiento hepático de natulareza fibrótica

[Estrogenic sulfuration and desulfuration processes and their significance in breast carcinoma]. / Procesos de sulfatación y desulfatación estrogénica y su importancia en el carcinoma mamario.

Estrogen conjugates are generally considered as inactivated forms devoid of any estrogenic activity. In some therapies, such as that used during menopause, high dose of estrogen sulfate are currently used as non estrogenic agent. However, precaution should be taken since a considerable amount of this conjugate can be converted into estradiol-17 beta (E2), the most biologically active hormone. In vitro, estrone sulfate (E1S), is converted into estrone (E1) and E2 by the action of estrogen sulfatase and 17 beta-oxydoreductase enzymes. Since the half life E1S in plasma is much higher than that of other estrogens, this conjugate could provide a continuous supply of E2 to estrogen target cells, which may be biologically important. It is the purpose of this review to point out the important role of estrogen sulfates in breast carcinoma.

[Role of embryonal steroidogenesis in early pregnancy]. / Papel de la esteroidogénesis embrionaria en el embarazo temprano.

Recent studies, have shown that pre-implanted embryos of several species synthesize steroid hormones: progesterone, progestins , androgens and several estrogens and it has been postulated that oviductal and endometrial functions are influenced by blastocyst synthesis and release of these molecules. Steroids may create an appropriate milieu for blastocyst migration, nutrition, development and implantation in the maternal uterus. It is the purpose of this paper to review a possible physiological role of steroid hormonal synthesis by the early embryo during the first stages of pregnancy.

Capacidad endócrina del blastocito de mamífero: II biosíntesis y metabolismo estrogénico / Endocrine capacity of blastocyst (mammal) II Biosynthesis and estrogenic, metabolism

De los estudios realizados en embriones preimplantados de mamíferos, llama la atención su capacidad endócrina para sintetizar hormonas esteroides: progesterona, progestinas y diversos estrógenos, los cuales efectuan localmente las propiedades del oviducto y del endometrio para crear un entorno apropiado para su nutrición, migración y desarrollo que permita su implantación en el útero materno. Entre los esteroides secretados por el embrión, los estrógenos son de un interés especial debido a su importancia potencial en los eventos bioquímicos asociados con el proceso de implantación. El propósito de este artículo es contribuir el conocimiento de la biosíntesis y metabolismo estrogénico por el embrión preimplantado.