Systemic activity and mortality in primary Sjögren syndrome: predicting survival using the EULAR-SS Disease Activity Index (ESSDAI) in 1045 patients.

OBJECTIVE: To score systemic activity at diagnosis and correlate baseline activity with survival in a large cohort of patients with primary Sjögren syndrome (SS). PATIENTS AND METHODS: We include 1045 consecutive patients who fulfilled the 2002 classification criteria for primary SS. The clinical and immunological characteristics and level of activity (EULAR-SS Disease Activity Index (ESSDAI) scores) were assessed at diagnosis as predictors of death using Cox proportional hazards regression analysis adjusted for age at diagnosis. The risk of death was calculated at diagnosis according to four different predictive models. RESULTS: After a mean follow-up of 117 months, 115 (11%) patients died. The adjusted standardised mortality ratio for the total cohort was 4.66 (95% CI 3.85 to 5.60), and survival rates at 5, 10, 20 and 30 years were 96%, 90%, 81% and 60%, respectively. The main baseline factors associated with overall mortality in the multivariate analysis were male gender, cryoglobulins and low C4 levels. Baseline activity in the constitutional, pulmonary and biological domains was associated with a higher risk of death. High activity in at least one ESSDAI domain (HR 2.14), a baseline ESSDAI score ≥14 (HR 1.85) and more than one laboratory predictive marker (lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4 and/or cryoglobulins) (HR 2.82) were associated with overall mortality; these HRs increased threefold to 10-fold when the analysis was restricted to mortality associated with systemic disease. CONCLUSIONS: Patients with primary SS, who present at diagnosis with high systemic activity (ESSDAI ≥14) and/or predictive immunological markers (especially those with more than one), are at higher risk of death.

How are we treating our systemic patients with primary Sjögren syndrome? Analysis of 1120 patients.

OBJECTIVE: To describe how systemic disease is treated in a large cohort of Spanish patients with primary Sjögren syndrome (pSS) in daily practice, focusing on the adequacy of therapies for the level of systemic activity measured by ESSDAI score. PATIENTS AND METHODS: By December 2014, our database included 1120 consecutive patients who fulfilled the 2002 classification criteria for SS. Therapeutic schedules were classified into 4 categories: no systemic therapies, hydroxychloroquine (HCQ) and/or low dose glucocorticoids (GCS) (<20mg/day), high dose GCS (>20mg/day) and use of second-line therapies (immunosuppressive agents, intravenous immunoglobulins [IVIG] and/or rituximab [RTX]). RESULTS: There were 1048 (94%) women and 72 (6%) men , with a mean age at diagnosis of 54 years. The main drug-based therapeutic approaches for systemic pSS during follow-up were HCQ in 282 (25%) patients, GCS in 475 (42%, at doses >20mg/day in 255-23%), immunosuppressive agents in 148 (13%), IVIG in 25 (2%) and RTX in 35 (3%) patients. HCQ was associated with a lower risk of death (adjusted HR of 0.57, 95% 0.34-0.95). We classified 16 (7%) of the 255 patients treated with >20mg GCS and 21/148 (14%) treated with immunosuppressive agents as patients inadequately treated, mainly associated with articular involvement of low/moderate activity. CONCLUSION: The management of pSS should be organ-specific, using low dose GCS in patients with moderate systemic activity, limiting the use of high dose GCS and second-line therapies to refractory or potentially severe scenarios. The use of systemic therapies for dryness, chronic pain or fatigue is not warranted.

Influence of physical training on the Syrian hamster's melatonin rhythm.

Melatonin secretion can be influenced by acute exercise. Using female Syrian hamsters we assessed the influence of physical exercise in the serum melatonin rhythm. Melatonin concentrations were determined by RIA. After a gradually increased training program in which experiments were performed at the end of the light phase of the photoperiod (14-h light:10-h dark; lights on at 21:00) animals were killed immediately after exercise (14 h light) and at different time points including 11h after light and 3, 6, 8 and 9h after dark. No differences in melatonin concentrations immediately after exercise practice between control and trained animals were observed. A slower melatonin nighttime increase in exercised hamsters, with significantly lower levels 6h after dark in comparison with controls was found. The peak value appeared 8h after dark but high melatonin levels were prolonged in exercised hamsters, showing significantly higher melatonin levels 9h after. In conclusion, our results indicate for the first time that Syrian hamsters submitted to a training program of increased activity at the end of the light phase, the rest period, showed an altered melatonin rhythm, resembling the response observed in humans.

Prenatal melatonin and its interaction with tachykinins in the hypothalamic-pituitary-gonadal axis.

The pineal gland, through its hormone melatonin, influences the function of the hypothalamic-pituitary-gonadal axis. Tachykinins are bioactive peptides whose presence has been demonstrated in the pineal gland, hypothalamus, anterior pituitary gland and the gonads, in addition to other central and peripheral structures. Tachykinins have been demonstrated to influence the function of the hypothalamic-pituitary-gonadal axis, acting as paracrine factors at each of these levels. In the present review, we examine the available evidence supporting a role for melatonin in the regulation of reproductive functions, the possible role of tachykinins in pineal function and the possible interactions between melatonin and tachykinins in the hypothalamic-pituitary-gonadal axis. Evidence is presented showing that melatonin, given to pregnant rats, influences the developmental pattern of tachykinins in the hypothalamus and the anterior pituitary gland of the offspring during postnatal life. In the gonads, the effects of melatonin on the tachykinin developmental pattern were rather modest. In particular, in the present review, we have included a summary of our own work performed in the past few years on the effect of melatonin on tachykinin levels in the hypothalamic-pituitary-gonadal axis.

[What is the opinion of Spanish internists on osteoporosis?]. / 'Qué opinan los internistas españoles de la osteoporosis?

OBJECTIVE: To conduct an opinion survey on osteoporosis in Spanish internists. METHOD: Survey sent by mail and by personal visit to members of the Spanish Internists Society. Collection of data on opinion on the disease, diagnostic and therapeutic attitude and means available (general laboratory analyses, conventional radiology, biochemical markers of bone remodeling, densitometry and ultrasounds) and preference when choosing a certain treatment. RESULTS: A total of 538 internists answered. More than 90% of those surveyed consider that osteoporosis is a disease that should be treated by internists. A total of 93% consider that osteoporosis is a prevalent disease. More than 80% have access to densitometry. CONCLUSIONS: The majority of Spanish internists consider that osteoporosis is a disease that should be treated by internists and that it is a disease that enters into their action scope. In general, they have the means necessary for its study and treatment. Bisphosphonates constitute the drug of choice and calcium and vitamin D supplements are indicated in almost all the cases.

¿Qué opinan los internistas españoles de la osteoporosis? / What is the opinion of Spanish internists on osteoporosis?

Objetivo. Realizar una encuesta de opinión sobre osteoporosis en internistas españoles. Método. Encuesta remitida por correo y por visita personal a miembros de la Sociedad Española de Medicina Interna. Recogida de datos sobre opinión acerca de la enfermedad, actitud diagnóstica y terapéutica y medios disponibles (analítica general, radiología convencional, marcadores bioquímicos de remodelamiento óseo, densitometría y ultrasonidos) y preferencias a la hora de elegir un determinado tratamiento. Resultados. Contestaron un total de 538 internistas. Más del 90% de los encuestados opina que la osteoporosis es una enfermedad que deben tratar los internistas. El 93% considera que la osteoporosis es una patología prevalente. Más del 80% tiene acceso a una densitometría. Conclusiones. Los internistas españoles opinan mayoritariamente que la osteoporosis es una enfermedad que deben tratar los internistas y que entra en su ámbito de actuación. Por lo general disponen de los medios que necesitan para su estudio y tratamiento. Los bifosfonatos constituyen el fármaco de elección y en la práctica totalidad de los casos indican un suplemento de calcio y vitamina D

Objective. To conduct an opinion survey on osteoporosis in Spanish internists. Method. Survey sent by mail and by personal visit to member of the Spanish Internists Society. Collection of data on opinion on the disease, diagnostic and therapeutic attitude and means available (general laboratory analyses, conventional radiology, biochemical markers of bone remodeling, densitometry and ultrasounds) and preference when choosing a certain treatment. Results. A total of 538 internists answered. More than 90% of those surveyed consider that osteoporosis is a disease that should be treated by internists. A total of 93% consider that osteoporosis is a prevalent disease. More than 80% have access to a densitometry. Conclusions. The majority of Spanish internists consider that osteoporosis is a disease that should be treated by internists and that it is a disease that enters into their action scope. In general, they have the means necessary for its study and treatment. Bisphosphonates constitute the drug of choice and calcium and vitamin D supplements are indicated in almost all the cases

Influence of maternal pineal gland on the developmental pattern of neurokinin A (NKA) and substance P (SP) in male-rat-offspring: relationship to the season of the year.

The present study examines the influence of maternal pineal gland on the frontal cortex, striatal and testicular concentrations of the tachykinins, neurokinin A (NKA) and substance P (SP). Control, pinealectomized (PIN-X) and PIN-X plus melatonin-treated (PIN-X + MEL) mother rats were prepared. Male offspring rats were studied at 21, 31 and 60 days of age, during the four seasons of the year. In control-offspring tachykinin concentrations in frontal cortex were found at their highest levels in 21-day-old rats with a moderate decrease up to 60 days of age. This developmental pattern was season-dependent, observed only during summer and fall. Maternal PIN-X or PIN-X + MEL resulted in alterations in the offspring, showing during spring and summer significantly higher concentrations (P < 0.01) and during fall significantly lower concentrations of tachykinins in the frontal cortex (P < 0.05, P < 0.01) as compared to control-offspring. The tachykinin concentration in the striatum of control-offspring showed no major modifications throughout the ages studied in the four seasons of the year. With very few exceptions, PIN-X- and PIN-X + MEL did not alter tachykinin concentrations in striatum. Testicular SP concentrations showed a decrease from 21 to 60 days of age. PIN-X or PIN-X + MEL only caused minor and inconsistent modifications in testicular SP levels. In conclusion, our data clearly indicate for the first time that the maternal pineal gland participates in the regulation of the postnatal tachykinin development in some areas of the central nervous system. This effect was more evident in the frontal cortex than in the striatum and testes.

Seasonal changes of SP and NKA in frontal cortex, striatum and testes in the rat. Role of maternal pineal gland.

The concentrations of neurokinin A (NKA) and substance P (SP), members of tachykinins family, have been studied in all seasons of the year in frontal cortex, striatum and testes of male offspring 21-, 31-, or 60 days old of mother Wistar rats: control, pinealectomized (PIN-X) and pinealectomized + melatonin during pregnancy (PIN- X + MEL) kept under 12h:12h L:D. Control-offspring: in spite of having been kept under constant environmental conditions throughout the year, had marked differences in tachykinin concentrations. The highest tachykinin concentrations in the frontal cortex were found in summer and fall and the lowest in winter and spring. Maternal PIN-X resulted in alterations of this developmental pattern, mainly in PIN-X- and PIN- X + MEL-offspring in which the highest tachykinin concentrations at 21 and 31 days of age were only observed during summer. The alterations were observed up to 60 days of age for both tachykinins, when at this age control-offspring showed similar NKA concentrations. Seasonal variations were still observed in PIN-X- and PIN- X + MEL-offspring. In striatum and testes no mayor modifications throughout the four seasons of the year were found, with very few exceptions. PIN-X did not alter tachykinin concentrations, neither treatment with melatonin did it. In conclusion, our data clearly indicate for the first time that NKA and SP do indeed have seasonal rhythms in frontal cortex and that the maternal pineal gland plays a role in their entrainment already during fetal life.

Valoración de la producción nocturna del catabolito de melatonina, 6-sulfatoximelatonina, durante el climaterio / Evaluation of nocturnal excretion of 6-sulfatoximelatonin during menopause

Introducción: durante el envejecimiento del eje reproductor femenino, el climaterio, el agotamiento folicular en los ovarios origina cambios hormonales entre los cuales se encuentra la melatonina. Sin embargo, el conocimiento de las interacciones entre dichos parámetros dista mucho de ser profundo. Objetivo: valorar el ritmo nocturno de producción de melatonina por medio de la excreción urinaria de 6-sulfatoximelatonina (6-SMEL). Pacientes y método: se realizó un estudio entre 27 mujeres que acudían a las consultas de Ginecología y Menopausia del Hospital Central de Asturias, con una edad de 43-60 años, sanas y sin ningún tipo de tratamiento excepto la terapia hormonal sustitutiva. Ninguna había tenido menopausia quirúrgica. La noche anterior a la correspondiente visita ginecológica recogieron muestras de orina a las siguientes horas: 22:00, 24:00, 04:00, 08:00 y 10:00.Resultados: el estudio del ritmo nocturno de producción de 6-SMEL mostró en el grupo de mujeres menopáusicas el valor más bajo a las 22:00 h, de 475 pg/ml, y el más elevado a las 08:00 h, de 6.063,33 pg/ml, con diferencias estadísticamente significativas: p < 0,01; p < 0,05 a las 22:00 h frente a las 10:00, 04:00 y 08:00 h. En el grupo de menopáusicas que recibían terapia hormonal sustitutiva, el valor más bajo se obtuvo a las 22:00 h, 385 pg/ml, y el valor pico a las 08:00 h, 8.560 pg/ml, con diferencias estadísticamente significativas: p < 0,01 a las 22:00 frente a las 24:00 h; p < 0,05 a las 08:00 frente a las 22:00, 24:00 y 10:00 h. En el grupo de perimenopausia no se demostró estadísticamente un valor pico a ninguna de las horas estudiadas. Conclusión: la terapia hormonal sustitutiva influyó sobre el ritmo nocturno de secreción de 6-SMEL, pero la cantidad total excretada no resultó afectada durante el climaterio (AU)

Developmental pattern of tachykinins during aging in several organs: effect of exogenous melatonin.

Mammalian neurokinin A (NKA) and substance P (SP) are neuropeptides widely distributed in the body; they are potential regulators of the basal blood flow and therefore of the function of many organs and tissues. In the present investigation, we studied the age-dependent changes in NKA and SP in ovary, liver, pancreas and spleen as well as the role of exogenous melatonin on these changes. Female rats of 5, 15 or 25 months of age were studied. In the ovary, NKA concentrations did not change during aging. SP concentrations in the control group were significantly higher (P<0.01) in old rats than in the other two age groups studied. Melatonin treatment resulted in reduced concentrations as compared with those of the control old rats. In the pancreas, NKA and SP concentrations increased during aging, the young rats showing significantly lower values (P<0.01) than middle-aged and old rats for NKA and significantly lower (P<0.01) than the old rats for SP. After melatonin treatment the differences in NKA concentrations disappeared and SP decreased in middle-aged as compared with those in old rats. In the liver, NKA and SP concentrations in the control and melatonin-treated groups did not differ significantly for the three age groups studied. Splenic NKA in control and melatonin-treated groups increased from young to middle-age up to old ages. SP concentrations showed similar values at all ages except in melatonin-treated old rats; in these animals there were significantly higher concentrations than in young melatonin-treated rats. The effect of melatonin was mainly observed on the ovary and pancreas in old rats, with a reduction in the concentrations as compared with those observed in the young groups.

Efectos de la melatonina sobre el mantenimiento de parámetros corporales durante el envejecimiento. Estudio en Rattus norvegicus / Effects of melatonin on the maintenance of body parameters during aging. Study in Rattus norvegicus

INTRODUCCIÓN Y OBJETIVO: Con la edad, la biosíntesis de melatonina disminuye, coincidiendo con cambios fisiológicos propios del envejecimiento. Ante este hecho, diversos investigadores han abordado estudios encaminados a valorar si la administración de melatonina podría retardar el proceso del envejecimiento. En este estudio hemos valorado la influencia de la melatonina sobre el mantenimiento de diversos parámetros y necesidades energéticas corporales, basándonos en hallazgos previos que ponen de manifiesto modificaciones de los mismos asociadas al envejecimiento. MATERIAL Y MÉTODOS: Hemos administrado melatonina en el agua de bebida (2 µg/ml), durante cinco meses, en ratas jóvenes (4-5 meses), mediana edad (15-18 meses) y edad avanzada (23-25 meses).Los parámetros estudiados fueron: peso corporal, peso de grasa retroperitoneal y de ovarios, ingesta sólida e hídrica y niveles de citrato sérico. RESULTADOS: La acción de la melatonina sobre la ingesta sólida se hizo notar en la edad avanzada, provocando menor consumo que en el grupo control. Sin embargo, sobre la ingesta hídrica, el suplemento con melatonina influyó en todas las edades desencadenando menor consumo. La administración de melatonina a ratas de edad avanzada disminuye el contenido de grasa retroperitoneal. Igualmente reduce el peso de los ovarios en ratas de mediana edad e impide que los niveles de citrato sérico en ratas de edad avanzada muestren valores significativamente elevados con respecto a las otras dos edades, como se observa en el grupo control. CONCLUSIONES: La administración de melatonina a ratas de edad avanzada conduce a un mejor aprovechamiento energético (AU)

Acción de la melatonina en el proceso de envejecimiento / Action of melatonin in the aging process

La melatonina es sintetizada por la glándula pineal siguiendo un patrón circadiano con los niveles elevados durante las horas de oscuridad. El patrón de secreción de melatonina evoluciona a lo largo de la vida, alcanza los valores más altos entre 1 y 3 años, entre 15 y 20 años experimenta una caída del 80 por ciento. Durante las décadas siguientes, sus niveles disminuyen moderadamente hasta los 70-90 años. Precisamente este descenso en los niveles de melatonina coincidiendo con el proceso de envejecimiento sano, ha movido a muchos investigadores a plantearse los posibles efectos de la melatonina como substancia capaz de retrasar el proceso del envejecimiento o paliar los desórdenes derivados del mismo. Los campos de investigación más destacados en estos últimos años han sido: efectos de la melatonina como agente antioxidante y como regulador circadiano, y/o variaciones relacionadas con el ciclo sueño/vigilia dependientes de la edad. Los resultados científicos han puesto de manifiesto la capacidad antioxidante de la melatonina en todos los modelos experimentales estudiados. Como hormona reguladora del sueño ha mostrado ser eficaz mejorando la calidad del sueño, siempre que el insomnio esté asociado a producción nocturna de melatonina disminuida (AU)

In vitro pituitary prolactin, growth hormone and follicle stimulating hormone secretion during sexual maturation of female rats primed with melatonin.

The influence of in vivo melatonin administration on in vitro pituitary follicle stimulating hormone (FSH), growth hormone (GH) and prolactin secretion, as well as the possible influence of dopamine (DA) were evaluated in prepubertal (31-day-old), pubertal (33-day-old) and adult female rats at diestrus phase of the sexual cycle. The in vitro pituitary hormone secretions were evaluated at basal rate for the first hour of incubation only, in Krebs Ringer phosphate (KRP) (I1) and after a second hour of incubation with KRP (I2) or with KRP+DA (I2 plus DA). I1PRL secretion was significantly higher in 33-day-old control and melatonin treated (MEL) rats as compared to I2 periods. However, in 31-day-old rats I1 secretion was higher than in the I2 or I2+DA periods, in MEL rats. In vitro GH secretion was significantly higher at I1 than during I2 periods in the control 31- and 33-day-old groups, but not in MEL rats. The only significant effect of DA was the elevation of GH in prepubertal MEL rats. In vitro FSH release was increased by melatonin in 31- and 33-day-old female rats. No differences in PRL, GH and FSH secretion were found in adult rats. In conclusion, the results show that melatonin effects upon in vitro pituitary gland activity are reproductive-stage-dependent modifying the secretory capacity of the lactotrop, gonadotrop and somatotrop during prepubertal and pubertal ages but not in adult rats studied at a quiescent phase of the sexual cycle.

Vertebral involvement in hyperphosphatemic tumoral calcinosis.

Hyperphosphatemic tumoral calcinosis (HTC) is an inherited metabolic disorder characterized by calcified soft tissue masses and hyperphosphatemia. Besides these typical features, a number of less common manifestations have been reported, all of them related to pathologic calcification of various tissues. We have investigated the case of a woman with hyperphosphatemia, recurrent episodes of lumbar pain, and a positive familial history of HTC. A bone scan showed markedly increased uptake in the lower lumbar spine. Magnetic resonance imaging showed pathological changes in L5 compatible with an inflammatory reaction and not suggestive of neoplastic process. There was no evidence of infection, trauma, malignancy, or other disease that could cause the lesion. We treated the patient with analgesics and NSAIDs and the pain remitted over a period of 1 week. In a follow-up magnetic resonance imaging 7 months later, the L5 lesion had disappeared completely. A computed tomography scan analysis with a bone window showed a sclerotic area at the L5 vertebral body. We believe that this patient was affected by the syndrome of HTC and that the inflammatory phenomena found in L5 are a manifestation of this disease.

Measuring quality of life in women with vertebral fractures due to osteoporosis: a comparison of the OQLQ and QUALEFFO.

INTRODUCTION: Studies comparing the performance of health-related quality of life instruments in osteoporosis are lacking. We compared the feasibility, validity and reliability of the osteoporosis quality of life questionnaire (OQLQ) and the QUALEFFO (test version) in women with vertebral deformities due to osteoporosis. METHODS: Three hundred and thirty-eight patients diagnosed with primary osteoporosis and vertebral deformity and a random sample of 304 women from the general population (control group) were recruited. Patients and controls were randomly assigned to receive either the OQLQ or the QUALEFFO, and the SF-36 and EQ-5D. Test-retest reliability was assessed in the patient group. RESULTS: The QUALEFFO had more items with missing data and took slightly longer to administer (20.7 vs. 18.7 min). Cronbach's alpha and intraclass correlation coefficient (ICC) values for OQLQ domains (alpha: 0.75-0.91; ICC: 0.85-0.93) were slightly higher than for the QUALEFFO (alpha: 0.63-0.90; and ICC: 0.80-0.93). OQLQ and QUALEFFO domain scores correlated as expected with SF-36 and EQ-5D domains. Both questionnaires discriminated between patients and controls though the OQLQ showed slightly better discriminant power. DISCUSSION: The superior performance of the OQLQ in terms of administration time, missing responses, and discriminatory capacity needs to be weighed against the advantages of using a self-administered instrument such as the QUALEFFO. A full comparison also requires data on sensitivity to change.

Ageing and melatonin influence on in vitro gonadotropins and prolactin secretion from pituitary and median eminence.

The effect of ageing and/or melatonin (MEL) on in vitro gonadotropins, luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (PRL) release and tissue content from pituitary and median eminence (ME) were investigated. Gonadotropins and PRL basal release (I-1) from hemipituitaries of young cyclic-rats was decreased by MEL to levels shown in old acyclic rats. Pituitary tissue content of LH and PRL were not affected by ageing or MEL treatment. However, pituitary FSH tissue content was decreased by ageing and MEL, suggesting a different regulatory mechanism. MEL inhibitory influence on pituitary hormones is mainly exerted on the secretory process. This effect is only exerted in young rats. ME LH and PRL release and content were significantly lower than in pituitary. However, FSH release and content in ME showed values similar to those found in the pituitary. This study confirms that the functional capacities of pituitary gland and ME are maintained during reproductive senescence.

Developmental changes of hypothalamic, pituitary and striatal tachykinins in response to testosterone: influence of prenatal melatonin.

Substance P (SP) and neurokinin A (NKA), members of the family of mammalian tachykinins, are involved in the regulation of many physiological functions and are widely distributed in mammalian tissues. In this report, the effects of prenatal melatonin on the postnatal developmental pattern of NKA, and SP, and on testosterone secretion were investigated. Also, tachykinin response to the administration of testosterone propionate (TP) was studied. The brain areas studied were medio-basal-hypothalamus, pituitary gland and striatum. Male rat offspring of control or melatonin treated mother rats were studied at different ages of the sexual development: infantile, juvenile or prepubertal periods, and pubertal period. Both groups received exogenous TP (control-offspring+TP and MEL-offspring+TP), or the vehicle (control-offspring+placebo and MEL-offspring+placebo). Hypothalamic concentrations of all peptides studied in control-offspring+placebo remained at low levels until the juvenile period, days 30-31 of age. After this age, increasing concentrations of these peptides were found, with peak values at puberty, 40-41 days of age, then declining until adulthood. In the MEL-offspring+placebo a different pattern of development was observed; hypothalamic concentrations of NKA and SP from the infantile period until the end of juvenile period were significantly higher than in control-offspring+placebo. TP administration exerted a more marked influence on MEL-offspring than on control-offspring and prevented the elevation in tachykinin concentrations associated with prenatal melatonin treatment. TP administration to control-offspring resulted in significantly reduced (P < 0.05) tachykinin concentration only at 40-41 days of age, and increased (P < 0.01) during infantile period as compared to control-offspring+placebo. Pituitary NKA concentrations were lower than in the hypothalamus. In control-offspring+placebo pituitary NKA levels did not show significant changes throughout sexual development. A different developmental pattern was observed in MEL-offspring+placebo, with significantly increased (P < 0.05) pituitary NKA concentrations at 35-36 days of age than in control-offspring+placebo. TP administration to control-offspring influenced pituitary NKA levels at the end of the infantile and pubertal periods, showing at both stages significantly higher (P < 0.05) NKA levels as compared to control-offspring+placebo. NKA levels in MEL-offspring+TP were only affected at 21-22 days of age, showing significantly increased (P < 0.01) values as compared to MEL-offspring+placebo. Striatal tachykinin concentrations in control-offspring did not undergo important modifications throughout sexual development, but during the prepubertal period they started to increase. Maternal melatonin and TP injections produced short-lived alterations during the infantile period. The results showed that prenatal melatonin delayed the postnatal testosterone secretion pattern until the end of the pubertal period and postnatal peptide secretion in brain structures. Consequently, all functions depending of the affected areas will in turn, be affected.

Prenatal melatonin influences developmental changes of tachykinins in response to estradiol benzoate.

The developmental changes of hypothalamic, pituitary, striatum and pineal gland tachykinin concentrations, as well as the response to estradiol-benzoate (EB) administration, were studied in offspring of control and melatonin (MEL) treated mother rats. Female rats were studied throughout different phases of the sexual development: infantile, prepubertal and pubertal periods, in the four following groups; control-offspring+vehicle; control-offspring+EB; MEL-offspring+vehicle; MEL-offspring+EB. Hypothalamic NKA in control-offspring+ vehicle was significantly increased only at 27 days of age and in control-offspring+EB at 27 days of age and during the infantile period. Hypothalamic SP levels increased similarly in control-offspring+EB during the infantile period but the EB influence was more pronounced with significantly increased concentrations at 32 days of age. Prenatal melatonin treatment produced major alterations in these patterns of postnatal development. In MEL-offspring+EB tachykinins concentrations in the hypothalamus during infantile and prepubertal periods did not increase, however at 37 days of age, they showed significantly higher values than in control-offspring+EB groups. The developmental pattern of pituitary NKA and SP concentrations in both; control-offspring+vehicle and control-offspring+EB groups, showed similar values from the infantile period to puberty, indicating that NKA and SP concentrations remained at similar levels independently of the sexual stage, only at 27 days of age in control-offspring+EB significantly increased values were found as compared to MEL-offspring+EB. Prenatal melatonin did not produce marked modifications, only significantly lower NKA and SP concentrations in MEL-offspring+EB group were observed at 25 days of age in comparison to control-offspring+EB group. Striatal NKA and SP concentrations showed a similar developmental pattern. In control-offspring, EB treatment produced NKA and SP decreased concentrations at the infantile period than in control-offspring+vehicle and significantly increased concentrations during the prepubertal period, then during the pubertal period NKA and SP concentrations decreased in control-group+EB. However, prenatal melatonin treatment reduced the levels of striatal NKA and SP during the prepubertal period after EB treatment and delayed until pubertal period the increase previously observed in control group during the prepubertal period. In MEL-offspring+vehicle group striatal concentrations of both tachykinins remained at low levels from infantile period until pubertal period. Prenatal melatonin and EB did not produce major alterations in SP pineal concentrations throughout sexual development. Plasma estradiol concentrations were significantly higher in the groups that received EB treatment than in those that received vehicle during prepubertal and juvenile periods in control-offspring+EB group and during the pubertal period in MEL-offspring+EB group. These data indicate that prenatal MEL treatment may influence NKA and SP developmental pattern from the infantile period until adulthood in the female rat.

Effect of exogenous melatonin on neuroendocrine-reproductive function of middle-aged female rats.

The possible role of melatonin in the regulation of the reproductive system of female rats during ageing was investigated in middle-aged female rats showing irregular duration of the oestrous cycle (n = 30). Blood samples were obtained by jugular venepuncture during the oestrous cycle in control rats. After this experiment was completed, the female rats were treated with melatonin for 2 months and blood samples were obtained at different stages of the oestrous cycle. Plasma LH, FSH and prolactin concentrations were significantly increased in the afternoon of the day of pro-oestrus after melatonin treatment compared with control rats. Moreover, FSH concentrations too were significantly increased on the morning of pro-oestrus and oestrus in melatonin treated rats compared with control rats. Similarly, oestradiol concentrations were significantly higher on the morning of pro-oestrus in melatonin treated rats compared with controls. Another group of rats showing irregular duration of the oestrous cycle was used to study the possible effect of melatonin treatment on the timing of pro-oestrous surges of LH and FSH. The results showed that LH and FSH peak values occurred at 5 h after melatonin treatment. Pituitary responsiveness to LHRH in a 90 min test was also studied in middle-aged rats showing irregular duration of the oestrous cycle that had been injected for 1 month with either melatonin or saline. Prolactin response was unaffected by exogenous melatonin, but a stimulatory effect of melatonin on LH and FSH pituitary responsiveness to LHRH was observed. The results indicate an improved function of the neuroendocrine-reproductive axis in middle-aged rats after melatonin treatment.