Patogenia del fenómeno de Raynaud / Pathogenesis of Raynaud's phenomenon

El fenómeno de Raynaud consiste en una respuesta vascular exagerada al frío o al estrés emocional, que se manifiesta por un cambio trifásico de coloración en la circulación terminal. Esta reacción afecta a un 3 por ciento a 20 por ciento de la población, presenta un predominio femenino, y puede ser primario o secundario a otra patología. Este fenómeno puede ser clasificado en dos grupos, según su etiología y complicaciones: Raynaud primario y Raynaud secundario, o síndrome de Raynaud. El eje del Raynaud primario se basa en la existencia de un sistema de retroalimentación positiva de los fenómenos regulatorios neuronales, endoteliales y musculares. En el síndrome de Raynaud, la secuencia de eventos, en cambio, depende fundamentalmente de la etiología basal. en el caso de la esclerodermia, principal causante del Raynaud secundario, se describen niveles aumentados de factores endoteliales, tales como la endotelina 1, óxido nítrico y el anión superóxido, los que ejercen sus efectos mediante sus propiedades vasoactivas profibróticas. Además, se describen otros factores citotóxicos, como autoanticuerpos, citoquinas y factores del complemento que llevan a la activación del sistema inmunológico y daño secundario.

Raynaud's phenomenon is an exaggerated vascular response to cold or emotional stress, and is manifested by a triphasic change in the color of the terminal circulation. This reaction affects 3 percent to 20 percent of the population, has a female predominance, and may be primary or secondary to other pathology. This phenomenon can be classified into two groups according to their etiology and complications: primary and secondary Raynaud, also called Raynaud's syndrome. The pathogeny of primary Raynaud is centered on a positive feedback loop between the neuronal, endothelial and muscle regulatory systems. The sequence of events in the secondary Raynaud, on the other hand, depends primarily on its etiology. In the case of scleroderma, the main cause of secondary Raynaud, there have been reported increased levels of endothelial factors such as endothelin 1, nitric oxide and superoxide anion, which exert their effects through its vasoactive and pro-fibrotic properties. Also there have been described other cytotoxic factors such as autoantibodies, cytokines and complement factors that lead to activation of the immune system and secondary damage.

Estrogen therapy arrests bone loss in elderly women.

Although osteoporosis is an age-related disorder, the accelerated bone loss observed in postmenopausal women may be preventable with early diagnosis and adequate estrogen replacement. In a prospective study, we investigated the effect of oral estrogen replacement using conjugated estrogens (Premarin, 0.625 mg) or micronized 17 beta-estradiol (Estrace, 1 mg) versus no estrogen in sequential single-photon bone density measurements over 3-year intervals in 397 postmenopausal women. Estradiol, 1 mg, and conjugated estrogens, 0.625 mg, were equally effective in regarding bone loss. The rate of bone loss was about the same for estrogen users regardless of age (51 to 80 years) and was approximately one third that of nonusers. Among nonusers a uniform accelerated rate of bone loss of 2.5% per year was noted between 56 and 70 years old, whereas between the ages of 51 and 55 years and after age 70 years, the rate of bone loss was significantly less. Ever users over age 65 years showed continued protection from bone loss as long as estrogen therapy was continued. Previous estrogen users who stopped estrogen after age 65 years lost bone more rapidly than women of similar age who had never taken estrogen. Thus to prevent accelerated bone loss in postmenopausal women, we recommend early and continued hormone replacement for life. Estrogen nonusers should be monitored at regular intervals to minimize accelerated bone loss.

Níveis circulantes de estradiol, estrona e gonadotrofina, após a administraçåo de 17 beta-estradiol ativo por via oral, em mulheres após a menopausa / Circulating estradiol, estrone and gonadotropin levels following the administration of orally active 17 B-estradiol in postmenopausal women

A ingeståo de um único comprimido contendo 2mg de 17 beta-estradiol micronizado (E2) resultou em acentuado aumento das concentraçöes séricas de E2 e estrona (E1), em 9 mulheres após a menopausa. O aumento do E2 circulante se tornou significativo dentro de 2 horas, atingiu o pico (110 pg/ml; 437 por cento de aumento) em 5 horas, e permaneceu significativamente elevado em 8 horas após o tratamento. Em 24 horas, a concentraçåo sérica de E2 nåo diferiu significativamente da básica. Ao contrário, foi observado um aumento mais rápido (dentro de 1 hora) e pronunciado (4 vezes) na concentraçåo sérica de E1. O aumento continuou até ser atingido um pico (467 pg/ml; 2.000 por cento) em 6 horas após o tratamento. A seguir, a concentraçåo sérica de E1 decdlinou progressivamente, mas continuou significativamente elevada (140 pg/ml; P<0,01) em 24 horas após o tratamento. As concentraçöes séricas de FSH e LH se mostraram significativamente reduzidas em 6 e 3 horas, respectivamente, e ambas as gonadotrofinas permaneceram significativamente reduzidas em 24 horas após a ingeståo de E2. As relaçöes de E1:E2 em circulaçåo aqui relatadas (ca.3-6) foram muito superiores às observadas por outros investigadores após a administraçåo endovenosa de E2 (i.e. < 1). Assim, os resultados mostram que o E2 micronizado por via oral é rapidamente absorvido, e que, durante esse processo, uma porçåo significativa do hormômio se converte em E1 no trato gastrintestinal. Além disso, 2 mg de E2 oral exercem significativa atividade biológica, conforme demonstrado pela supressåo de gonadotrofina do soro. (J Clin Endocrinol Metab 40:518, 1975)

Estradiol, estrone, and gonadotropin levels after use of vaginal estradiol.

The vaginal absorption of 0.5-mg tablets of micronized estradiol was evaluated in postmenopausal women. In a single-dose study, one hour after insertion, a 5.3-fold rise in mean serum estradiol levels and 1.5-fold rise in mean serum estrone levels were observed. Mean levels of luteinizing hormone and follicle-stimulating hormone were significantly depressed. In a three-week alternate-day regimen, mean serum levels of estradiol were consistently two to three times greater than those of estrone 12 hours after insertion. Vaginal absorption of micronized estradiol tablets into the systemic circulation was found to be rapid and efficient. The vaginal route was acceptable and well tolerated by patients. In addition, the major conversion of estradiol to estrone that follows oral or sublingual administration was reduced. The vagina may be a preferred alternate route for estrogen replacement therapy in selected patients.

Sublingual absorption of micronized 17beta-estradiol.

The sublingual absorption rates, the sustained effects, te biologic activity, and the metabolism of micronized 17beta-estradiol (E2) were measured in 10 postmenopausal women. E2 (0.5 mg) was administered in a single sublingual dose to five of the patients. An alternate-day schedule with the same dosage was used for the other five patients. In the single-dose study, a twenty-six fold increase in serum E2 and a ninefold increase in serum estrone (E1) concentrations were observed 1 hour after the sublingual deposition of E2 (0.5 mg). Serum concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were significantly decreased within 6 hours. The rise in E2 was early and peaked in the first 2 hours. The rise in E1 was slower and progressive, reaching its maximum thirteenfold increase at 4 hours, and remained two and one half times the baseline of 29 pg/ml at 24 hours, whereas E2 returned to the baseline level of 24 pg/ml. When micronized E2 was given in a dosage of 0.5 mg sublingually every other night, increased circulating levels of estrogens continued to be elevated at a minimum two and one-half fold baseline level for the week of study.

Systemic absorption and sustained effects of vaginal estrogen creams.

Systemic absorption and sustained effects of two estrogen vaginal cream preparations (Premarin and Estrace) were measured in 29 postmenopausal women receiving daily applications. With both preparations, vaginal absorption of estrogens into the systemic circulation was rapid, efficient, and sustained. It is apparent that estrogen vaginal cream preparations, as widely used in clinical practice for their local effects on the vaginal mucosa, actually result in sustained high estrogen levels in the systemic circulation. The vaginal route shows promise when systemic estrogen therapy is indicated, but is dangerous when estrogen is contraindicated.

Circulating estradiol, estrone and gonadotropin levels following the administration of orally active 17beta-estradiol in postmenopausal women.

Ingestion of a single tablet containing 2 mg micronized 17beta-estradiol (E-2) produced marked increases in the serum concentrations of E-2 and estrone (E-1) in 9 postmenopausal women. The rise in circulating E-2 became significant within 2 h, reached a maximum (110 pg/ML; 437% increase) at 5 h, and remained significantly elevated at 8 h posttreatment. By 24 h, the serum E-2 concentration was not significantly different than baseline. In contrast, a more rapid (within 1 h) and pronounced (4-fold) increase in the serum concentration of E-1 was observed. This rise continued until a peak (467 pg/ml; 2000%) was reached 6 h posttreatment. Thereafter, the serum E-1 concentration declined progressively but was still significantly elevated (140 pg/ml; P smaller than 0.01) 24 h after treatment. Serum concentrations of FSH AND LH were significantly decreased within 6 and 3 h, respectively and both gonadotropins remained significantly suppressed 24 h following the ingestion of E-2. The ratios of circulating E-1: E-2 reported herein (ca. 3-6) were much higher than those observed by other investigators following iv E-2 (I.E., smaller than 1). Thus the data indicate that micronized E-2 peros is readily absorbed and that during this process a significant portion of the hormone is converted to E-1 by the gstrointestinal tract. In addition, 2 mg oral E-2 exerts significant biologic activity as assessed by serum gonadotropin suppression.