Estrógeno unido al tejido en el envejecimiento

La industria del “Reemplazo de Estrógeno” está basada en la doctrina de que los tejidos de la mujer están desplegados de estrógeno luego de la menopausia. Esta doctrina es falsa.

La concentración de una hormona en sangre no representa directamente la concentración en varios órganos.

La cantidad de estrógeno en tejidos disminuye cuando la progesterona es abundante. En ausencia de progesterona, los tejidos retienen estrógeno incluso cuando hay poco circulando en sangre.

Muchas cosas sugieren un incremento de la actividad estrogénica luego de la menopausia. Por ejemplo, la melatonina disminuye significativamente en la pubertad cuando el estrógeno aumenta, y de nuevo disminuye en la menopausia. La prolactina (estimulada por el estrógeno) aumenta alrededor de la pubertad, y en lugar de disminuir en la menopausia, a menudo aumenta, y su incremento está asociado con la osteoporosis y otros síntomas relacionados con el envejecimiento.

El estrógeno es producido en muchos tejidos por la enzima aromatasa, incluso en el seno y endometrio, aunque estos son considerados “tejidos objetivo” en lugar de glándulas endocrinas. La aromatasa incrementa con la edad.

El estrógeno es desactivado, principalmente en hígado y cerebro, haciéndolo soluble en agua acoplándole ácido glucurónico y/o ácido sulfúrico.

La concentración del estrógeno en un tejido en particular depende de muchas cosas, incluyendo su afinidad o fuerza de unión para componentes de ese tejido, relativa a la afinidad de la sangre; la actividad en ese tejido de la enzima aromatasa, que convierte andrógenos en estrógeno, la actividad de la enzima glucuronidasa , que convierte glucurónidos de estrógenos solubles en agua en formas activas de estrógeno solubles en aceite; y las sulfatasas y varias otras enzimas que modifican la actividad y solubilidad de los estrógenos. Los “receptores estrogénicos”, proteínas que se acoplan con estrógeno en las células, son desactivados por la progesterona, y activado por muchas condiciones físicas y químicas.

La inflamación activa la beta-glucuronidasa, y sustancias anti-inflamatorias como la aspirina reducen muchos de los efectos del estrógeno.

Las doctrinas son admitidas en el “canon científico” por aquellos que tienen el poder de censura. En la astronomía, el descubrimiento de Halton Arp de cambios rojos galácticos “anómalos” es prácticamente desconocido, porque los editores de la revista dijeron que las observaciones eran “sólo anomalías”, o que las teorías que podrían explicarlo son poco convencionales; pero el problema real es que son una gran evidencia contra el Big Bang, La Ley de Hubble, y el Universo en Expansión. La ciencia estadounidense, desde los 40, ha probado ser la más censurada y doctrinaria del mundo.

La revolución de Gilbert Ling en la biología celular permanece fuera del canon, a pesar de profundas influencias de las Imagenología con Resonadores Magnéticos, que creció a partir de su punto de vista de la célula, debido a que su trabajo proveyó evidencia conclusiva de que las células no son reguladas por “membranas semipermeables y bombas de membrana.” Cada campo de la ciencia es dominado por un establishment doctrinario.

Charles E. Brown-Séquard (1.817-1.894) era un fisiólogo que fue pionero en endocrionología científica, pero que fue ridiculizado por asegurar que extractos de glándulas animales tenían un efecto vigorizante cuando eran inyectadas. Su lugar en el canon científico es principalmente un objeto de ridículo, y los detalles de su caso son perfectamente representativos de la manera en que nuestro “canon” se ha construido. La razón de descartar sus observaciones fue que usó un extracto en agua de testículos, y, de acuerdo a los biólogos estadounidenses del siglo XX, la testosterona no es soluble en agua, y, si el extracto en agua “No habría tenido ninguna hormona”. El argumento es tonto, porque los órganos vivos tienen innumerables sustancias que solubilizan moléculas aceitosas, pero también porque Brown-Séquard estaba describiendo un efecto que no estaba necesariamente limitado a una sola sustancia química. (El transplante de células vivas para reparar tejidos es finalmente aceptado, pero los pioneros en promover la regeneración o reparación de tejido con el transplante de células vivas, muertas o estresadas—V. Filatov, L.V. Polezhaev, W.T. Summerlin, por ejemplo, fueron simplemente sacados de la historia.)

Si el extracto de Brown-Séquard no podía funcionar porque la testosterona no era soluble en agua, entonces qué deberíamos pensar de miles de publicaciones médicas que hablan de “hormonas libres” como las únicas hormonas activas? (“Hormona libre” es definido como la hormona que no está unida a una proteína de transporte, con la más o menos explícita idea de que está disuelta en agua del plasma o fluido extra-celular.) El extracto de tejido de Brown-Séquard habría contenido sustancias solubilizantes incluyendo proteínas y fosfolípidos, así las hormonas aceitosas estarían ciertamente presentes (y activas) en sus extractos. Pero los miles que le ridiculizaron se comprometieron con el hecho de que las hormonas esteroides son insolubles en agua. Por su propia lógica, están vendiendo la imposibilidad cuando hacen cálculos para revelar el monto real de “hormona libre”, como algo distinto de hormona unida a proteína, en la sangre del paciente.

La inmensa industria de la Terapia de Reemplazo Hormonal —que presagiaron los experimentos de Brown-Séquard— está basada en le hecho de que la concentración de algunas hormonas en el serum sanguíneo disminuye con el envejecimiento.

Al principio, era asumido que la cantidad de hormona en la sangre correspondía con la efectividad de esa hormona. Lo que sea que hubiera en la sangre estaba siendo entregado a “tejidos objetivo”. Pero la idea de medir la “iodina acoplada a proteína” (PBI) para determinar la función de la tiroides cayó en descrédito (porque nunca tuvo basamento científico alguno), nuevas ideas de medir “hormonas activas” entraron al mercado, y actualmente la doctrina es que las hormonas “unidas” son inactivas, y las activas son las “libres”. Se supone que las hormonas “libes” son las únicas que pueden entrar a las células para entregar sus señales, pero el problema es que las “hormonas libres” sólo existen en la imaginación de gente que interpreta ciertos resultados de laboratorio, como discutí en un boletín informativo acerca de pruebas tiroides (Mayo, 2.000).

En los 60 y 70, cuando el PBI estaba en desaparición, hubo un interés intenso en —una especie de manía con ello— el rol de las “membranas” en regular las funciones celulares, y la membrana todavía estaba siendo vista por la mayoría de los biólogos como la “membrana semipermeable” que, “obviamente”, excluiría moléculas tan grandes como la albúmina y otras proteínas que transportan tiroides y otras hormonas en la sangre. (En realidad, y observaciones experimentales, la albúmina y otras proteínas entran a las células más o menos libremente, dependiendo de condiciones prevalecientes). La doctrina de la membrana llevó directamente a la doctrina de la “hormona libre”.

Este asunto, de discutir acerca de cual forma de una hormona es la forma “activa”, tiene que ver con explicar cuánto de la hormona transportada en sangre va a alcanzar los “tejidos objetivos”. Si la barrera de membrana es “semipermeable” a moléculas como hormonas, entonces receptores específicos y transportadores van a hacer falta. Si la concentración de una hormona dentro de una célula es más alta que en la sangre, una “bomba” normalmente va a ser invocada, para producir un “transporte activo” de la hormona contra el gradiente de concentración.

Pero si la membrana regula el paso de hormonas desde la sangre al tejido celular, y especialmente si son necesarias bombas para mover la hormona dentro de la célula, ¿cuán relevante es medir la cantidad de hormonas en sangre?

En la sangre, la progesterona y la hormona tiroides (T3) están mucho más concentradas en los glóbulos rojos que en el serum. Debido a que no es común que los glóbulos rojos sean “objetivos” de hormonas sexuales, o de progesterona o incluso tiroides, su concentración “contra su gradiente” en estas células sugiere que una simple distribución por solubilidad está implicada. Las sustancias grasas naturalmente tienden a concentrarse en el interior de las células por su insolubilidad en el entorno acuoso del plasma y fluido extracelular. Las proteínas que tienen regiones “aceitosas” efectivamente se acoplan sólo a moléculas aceitosas, como grasas y esteroides. Incluso los glóbulos rojos tienen tales proteínas.

En el caso de moléculas solubles en aceite, como la progesterona y el estrógeno, es importante para explicar que la mayoría de sus “uniones” a proteínas u otras moléculas amantes del aceite es realmente la casi pasiva consecuencia de moléculas siendo forzadas a alejarse de la etapa acuosa — son hidrofóbicas, y a pesar de que tomaría una gran cantidad de energía hacer que estas sustancias insolubles entraran en la etapa acuosa, la fuerza de atracción entre ellas y la célula es normalmente baja. Esto quiere decir que pueden ser libres de moverse, mientras estén “unidas” o concentradas dentro de la célula. Los átomos de oxígeno, y especialmente el grupo fenólico del estrógeno, ligeramente reducen la afinidad de las hormonas por aceites simples, pero interactúan con otros grupos polares o aromáticos, dando la habilidad al estrógeno para acoplarse más fuerte y específicamente con algunas proteínas y otras moléculas. Encimas que canalizan las acciones oxidación-reducción del estrógeno están entre las proteínas específicas de acople del estrógeno.

Muchas proteínas y lipoproteínas acoplan esteroides, pero algunas proteínas intracelulares se acoplan a estos tan fuerte que han sido —a manera muy teleológica, si no antropomórfica — considerada como el switch por el cuál la hormona enciende la respuesta celular. En la doctrina popular del Receptor de Estrógeno, unas pocas moléculas de estrógeno se acoplan a los receptores, que las transportan al núcleo de la célula, donde los receptores activados encienden los genes a cargo de la respuesta femenina. (O la respuesta masculina, o respuesta de crecimiento, o la respuesta de atrofia, o lo que sea de respuesta genética que el estrógeno esté produciendo.) Una vez que el switch ha sido pasado, las moléculas de estrógeno han cumplido su deber hormonal, y deben perderse, así que la respuesta no es perpetuada indefinidamente por unas pocas moléculas.

A pesar de que la doctrina del Receptor de Estrógeno es más que tonta, hay proteínas reales que se acoplan al estrógeno, y algunas de estas son llamadas receptores. El útero, seno, y cerebro, que son bastante sensibles al estrógeno, unen, o concentran, moléculas de estrógeno.

Cuando estaba trabajando en mi disertación, intenté extraer estrógenos del útero de un hamster, pero las técnicas químicas que usaba para medir estrógeno no eran precisas para tan pequeñas cantidades. Unos pocos años luego, S. Batra fue capaz de extraer el estrógeno del tejido humano en cantidades suficientemente grandes para un análisis preciso por radioinmunoensayo. (Batra, 1976.)

Su observación crucial fue que las diferencias en la concentración de estrógeno entre tejido y sangre era más baja en la fase luteal, cuando la progesterona era alta:

“La relación tejido/plasma para el E2 [estradiol] varió entre 1,45 a 20,36 con valores muy altos en la fase folicular temprana y los más bajos en la mitad de la fase luteal.” Esto quiere decir que la progesterona previene que el tejido concentre estrógeno. Hizo unas observaciones similares durante el embarazo, con el estrógeno en tejido disminuyendo a medida que la progesterona aumentaba, así habiendo menos estrógeno en tejido que en plasma. Pero las mujeres que no están embarazadas, y cuando su progesterona está baja, el tejido puede contener 20 a 30 veces más estrógeno que el plasma (en igual volumen).

Durante el envejecimiento, la marcada reducción de la producción de progesterona crea una situación que recrea la fase folicular del ciclo menstrual, permitiendo que los tejidos concentren estrógeno incluso cuando el estrógeno en serum podría estar bajo.

“En mujeres postmenopáusicas, la concentración en tejido del E2 no era significativamente más baja que en mujeres menstruando en fase folicular...” (Akerlund, et al., 1981.)

A pesar de las relativamente directas acciones de la progesterona en los receptores de estrógeno, mantener su concentración baja, y su acción inderecta previniendo que la prolactina estimule la formación de receptores estrogénicos, hay muchos otros procesos que pueden aumentar o disminuir la concentración en tejido del estrógeno, y muchas otras influencias cambian con la edad.

Hay dos tipos de enzimas que producen estrógeno. La aromatasa convierte hormonas masculinas a estrógenos. La beta-glucuronidasa convierte los inactivos glucuronidos de estrógeno en estrógeno activo. El hígado sano desactiva prácticamente todo el estrógeno que le alcanza, principalmente combinándolo con “ácido de azúcar”, ácido glucurónico. Esto hace que el estrógeno se torne soluble en agua, y es rápidamente eliminado a través de la orina. Pero cuando pasa a través de tejido infamado, estos tejidos contienen grandes cantidades de beta-glucuronidasa, que removerá el ácido glucurónico, dejando que el estrógeno puro se acumule en el tejido.

Muchos tipos de transtornos del hígado disminuyen su habilidad de excretar estrógeno, y este contribuye a una variedad de enfermedades del hígado. El trabajo de Biskinds en los años 40 mostró que la deficiencia protéica en la dieta impedía al hígado desintoxicar estrógeno. El hipotiroidismo impide que el hígado acople ácido glucurónico al estrógeno, así aumenta la retención del cuerpo de estrógeno, que a su vez altera la habilidad de la tiroides de segregar hormona tiroidea. El hipotiroidismo a menudo resutla de deficiencia nutricional de proteína.

A pesar de que comúnmente pensamos que los ovarios son la mayor fuente de estrógeno, la enzima que lo hace puede ser encontrada en todas las partes del cuerpo. Sorpresivamente en macacos Rhesus, la aromatasa en los brazos forma parte enorme de la producción de estrógeno. La grasa y la piel son las mayores fuentes de estrógeno, especialmente en gente anciana. La actividad de la aromatasa incrementa con la edad, y bajo la influencia de la prolactina, el cortisol, la prostaglandina, y las hormonas pituitarias, FSH (hormona folículo estimulante) y la hormona de crecimiento. Es inhibido por la progesterona, tiroides, aspirina y altitud elevada.

La aromatasa puede producir estrógeno en células grasas, fibroblastos, células de músculo liso, tejido mamario y uterino, páncreas, hígado, cerebro, hueso, piel, etc. Su acción en el cáncer de seno, endometriosis, cáncer uterino, lupus, ginecomastia, y muchas otras enfermedades es especialmente importante. La aromatasa en tejido mamario parece incrementar los receptores de estrógeno y causar neoplasia en el seno, independientemente del estrógeno ovárico (Tekmal, et al., 1999).

A mujeres le han sido retirados los ovarios y usualmente les dicen que necesitan tomar estrógeno, pero experimentos animales consistentemente muestran que remover las gónadas causa que la aromatasa en tejido aumente. La pérdida de progesterona y andrógenos del ovario es probablemente responsable del incremento generalizado en la formación de estrógeno. En el cerebro, la aromatasa aumenta bajo la influencia del tratamiento de estrógeno.

La sulfatasa es otra enzima que libera estrógeno en tejidos, y su actividad es inhibida por hormonas antiestrogénicas.

En al menos algunos tejidos, la progesterona inhibe la liberación o activación de la beta-glucuronidasa (que, de acuerdo a Cristofalo y Kabakjian, 1.975, aumenta con la edad). El ácido glucárico, que inhibe esta enzima, está siendo usado para tratar cáncer de seno, el ácido glucurónico también tiene a inhibir la liberación celular de estrógeno por la beta-glucuronidasa.

A pesar de que hay claramente una tendencia hacia el uso racional de tratamientos anti-estrogénicos para el cáncer de seno, en otras enfermedades el mito de la deficiencia de estrógeno sigue impidiendo incluso enfoques rudimentarios.

Desde el trabajo de Lipshutz en los 40, se ha establezido que el efecto ininterrumpido de un poco de estrógeno es más dañino que más grandes pero intermitentes exposiciones. Pero luego de la menopausia, cuando la progesterona comienza su desplazamiento cíclico por el estrógeno en tejidos, los tejidos retienne grandes cantidades de estrógeno continuamente.

La menopausia en sí misma es producida por la prolongada exposición al estrógeno en la pubertad, a pesar de la protección mensual de la progesterona producida cíclicamente por ovarios. La acción sin oposición de altas concentraciones de estrógeno acoplado a tejido luego de la menopausia debe ser aún más dañina.

El detrimento de los factores anti-estrogénicos en el envejecimiento, combinado con el aumento de factores pro-estrogénicos como el cortisol, la prolactina y FSH, ocurre tanto en hombres como mujeres. Durante los años reproductivos, la producción cíclica de grandes cantidades de progesterona probablemente retrasa su envejecimiento suficiente para contar por su más larga longevidad. La maternidad también tiene un residual efecto anti-estrogénico y está asociado con longevidad mayor.

Estar al tanto de este incremento generalizado en la exposición al estrógeno con el envejecimiento debe hacer posible dirigir una serie de métodos amplios para oponerse a las tendencias de la degeneración. 


REFERENCES 


Contraception 1981 Apr;23(4):447-55. Comparison of plasma and myometrial tissue concentrations of estradiol-17 beta and progesterone in nonpregnant women. Akerlund M, Batra S, Helm G Plasma and myometrial tissue concentrations of estradiol (E2) and progesterone (P) were measured by radioimmunoassay techniques in samples obtained from women with regular menstrual cycles and from women in pre- or postmenopausal age. In women with regular cycles, the tissue concentration of E2 ranged from 0.13 to 1.06 ng/g wet weight, with significantly higher levels around ovulation than in follicular or luteal phases of the cycle. The tissue concentration of P ranged from 2.06 to 14.85 ng/g wet weight with significantly higher level in luteal phase than in follicular phase. The tissue/plasma ratio of E2 ranged from 1.45 to 20.36 with very high values in early follicular phase and the lowest in mid-luteal phase. The ratio for P ranged from 0.54 to 23.7 and was significantly lower in the luteal phase than in other phases of the cycle. One woman in premenopausal age with an ovarian cyst was the only case with a tissue/plasma ratio of E2 Less Than 1, since her plasma E2 levels were exceptionally high. In postmenopausal women, the tissue concentration of E2 was not significantly lower than in menstruating women in follicular phase, and the tissue concentration of P was not significantly lower than in fertile women in any of the phases. Neither in these women nor in menstruating women was there a close correlation between tissue and plasma levels. The present data indicate that the myometrial uptake capacity for ovarian steroids may be saturated, and also that a certain amount of these steroids is bound to tissue even if plasma levels are low. 


Biokhimiia 1984 Aug;49(8):1350-6. [The nature of thyroid hormone receptors. Translocation of thyroid hormones through plasma membranes]. Azimova ShS, Umarova GD, Petrova OS, Tukhtaev KR, Abdukarimov A The in vivo translocation of thyroxine-binding blood serum prealbumin (TBPA) was studied. It was found that the TBPA-hormone complex penetrates-through the plasma membrane into the cytoplasm of target cells. Electron microscopic autoradiography revealed that blood serum TBPA is localized in ribosomes of target cells as well as in mitochondria, lipid droplets and Golgi complex. Negligible amounts of the translocated TBPA is localized in lysosomes of the cells insensitive to thyroid hormones (spleen macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm demonstrated that one of them has the antigenic determinants common with those of TBPA. It was shown autoimmunoradiographically that the structure of TBPA is not altered during its translocation. 


Biokhimiia 1985 Nov;50(11):1926-32. [The nature of thyroid hormone receptors. Intracellular functions of thyroxine-binding prealbumin] Azimova ShS; Normatov K; Umarova GD; Kalontarov AI; Makhmudova AA The effect of tyroxin-binding prealbumin (TBPA) of blood serum on the template activity of chromatin was studied. It was found that the values of binding constants of TBPA for T3 and T4 are 2 X 10(-11) M and 5 X 10(-10) M, respectively. The receptors isolated from 0.4 M KCl extract of chromatin and mitochondria as well as hormone-bound TBPA cause similar effects on the template activity of chromatin. Based on experimental results and the previously published comparative data on the structure of TBPA, nuclear, cytoplasmic and mitochondrial receptors of thyroid hormones as well as on translocation across the plasma membrane and intracellular transport of TBPA, a conclusion was drawn, which suggested that TBPA is the "core" of the true thyroid hormone receptor. It was shown that T3-bound TBPA caused histone H1-dependent conformational changes in chromatin. Based on the studies with the interaction of the TBPA-T3 complex with spin-labeled chromatin, a scheme of functioning of the thyroid hormone nuclear receptor was proposed. 


Biokhimiia 1984 Sep;49(9):1478-85[The nature of thyroid hormone receptors. Thyroxine- and triiodothyronine-binding proteins of mitochondria] Azimova ShS; Umarova GD; Petrova OS; Tukhtaev KR; Abdukarimov A. T4- and T3-binding proteins of rat liver were studied. It was found that the external mitochondrial membranes and matrix contain a protein whose electrophoretic mobility is similar to that of thyroxine-binding blood serum prealbumin (TBPA) and which binds either T4 or T3. This protein is precipitated by monospecific antibodies against TBPA. The internal mitochondrial membrane has two proteins able to bind thyroid hormones, one of which is localized in the cathode part of the gel and binds only T3, while the second one capable of binding T4 rather than T3 and possessing the electrophoretic mobility similar to that of TBPA. Radioimmunoprecipitation with monospecific antibodies against TBPA revealed that this protein also the antigenic determinants common with those of TBPA. The in vivo translocation of 125I-TBPA into submitochondrial fractions was studied. The analysis of densitograms of submitochondrial protein fraction showed that both TBPA and hormones are localized in the same protein fractions. Electron microscopic autoradiography demonstrated that 125I-TBPA enters the cytoplasm through the external membrane and is localized on the internal mitochondrial membrane and matrix. 


Biokhimiia 1984 Aug;49(8):1350-6. [The nature of thyroid hormone receptors. Translocation of thyroid hormones through plasma membranes] Azimova ShS; Umarova GD; Petrova OS; Tukhtaev KR; Abdukarimov A The in vivo translocation of thyroxine-binding blood serum prealbumin (TBPA) was studied. It was found that the TBPA-hormone complex penetrates-through the plasma membrane into the cytoplasm of target cells. Electron microscopic autoradiography revealed that blood serum TBPA is localized in ribosomes of target cells as well as in mitochondria, lipid droplets and Golgi complex. Negligible amounts of the translocated TBPA is localized in lysosomes of the cells insensitive to thyroid hormones (spleen macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm demonstrated that one of them has the antigenic determinants common with those of TBPA. It was shown autoimmunoradiographically that the structure of TBPA is not altered during its translocation. 


Probl Endokrinol (Mosk), 1981 Mar-Apr, 27:2, 48-52. [Blood estradiol level and G2-chalone content in the vaginal mucosa in rats of different ages] Anisimov VN; Okulov VB. “17 beta-Estradiol level was higher in the blood serum of rats aged 14 to 16 months with regular estral cycles during all the phases as compared to that in 3- to 4-month-old female rats. The latter ones had a higher vaginal mucosa G2-chalone concentration. The level of the vaginal mucosa G2-chalone decreased in young rats 12 hours after subcutaneous benzoate-estradiol injection. . . .”. “Possible role of age-associated disturbances of the regulatory cell proliferation stimulant (estrogen) and its inhibitor (chalone) interactions in neoplastic target tissue transformation is discussed.” 


Clin Endocrinol (Oxf) 1979 Dec;11(6):603-10. Interrelations between plasma and tissue concentrations of 17 beta-oestradiol and progesterone during human pregnancy. Batra S, Bengtsson LP, Sjoberg NO Oestradiol and progesterone concentration in plasma, decidua, myometrium and placenta obtained from women undergoing Caesarian section at term and abortion at weeks 16-22 of pregnancy were determined. There was a significant increase in oestradiol concentration (per g wet wt) both in placenta, decidua and myometrium from mid-term to term. Both at mid-term and term oestradiol concentrations in decidua and myometrium were much smaller than those in the plasma (per ml). Progesterone concentration in placenta and in myometrium did not increase from mid-term to term where it increased significantly in decidua. Decidual and myometrial progesterone concentrations at mid-term were 2-3 times higher than those in plasma, but at term the concentrations in both these tissues were lower than in plasma. The ratio progesterone/oestradiol in plasma, decidua, myometrium and placenta at mid-term was 8.7, 112.2, 61.4 and 370.0, respectively, and it decreased significantly in the myometrium and placenta but was nearly unchanged in plasma and decidua at term. The general conclusion to be drawn from the present study is the lack of correspondence between the plasma concentrations and the tissue concentrations of female sex steroids during pregnancy. 


Endocrinology 1976 Nov; 99(5): 1178-81. Unconjugated estradiol in the myometrium of pregnancy. Batra S. By chemically digesting myometrium in a mixture of NaOH and sodium dodecyl sulphate, estradiol could be recovered almost completely by extraction with ethyl acetate. The concentration of estradiol-17beta (E2) in the extracted samples could reliably be determined by radioimmunoassay. Compared to its concentration in the plasma, E2 in the pregnant human myometrium was very low, and as a result, the tissue/plasma estradiol concentration ratio was less than 0.5. In the pseudopregnant rabbit, this ratio ranged between 16 and 20. 


J Steroid Biochem 1989 Jan;32(1A):35-9. Tissue specific effects of progesterone on progesterone and estrogen receptors in the female urogenital tract. Batra S, Iosif CS. The effect of progesterone administration on progesterone and estrogen receptors in the uterus, vagina and urethra of rabbits was studied. After 24 h of progesterone treatment the concentration of cytosolic progesterone receptors decreased to about 25% of the control value in the uterus, whereas no significant change in receptor concentration was observed in the vagina or the urethra. The concentration of the nuclear progesterone receptor did not change in any of the three tissues studied. The apparent dissociation constant (Kd) of nuclear progesterone receptor increased after progesterone treatment in all three tissues. Although the Kd of the cytosolic progesterone receptor also increased in all tissues, the difference was significant for only the vagina and urethra. The concentration of cytosolic estrogen receptors in the uterus decreased significantly (P less than 0.001) after progesterone treatment whereas the Kd value increased slightly (P less than 0.05). In vagina or the urethra, there was no change in either estrogen receptor concentration or Kd values after progesterone treatment. These data clearly showed that the reduction by progesterone of progesterone and estrogen receptor concentrations occurs only in the uterus and not in the vagina or the urethra. 


Am J Obstet Gynecol 1980 Apr 15;136(8):986-91. Female sex steroid concentrations in the ampullary and isthmic regions of the human fallopian tube and their relationship to plasma concentrations during the menstrual cycle. Batra S, Helm G, Owman C, Sjoberg NO, Walles B. The concentrations of estradiol-17 beta (E2) and progesterone (P) were measured in the ampullary and isthmic portions of the fallopian tube of nonpregnant menstruating women and the cyclic fluctuations were related to the concentrations of these hormones in plasma. The steroid concentrations were determined by radioimmunoassays. There was no significant difference in the isthmic and ampullary concentrations of either steroid in any of the menstrual phases. The mean value for E2 was highest in the ovulatory phase and for P during the luteal phase. The tissue (per gm)/plasma (per ml) ratio for the steroid concentrations was above unity in all measurements. The ratio for E2 was highest (isthmus:12, ampulla:8) in the follicular phase and for P (isthmus:26, ampulla:18) during ovulation. Since these highest ratios were attained when plasma steroid concentrations were relatively low they were interpreted as reflections of a maximal receptor contribution. 


Biol Reprod 1980 Apr;22(3):430-7. Sex steroids in plasma and reproductive tissues of the female guinea pig. Batra S, Sjoberg NO, Thorbert G. 


J Steroid Biochem Mol Biol 1997 Apr;61(3-6):323-39. Steroid control and sexual differentiation of brain aromatase. Balthazart J. “Together, these data indicate that the removal of estrogens caused by steroidal inhibitors decreases the synthesis of ARO, presumably at the transcriptional level.” 


Science, Vol. 94, No. 2446 (Nov. 1941), p. 462. Diminution in Ability of the Liver to Inactivate Estrone in Vitamin B Complex Deficiency, Biskind, M.S., and G. R. Biskind. 


Am. Jour. Clin. Path., Vol. 16 (1946), No. 12, pages 737-45. The Nutritional Aspects of Certain Endocrine Disturbances, Biskind, G. R., and M. S. Biskind. 


Biol Reprod, 1993 Oct, 49:4, 647-52. Pathologic effect of estradiol on the hypothalamus. Brawer JR; Beaudet A; Desjardins GC; Schipper HM. Estradiol provides physiological signals to the brain throughout life that are indispensable for the development and regulation of reproductive function. In addition to its multiple physiological actions, we have shown that estradiol is also selectively cytotoxic to beta-endorphin neurons in the hypothalamic arcuate nucleus. The mechanism underlying this neurotoxic action appears to involve the conversion of estradiol to catechol estrogen and subsequent oxidation to o-semiquinone free radicals. The estradiol-induced loss of beta-endorphin neurons engenders a compensatory increment in mu opioid binding in the medial preoptic area rendering this region supersensitive to residual beta-endorphin or to other endogenous opioids. The consequent persistent opioid inhibition results in a cascade of neuroendocrine deficits that are ultimately expressed as a chronically attenuated plasma LH pattern to which the ovaries respond by becoming anovulatory and polycystic. This neurotoxic action of estradiol may contribute to a number of reproductive disorders in humans and in animals in which aberrant hypothalamic function is a major component. 


Mech Ageing Dev, 1991 May, 58:2-3, 207-20. Exposure to estradiol impairs luteinizing hormone function during aging. Collins TJ; Parkening TA Department of Anatomy and Neurosciences, University of Texas Medical Branch, Galveston 77550. “This work evaluated the anterior pituitary (AP) component of the H-P axis by determining the ability of perifused AP to release LH following sustained but pulsatile LHRH stimulation. The normal dual discharge profile of LH was affected by age.” “The role of estradiol (E2) in AP aging was further tested as AP from ovariectomized (OVXed) mice, deprived of E2 since puberty, responded as well as the mature proestrous group. In contrast, aged mice subjected to long-term E2 exposure (cycling or OVXed plus E2 replacement) failed to produce the dual response pattern.” “Furthermore, E2 is a major factor in altering LH function and appears to act before middle age.” 


Mech Ageing Dev 1975 Jan-Feb;4(1):19-28. Lysosomal enzymes and aging in vitro: subcellular enzyme distribution and effect of hydrocortisone on cell life-span. Cristofalo VJ, Kabakjian J. “The acid phosphatase and beta glucuronidase activities of four subcellular fractions (nuclear, mitochondrial-lysosomal, microsomal, supernatant) of WI-38 cells were compared during in vitro aging. All of the fractions showed an age-associated increase in activity.” 


Endocrinology, 1992 Nov, 131:5, 2482-4. Vitamin E protects hypothalamic beta-endorphin neurons from estradiol neurotoxicity. Desjardins GC; Beaudet A; Schipper HM; Brawer JR. Estradiol valerate (EV) treatment has been shown to result in the destruction of 60% of beta-endorphin neurons in the hypothalamic arcuate nucleus. Evidence suggests that the mechanism of EV-induced neurotoxicity involves the conversion of estradiol to catechol estrogen and subsequent oxidation to free radicals in local peroxidase-positive astrocytes. In this study, we examined whether treatment with the antioxidant, vitamin E, protects beta-endorphin neurons from the neurotoxic action of estradiol. Our results demonstrate that chronic vitamin E treatment prevents the decrement in hypothalamic beta-endorphin concentrations resulting from arcuate beta-endorphin cell loss, suggesting that the latter is mediated by free radicals. Vitamin E treatment also prevented the onset of persistent vaginal cornification and polycystic ovarian condition which have been shown to result from the EV-induced hypothalamic pathology. 


Exp Gerontol, 1995 May-Aug, 30:3-4, 253-67. Estrogen-induced hypothalamic beta-endorphin neuron loss: a possible model of hypothalamic aging. Desjardins GC; Beaudet A; Meaney MJ; Brawer JR. Over the course of normal aging, all female mammals with regular cycles display an irreversible arrest of cyclicity at mid-life. Males, in contrast, exhibit gametogenesis until death. Although it is widely accepted that exposure to estradiol throughout life contributes to reproductive aging, a unified hypothesis of the role of estradiol in reproductive senescence has yet to emerge. Recent evidence derived from a rodent model of chronic estradiol-mediated accelerated reproductive senescence now suggests such a hypothesis. It has been shown that chronic estradiol exposure results in the destruction of greater than 60% of all beta-endorphin neurons in the arcuate nucleus while leaving other neuronal populations spared. This loss of opioid neurons is prevented by treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals. Furthermore, we have shown that this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the vicinity of LHRH cell bodies. The increment in mu opioid receptors presumably renders the opioid target cells supersensitive to either residual beta-endorphin or other endogenous mu ligands, such as met-enkephalin, thus resulting in chronic opioid suppression of the pattern of LHRH release, and subsequently that of LH. Indeed, prevention of the neuroendocrine effects of estradiol by antioxidant treatment also prevents the cascade of neuroendocrine aberrations resulting in anovulatory acyclicity. The loss of beta-endorphin neurons along with the paradoxical opioid supersensitivity which ensues, provides a unifying framework in which to interpret the diverse features that characterize the reproductively senescent female. 


Geburtshilfe Frauenheilkd 1994 Jun; 54(6):321-31. Hormonprofile bei hochbetagten Frauen und potentielle Einflussfaktoren. Eggert-Kruse W; Kruse W; Rohr G; Muller S; Kreissler-Haag D; Klinga K; Runnebaum B. [Hormone profile of elderly women and potential modifiers]. Eggert-Kruse W, Kruse W, Rohr G, Muller S, Kreissler-Haag D, Klinga K, Runnebaum B. “In 136 women with a median age of 78 (60-98) years the serum concentrations of FSH, LH, prolactin, estradiol-17 beta, testosterone and DHEA-S were determined completed by GnRH and ACTH stimulation tests in a subgroup. This resulted in median values for FSH of 15.8 ng/ml, LH 6.4 ng/ml, prolactin 6.9 ng/ml, estradiol 16 pg/ml, testosterone 270 pg/ml and 306 ng/ml for DHEA-S. No correlation with age in this population was found for gonadotropins as well as the other hormones for an age level of up to 98 years.” 


Acta Physiol Hung 1985;65(4):473-8. Peripheral blood concentrations of progesterone and oestradiol during human pregnancy and delivery. Kauppila A, Jarvinen PA To evaluate the significance of progesterone and estradiol in human uterine activity during pregnancy and delivery the blood concentrations of these hormones were monitored weekly during the last trimester of pregnancy and at the onset of labour in 15 women, and before and 3 hours after the induction of term delivery in 83 parturients. Neither plasma concentrations of progesterone or estradiol nor the ratio of progesterone to estradiol changed significantly during the last trimester of pregnancy or at the onset of delivery. After the induction of delivery parturients with initial progesterone dominance (ratio of progesterone to estradiol higher than 5 before induction) demonstrated a significant fall in serum concentration of progesterone and in the ratio of progesterone to estradiol while estradiol concentration rose significantly. In estrogen dominant women (progesterone to estradiol ratio equal to or lower than 5) the serum concentration of progesterone and the ratio of progesterone to estradiol rose significantly during the 3 hours after the induction of delivery. Our results suggest that the peripheral blood levels of progesterone and estradiol do not correlate with the tissue biochemical changes which prepare the uterine cervix and myometrium for delivery. The observation that the ratio of progesterone to estradiol decreased in progesterone-dominant and increased in estrogen-dominant women stresses the importance of a well balanced equilibrium of these hormones for prostaglandin metabolism during human delivery. 


Am J Obstet Gynecol 1984 Nov 1;150(5 Pt 1):501-5. Estrogen and progesterone receptor and hormone levels in human myometrium and placenta in term pregnancy. Khan-Dawood FS, Dawood MY. Estradiol and progesterone receptors in the myometrium, decidua, placenta, chorion, and amnion of eight women who underwent elective cesarean section at term were determined by means of an exchange assay. The hormone levels in the peripheral plasma and cytosol of these tissues were measured by radioimmunoassays. Maternal plasma and the placenta had high concentrations of estradiol and progesterone, with the placenta having 12 times more progesterone than in maternal plasma but only half the concentrations of estradiol in maternal plasma. The decidua and placenta had detectable levels of cytosol and nuclear estradiol receptors, but the myometrium had no measurable cytosol estradiol receptors, whereas the chorion and amnion had neither cytosol nor nuclear estradiol receptors. However, the chorion and amnion had significantly higher concentrations of estradiol in the cytosol than those in the decidua and myometrium. Only the decidua and myometrium had cytosol and nuclear progesterone receptors, but the placenta, amnion, and chorion had neither cytosol nor nuclear progesterone receptors. In contrast, progesterone hormone levels were significantly higher in the placenta, amnion, and chorion than in the decidua and myometrium. The findings indicate that, in the term pregnant uterus, (1) the placenta, amnion, and chorion are rich in progesterone, estradiol, and nuclear estradiol receptors but have no progesterone receptors, (2) the decidua and myometrium have nuclear estradiol and progesterone receptors, and (3) the myometrium has a higher progesterone/estradiol ratio than that of the peripheral plasma, thus suggesting a highly progesterone-dominated uterus. 


Biochem Biophys Res Commun 1982 Jan 29;104(2):570-6. Progesterone-induced inactivation of nuclear estrogen receptor in the hamster uterus is mediated by acid phosphatase. MacDonald RG, Okulicz WC, Leavitt, W.W. 


Steroids 1982 Oct;40(4):465-73. Progesterone-induced estrogen receptor-regulatory factor is not 17 beta-hydroxysteroid dehydrogenase. MacDonald RG, Gianferrari EA, Leavitt WW These studies were done to determine if the progesterone-induced estrogen receptor-regulatory factor (ReRF) in hamster uterus is 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), i.e. that rapid loss of nuclear estrogen receptor (Re) might be due to enhanced estradiol oxidation to estrone catalyzed by 17 beta-HSD. Treatment of proestrous hamsters with progesterone (approximately 25 mg/kg BW) for either 2 h or 4 h had no effect on 17 beta-HSD activity measured as the rate of conversion of [6,7-3H]estradiol to [3H]estrone by whole uterine homogenates at 35 degrees C. During this same time interval, progesterone treatment increased the rate of inactivation of the occupied form of nuclear Re as determined during a 30 min incubation of uterine nuclear extract in vitro at 36 degrees C. Since we previously demonstrated that such in vitro Re-inactivating activity represents ReRF, the present studies show that ReRF is not 17 beta-HSD or a modifier of that enzyme. 


Am J Obstet Gynecol 1987 Aug; 157(2):312-317. Age-related changes in the female hormonal environment during reproductive life. Musey VC, Collins DC, Musey PI, Martino-Saltzman D, Preedy JR Previous studies have indicated that serum levels of follicle-stimulating hormone rise with age during the female reproductive life, but the effect on other hormones is not clear. We studied the effects of age, independent of pregnancy, by comparing serum hormone levels in two groups of nulliparous, premenopausal women aged 18 to 23 and 29 to 40 years. We found that increased age during reproductive life is accompanied by a significant rise in both basal and stimulated serum follicle-stimulating hormone levels. This was accompanied by an increase in the serum level of estradiol-17 beta and the urine levels of estradiol-17 beta and 17 beta-estradiol-17-glucosiduronate. The serum level of estrone sulfate decreased with age. Serum and urine levels of other estrogens were unchanged. The basal and stimulated levels of luteinizing hormone were also unchanged. There was a significant decrease in basal and stimulated serum prolactin levels. Serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate decreased with age, but serum testosterone was unchanged. It is concluded that significant age-related changes in the female hormonal environment occur during the reproductive years. 


Endocrinology 1981 Dec;109(6):2273-5. Progesterone-induced estrogen receptor-regulatory factor in hamster uterine nuclei: preliminary characterization in a cell-free system. Okulicz WC, MacDonald RG, Leavitt WW. “In vitro studies have demonstrated a progesterone-induced activity associated with the uterine nuclear fraction which resulted in the loss of nuclear estrogen receptor.” “This progesterone-dependent stimulation of estrogen receptor loss was absent when nuclear extract was prepared in phosphate buffer rather than Tris buffer. In addition, sodium molybdate and sodium metavanadate (both at 10 mM) inhibited this activity in nuclear extract. These observations support the hypothesis that progesterone modulation of estrogen action may be accomplished by induction (or activation) of an estrogen receptor-regulatory factor (Re-RF), and this factor may in turn act to eliminate the occupied form of estrogen receptor from the nucleus, perhaps through a hypothetical dephosphorylation-inactivation mechanism.” 


American Journal of Human Biology, v.8, n.6, (1996): 751-759. Ovarian function in the latter half of the reproductive lifespan. O'Rourke, M T; Lipson, S F; Ellison, P T. “Thus, ovarian endocrine function over the course of reproductive life represents a process of change, but not one of generalized functional decline.” 


J Gerontol, 1978 Mar, 33:2, 191-6. Circulating plasma levels of pregnenolone, progesterone, estrogen, luteinizing hormone, and follicle stimulating hormone in young and aged C57BL/6 mice during various stages of pregnancy. Parkening TA; Lau IF; Saksena SK; Chang MC Young (3-5 mo of age) and senescent (12-15 mo of age) multiparous C57BL/6 mice were mated with young males (3-6 mo of age) and the numbers of preimplantation embryos and implantation sites determined on days 1 (day of plug), 4, 9, and 16 of pregnancy. The numbers of viable embryos were significantly lower (p less than 0.02 to p less than 0.001) in senescent females compared with young females on all days except day 1 of pregnancy. Plasma samples tested by radioimmunoassay indicated circulating estradiol-17B was significantly lower (P less than 0.05) on day 1 and higher (p less than 0.05) on day 4 in older females, whereas FSH was higher on days 4, 9, and 16 (p less than 0.02 to p less than 0.001) in senescent females when compared with samples from young females. Levels of pregnenolone, progesterone, estrone, and LH were not significantly different at any stage of pregnancy in the two age groups. From the hormonal data it did not appear that degenerating corpora lutea were responsible for the declining litter size in this strain of aged mouse. 


Biol Reprod, 1985 Jun, 32:5, 989-97. Orthotopic ovarian transplantations in young and aged C57BL/6J mice. Parkening TA; Collins TJ; Elder FF. “Orthotopic ovarian transplantations were done between young (6-wk-old) and aged (17-mo-old) C57BL/6J mice. The percentages of mice mating following surgery from the four possible ovarian transfer combinations were as follows: young into young, 83%; young into aged, 46%; aged into young, 83%; and aged into aged, 36%.” “The only statistical differences found between the transfer groups occurred in FSH concentrations. Plasma FSH was markedly elevated (P less than 0.005) in young recipients with ovaries transplanted from aged donors, in comparison to young recipients with ovaries from young donors. These data indicate that the aging ovary and uterus play a secondary role in reproductive failure and that the aging hypothalamic-hypophyseal complex is primarily responsible for the loss of fecundity in older female C57BL/6J mice.” 


J Endocrinol, 1978 Jul, 78:1, 147-8. Postovulatory levels of progestogens, oestrogens, luteinizing hormone and follicle-stimulating hormone in the plasma of aged golden hamsters exhibiting a delay in fertilization. Parkening TA; Saksena SK; Lau IF. 


Biology of Reproduction, v.49, n.2, (1993): 387-392. Controlled neonatal exposure to estrogens: A suitable tool for reproductive aging studies in the female rat. Rodriguez, P; Fernandez-Galaz, C; Tejero, A. “The present study was designed to determine whether the modification of exposure time to large doses of estrogens provided a reliable model for early changes in reproductive aging.” “Premature occurrence of vaginal opening was observed in all three estrogenized groups independently of EB exposure. However, females bearing implants for 24 h had first estrus at the same age as their controls and cycled regularly, and neither histological nor gonadal alterations could be observed at 75 days. Interestingly, they failed to cycle regularly at 5 mo whereas controls continued to cycle.” “On the other hand, the increase of EB exposure (Ei5, EI) resulted in a gradual and significant delay in the onset of first estrus and in a high number of estrous phases, as frequently observed during reproductive decline. At 75 days, the ovaries of these last two groups showed a reduced number of corpora lutea and an increased number of large follicles. According to this histological pattern, ovarian weight and progesterone (P) content gradually decreased whereas both groups showed higher estradiol (E-2) content than controls. This resulted in a higher E-2:P ratio, comparable to that observed in normal aging rats. The results allow us to conclude that the exposure time to large doses of estrogens is critical to the gradual enhancement of reproductive decline. Furthermore, exposures as brief as 24 h led to a potential early model for aging studies that will be useful to verify whether neuroendocrine changes precede gonadal impairment.” 


J Clin Endocrinol Metab 1996 Apr;81(4):1495-501. Characterization of reproductive hormonal dynamics in the perimenopause. Santoro N, Brown JR, Adel T, Skurnick JH. “Overall mean estrone conjugate excretion was greater in the perimenopausal women compared to that in the younger women [76.9 ng/mg Cr (range, 13.1-135) vs. 40.7 ng/mg Cr (range, 22.8-60.3); P = 0.023] and was similarly elevated in both follicular and luteal phases. Luteal phase pregnanediol excretion was diminished in the perimenopausal women compared to that in younger normal subjects (range for integrated pregnanediol, 1.0-8.4 vs. 1.6-12.7 microg/mg Cr/luteal phase; P = 0.015).” “We conclude that altered ovarian function in the perimenopause can be observed as early as age 43 yr and include hyperestrogenism, hypergonadotropism, and decreased luteal phase progesterone excretion. These hormonal alterations may well be responsible for the increased gynecological morbidity that characterizes this period of life.” 


Brain Res, 1994 Jul 25, 652:1, 161-3. The 21-aminosteroid antioxidant, U74389F, prevents estradiol-induced depletion of hypothalamic beta-endorphin in adult female rats. Schipper HM; Desjardins GC; Beaudet A; Brawer JR. “A single intramuscular injection of 2 mg estradiol valerate (EV) results in neuronal degeneration and beta-endorphin depletion in the hypothalamic arcuate nucleus of adult female rats.” “The present findings support the hypothesis that the toxic effect of estradiol on hypothalamic beta-endorphin neurons is mediated by free radicals.” 


Clin Exp Obstet Gynecol 2000;27(1):54-6. Hormonal reproductive status of women at menopausal transition compared to that observed in a group of midreproductive-aged women. Sengos C, Iatrakis G, Andreakos C, Xygakis A, Papapetrou P. CONCLUSION: The reproductive hormonal patterns in perimenopausal women favor a relatively hypergonadotropic hyper-estrogenic milieu. 


Endocr Relat Cancer 1999 Jun;6(2):307-14. Aromatase overexpression and breast hyperplasia, an in vivo model--continued overexpression of aromatase is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate these preneoplastic changes in mammary glands. Tekmal RR, Kirma N, Gill K, Fowler K “To test directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the aromatase-transgenic mouse model and demonstrated for the first time that increased mammary estrogens resulting from the overexpression of aromatase in mammary glands lead to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer.” “Our current studies show aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes in female mice without circulating ovarian estrogen. Preneoplastic and neoplastic changes induced in mammary glands as a result of aromatase overexpression can be completely abrogated with the administration of the aromatase inhibitor, letrozole. Consistent with complete reduction in hyperplasia, we have also seen downregulation of estrogen receptor and a decrease in cell proliferation markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies demonstrate that aromatase overexpression alone, without circulating estrogen, is responsible for the induction of breast hyperplasia and these changes can be abrogated using aromatase inhibitors.” 


J Steroid Biochem Mol Biol 2000 Jun;73(3-4):141-5. Elevated steroid sulfatase expression in breast cancers. Utsumi T, Yoshimura N, Takeuchi S, Maruta M, Maeda K, Harada N. In situ estrogen synthesis makes an important contribution to the high estrogen concentration found in breast cancer tissues. Steroid sulfatase which hydrolyzes several sulfated steroids such as estrone sulfate, dehydroepiandrosterone sulfate, and cholesterol sulfate may be involved. In the present study, we therefore, assessed steroid sulfatase mRNA levels in breast malignancies and background tissues from 38 patients by reverse transcription and polymerase chain reaction. The levels in breast cancer tissues were significantly increased at 1458.4+/-2119.7 attomoles/mg RNA (mean +/- SD) as compared with 535.6+/-663.4 attomoles/mg RNA for non-malignant tissues (P<0.001). Thus, increased steroid sulfatase expression may be partly responsible for local overproduction of estrogen and provide a growth advantage for tumor cells. 


Ann N Y Acad Sci 1986;464:106-16. Uptake and concentration of steroid hormones in mammary tissues. Thijssen JH, van Landeghem AA, Poortman J In order to exert their biological effects, steroid hormones must enter the cells of target tissues and after binding to specific receptor molecules must remain for a prolonged period of time in the nucleus. Therefore the endogenous levels and the subcellular distribution of estradiol, estrone, DHEAS, DHEA ad 5-Adiol were measured in normal breast tissues and in malignant and nonmalignant breast tumors from pre- and postmenopausal women. For estradiol the highest tissue levels were found in the malignant samples. No differences were seen in these levels between pre- and postmenopausal women despite the largely different peripheral blood levels. For estrone no differences were found between the tissues studied. Although the estradiol concentration was higher in the estradiol-receptor-positive than in the receptor-negative tumors, no correlation was calculated between the estradiol and the receptor consent. Striking differences were seen between the breast and uterine tissues for the total tissue concentration of estradiol, the ratio between estradiol and estrone, and the subcellular distribution of both estrogens. At similar receptor concentrations in the tissues these differences cannot easily be explained. Regarding the androgens, the tissue/plasma gradient was higher for DHEA than for 5-Adiol, and for DHEAS there was very probably a much lower tissue gradient. The highly significant correlation between the androgens suggests an intracellular metabolism of DHEAS to DHEA and 5-Adiol. Lower concentrations of DHEAS and DHEA were observed in the malignant tissues compared with the normal ones and the benign lesions. For 5-Adiol no differences were found and therefore these data do not support our original hypothesis on the role of this androgen in the etiology of breast abnormalities. Hence the way in which adrenal androgens express their influence on the breast cells remains unclear. 


Clin Endocrinol (Oxf) 1978 Jul;9(1):59-66. Sex hormone concentrations in post-menopausal women. Vermeulen A, Verdonck L. “Plasma sex hormone concentrations (testosterone, (T), androstenedione (A), oestrone (E1) and oestradiol (E2) were measured in forty post-menopausal women more than 4 years post-normal menopause.” “Sex hormone concentrations in this group of postmenopausal women (greater than 4YPM) did not show any variation as a function of age, with the possible exception of E2 which showed a tendency to decrease in the late post-menopause. E1 and to a lesser extent E2 as well as the E1/A ratio were significantly corelated with degree of obesity or fat mass, suggesting a possible role of fat tissue in the aromatization of androgens. Neither the T/A nor the E2/E1 ratios were correlated with fat mass, suggesting that the reduction of 17 oxo-group does not occur in fat tissue. The E1/A ratio was significantly higher than the reported conversion rate of A in E1.” 


J Steroid Biochem 1984 Nov;21(5):607-12. The endogenous concentration of estradiol and estrone in normal human postmenopausal endometrium. Vermeulen-Meiners C, Jaszmann LJ, Haspels AA, Poortman J, Thijssen JH The endogenous estrone (E1) and estradiol (E2) levels (pg/g tissue) were measured in 54 postmenopausal, atrophic endometria and compared with the E1 and E2 levels in plasma (pg/ml). The results from the tissue levels of both steroids showed large variations and there was no significant correlation with their plasma levels. The mean E2 concentration in tissue was 420 pg/g, 50 times higher than in plasma and the E1 concentration of 270 pg/g was 9 times higher. The E2/E1 ratio in tissue of 1.6, was higher than the corresponding E2/E1 ratio in plasma, being 0.3. We conclude that normal postmenopausal atrophic endometria contain relatively high concentrations of estradiol and somewhat lower estrone levels. These tissue levels do not lead to histological effects. 


J Clin Endocrinol Metab 1998 Dec; 83(12):4474-80. Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol. Zeitoun K, Takayama K, Sasano H, Suzuki T, Moghrabi N, Andersson S, Johns A, Meng L, Putman M, Carr B, Bulun SE. “Aberrant aromatase expression in stromal cells of endometriosis gives rise to conversion of circulating androstenedione to estrone in this tissue, whereas aromatase expression is absent in the eutopic endometrium. In this study, we initially demonstrated by Northern blotting transcripts of the reductive 17beta-hydroxysteroid dehydrogenase (17betaHSD) type 1, which catalyzes the conversion of estrone to 17beta-estradiol, in both eutopic endometrium and endometriosis. Thus, it follows that the product of the aromatase reaction, namely estrone, that is weakly estrogenic can be converted to the potent estrogen, 17beta-estradiol, in endometriotic tissues. It was previously demonstrated that progesterone stimulates the inactivation of 17beta-estradiol through conversion to estrone in eutopic endometrial epithelial cells.” “In conclusion, inactivation of 17beta-estradiol is impaired in endometriotic tissues due to deficient expression of 17betaHSD-2, which is normally expressed in eutopic endometrium in response to progesterone.” 


Biochem Biophys Res Commun 1999 Aug 2;261(2):499-503. Piceatannol, a stilbene phytochemical, inhibits mitochondrial F0F1-ATPase activity by targeting the F1 complex. Zheng J, Ramirez VD. 


Eur J Pharmacol 1999 Feb 26;368(1):95-102. Rapid inhibition of rat brain mitochondrial proton F0F1-ATPase activity by estrogens: comparison with Na+, K+ -ATPase of porcine cortex. Zheng J, Ramirez VD. “The data indicate that the ubiquitous mitochondrial F0F1-ATPase is a specific target site for estradiol and related estrogenic compounds; however, under this in vitro condition, the effect seems to require pharmacological concentrations.” 


J Steroid Biochem Mol Biol 1999 Jan;68(1-2):65-75. Purification and identification of an estrogen binding protein from rat brain: oligomycin sensitivity-conferring protein (OSCP), a subunit of mitochondrial F0F1-ATP synthase/ATPase. Zheng J, Ramirez VD. “This finding opens up the possibility that estradiol, and probably other compounds with similar structures, in addition to their classical genomic mechanism, may interact with ATP synthase/ATPase by binding to OSCP, and thereby modulating cellular energy metabolism.”

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