ABSTRACT
It has been proposed that gonadal hormones participate in regulation of mood and emotion in men as well as in the effect of psychoactive drugs, such as antidepressants. However, evaluation of this type of interactions has been poorly studied in clinic and basic studies. The objective of the present study was to determine the role of gonadal hormones, testosterone (T) and 17β-estradiol (E2), one of its main metabolites, in the effect of two antidepressant drugs: desipramine and fluoxetine. The former is a tricyclic antidepressant that inhibits noradrenaline reuptake in a preferential manner, while the second is a serotonin selective reup-take inhibitor (SSRI) and the most prescribed antidepressant. Behavioral evaluations were conducted in adult male rats, intact or orchidectomized (Orx), treated with T (0-2 mg/rata), E2 (0-40 µg/rata), desipramine (0-20 mg/kg), fluoxetine (0-20 mg/kg) and their combinations. Forced swimming test was used as an animal model to detect antidepressant-like effect induced by treatments, on the basis of its predictive validity. We found that desipramine and fluoxetine produced an anti-depressant-like effect in gonadally intact male rats. However, the antidepressant-like effect of both treatments was cancelled in Orx males. Treatment with E2, but not with T, produced antidepressant-like actions in Orx males. Interestingly, treatment with E2 restored the antidepressant-like effect of desipramine and fluoxetine, while supplementation with T only reestablished the antidepressant-like action of desipramine, evidencing that gonadal hormones have a differential participation in regulation of neurotransmitter systems involving in the antidepressant effect. In conclusion, the main testicular androgen T, participates in the expression of the effect of antidepressant drugs, mainly via conversion to its estrogenic metabolite E2. These results give support to the idea that a combined therapy of gonadal hormones and antidepressant drugs may be more convenient to treat depressive disorders in hypogonadal men resistant to conventional antidepressant drugs.
Se ha propuesto que las hormonas gonadales participan en la regulación del estado de ánimo en los varones, y en el efecto de los fármacos psicoactivos, tales como los antidepresivos. Sin embargo, la evaluación de este tipo de interacciones ha sido estudiada escasamente. El objetivo del presente trabajo fue determinar el papel que cumplen las hormonas testosterona (T) y 17β-estradiol (E2), uno de sus principales metabolitos, en el efecto de dos fármacos antidepresivos utilizados en la práctica clínica, desipramina y fluoxetina. El primero es un tricíclico con acciones sobre el sistema noradrenérgico, mientras que la fluoxetina es un inhibidor selectivo de la recaptura de serotonina. Las evaluaciones se llevaron a cabo utilizando ratas macho adultas jóvenes, gonadalmente intactas u orquidectomizadas (Orx), bajo tratamiento con T (0-1 mg/rata), E2 (0-40 µg/rata), desipramina (0-20 mg/kg), fluoxetina (0-20 mg/kg) y sus respectivas combinaciones. Se utilizó la prueba de nado forzado (PNF) para detectar las acciones antidepresivas de los tratamientos. Encontramos que desipramina y fluoxetina redujeron la conducta de depresión en los machos gonadalmente intactos; sin embargo, el efecto de ambos tratamientos fue abolido por la orquidectomía. El tratamiento de restitución hormonal con E2, pero no con T, indujo acciones antidepresivas en los machos Orx. A su vez, cuando los animales Orx recibieron la restitución con T se produjo la recuperación del efecto antidepresivo de la desipramina, mientras que el E2 restableció las acciones antidepresivas de ambos fármacos. En conclusión, el principal andrógeno de origen testicular, la T, participa en la expresión del efecto de los fármacos antidepresivos explorados en el presente estudio, principalmente a través de su metabolito estrogénico, el E2. Estos resultados apoyan la idea de que una terapia adjunta de tratamientos hormonales y antidepresivos sería de beneficio para varones hipogonadales que cursen con depresión resistente a los fármacos antidepresivos convencionales.
ABSTRACT
Depression is an affective disorder that is more frequent in women than men. The etiology of depression disorders is multi-factorial, since social and biological influences have been determined. Coincidence between periods with hormonal fluctuations and affective alterations has lead to a hypothesis that considers fluctuations in gonadal hormones as a possible cause of depression in women. In this respect, pre-clinical studies by using laboratory animals (rodents) point toward a stronger relationship between hormonal oscillations and depressive behavior in different models designed to evaluate the antidepressant effect of drugs. This evidence could be interesting since in pre-clinical studies social factors are not included. Specifically, several authors have reported that depressive behavior is more prevalent in stages of rats' life characterized by low concentrations of gonadal hormones, such as postpartum, diestrous phase, lactancy and after ovariectomy. In contrast, a major presence of depressive behavior is observed in phases with higher concentration of hormones, like proestrus (a phase coincident with ovulation), pregnancy and after hormonal restitution with estrogens and progestins. Interestingly, the development of depressive behavior after ovari-ectomy has been established in female mice, with a critical period 12 weeks after ovaries extirpation. The participation of specific hormones in female depression could be studied in lab animals, since rodent female progress from a reproductive to a non-reproductive phase with vaginal and endocrine changes. Young females have a 4-5 days cycle named estrous cycle, in which each vaginal phase is associated with different concentrations of gonadal hormones. Although rodents do not exhibit menses, a state similar to peri- and post-menopause could be identified. Aging females exhibit irregular cycles before progressing to an estrous constant phase with elevated levels of estrogens. Decline of estrogen levels produces a persistent diestrous phase considered as a post-menopausal state. Aging rats in persistent diestrous, as well as ovari-ectomized females (the most economic model of post-menopause in lab animals) show physiological and behavioral changes associated to hormonal deprivation. Thus, they are considered a good model to evaluate affective and cognitive alterations as well as potential hormonal substitutive treatments. Clinical and epidemiologic studies report that perimenopause is linked to an increased risk of developing depression in women, or with the presence of more intense symptoms of depression. In agreement with Stages of Reproductive Aging Workshop (STRAW), perimenopause includes the period named transition to menopause plus one year after the last menses. This period is characterized by irregular menstrual cycles and fluctuations in levels of estrogens. In this stage, the levels of follicle-stimulating hormone (FSH) are elevated in order to further stimulate the production of estrogens from ovaries. Finally, concentrations of estrogens are significantly reduced in late perimenopause, although the levels of FSH continue to be increased. Fluctuations of estrogens and FSH have been related to symptoms such as affective alterations, hot flushes and insomnia, while hormonal deprivation in post-menopause is linked to changes in body fat, fatigue, cognitive disorders and reduction in bone density. Variations in estrogens and FSH level have been consistently related to depression symptoms in perimenopausal women, while changes in progestins and testosterone are associated with dysphoric mood and aggression, respectively. Thus, in agreement with the main hormonal hypothesis, a substitutive therapy with estrogens as an antidepressant therapy in peri- and post-menopausal women has been implemented. The results of different clinical studies are contradictory possibly due to methodological differences as the type of hormone used as an antidepressant therapy, dosage, time of administration of treatments and the period of hormonal deprivation in women. In a consistent manner, basic studies support the idea that steroi-dal gonadal hormones have antidepressant properties, but these seem to depend on both specific features of hormonal treatments and endocrine conditions in females. It has been reported that 17β-estradiol (E2), ethinyl-estradiol (EE2) and estradiol benzoate produce antidepres-sant-like actions in ovariectomized young females. Pharmacological studies have demonstrated that the serotonergic system has a major participation in the antidepressant-like effect of E2, revealing its potential as a treatment for depressed women. In the same sense, estrogens that bind to estrogen receptors β (ERβ) are more effective to produce antidepressant- and anxiolytic-like effects than estrogens with higher affinity at ERa This evidence leads to consider ERβ as an important pharmacological target in depression. Studies evaluating estrogens in depression have determined that dosage is an important issue in the production of antidepressant-like effects. Dosage of estrogens that attain a physiological range have been reported to have more antidepressant efficacy in respect to lower or higher dose provoking infra- or supra-physiological levels of estradiol. In fact, a U-shape in the antidepressant effect of E2 has been detected. Finally, timing of hormonal therapy seems to be a more relevant factor at moment to attain an antidepressant effect with estrogen treatment. Old rats (14 months) that received a prolonged estrogen treatment immediately after ovariectomy showed an antidepressant-like response which was not observed when treatment was began five months after ovaries extirpation. ERs are dependent on endogenous estrogens levels which suggest that a reduction in the target site of E2 may be linked to its reduced antidepressant-like effect in females with a long-term hormonal deprivation. An apparently successful strategy to reduce depression in women has been to adjunct a hormonal treatment with antidepressant drugs in order to enhance antidepressant efficacy. Studies with a reduced number of patients have determined that combined therapy is able to reduce the scores in the Hamilton Depression Scale, and to allow the effect of antidepressant drugs in women with refractory depression. At this respect, basic studies have established that estrogens facilitate the antidepressant effects of several antidepressant drugs. It was reported that the anxiolytic effect of desipramine was more evident in the proestrus, a phase characterized by high levels of estrogens and progesterone in young females. Both estrogens and progesterone participate in the anxiolytic effect of desipramine, although the synergism with estradiol was more significant. By using specific animal models of antidepressant effects, it was found that E2 facilitated the antidepressant effect of fluoxetine, desipramine, venlafaxine and bupropion in young, ovariectomized female rodents. In contrast, a chronic study using old, ovariectomized female rats showed that estradiol valerate was unable to improve the antidepressant effect of citalopram, even though the antidepressant efficacy of both estrogen and citalopram was established previously. Differences in results could be due to variations in methodological aspects such as age of rats (young, three months, versus old, 15 month), type of estrogen used in each study (E2 versus estradiol valerate), animal model of depression (forced swimming test, acute model, versus chronic mild stress model), type of antidepressant used (citalopram in the last case), and dosage for both estrogens and antidepressant drugs. Interestingly, the strategy of a combined treatment could be a therapeutic advantage for those women that suffer depression associated to endocrine changes. Evidence from clinical and basic studies should be taken into account at moment to select the most advantageous therapy to treat depression in mature women.
La depresión es un trastorno afectivo de origen multifactorial que se presenta con mayor frecuencia en la mujer que en el hombre. Las causas de esta diferencia se atribuyen tanto a factores sociales como biológicos. La coincidencia entre los periodos de fluctuaciones hormonales y la presencia de síntomas afectivos ha dado fuerza a la teoría de que los factores hormonales pueden ser una causa de la mayor prevalencia de depresión en la mujer. Los estudios básicos en los cuales no se presentan factores sociales sugieren que la depresión en la mujer podría tener un origen biológico. Uno de los periodos de mayor riesgo en la mujer es la perimenopausia. De acuerdo con el Grupo de Trabajo de los Estadios de la Edad Reproductiva (STRAW), la perimenopausia comprende el periodo denominado transición a la menopausia más un año después de la última menstruación. Este periodo se caracteriza por ciclos menstruales de duración variable y fluctuaciones en la concentración de estrógenos y progesterona. Conforme los ciclos se hacen impredecibles, ocurre una disminución de estrógenos, que genera alteraciones fisiológicas y afectivas. Diversos estudios epidemiológicos han logrado relacionar la perimenopausia con cambios en el estado afectivo de la mujer. Tomando en cuenta la hipótesis de que la privación de estrógenos se relaciona con los síntomas depresivos en la mujer, los tratamientos con estrógenos han sido considerados como una de las opciones terapéuticas. Los hallazgos clínicos son controvertidos, y la posible explicación son las diferencias en la metodología empleada en cada estudio, así como la falta de consistencia en la definición de perimenopausia y en los instrumentos de medición hormonal y del estado emocional de la mujer. De manera interesante, los estudios básicos apoyan la idea de que los estrógenos producen efectos antidepresivos importantes. Sin embargo, existen diferencias en la respuesta antidepresiva que dependen tanto del tipo de estrógeno como del estado hormonal de la hembra. Hasta el momento, los hallazgos más consistentes refieren al 17β-estradiol como la hormona más relevante para producir acciones antidepresivas en la hembra. El mismo estrógeno es efectivo en ratas viejas, con un periodo de privación hormonal moderado; sin embargo, deja de ser efectivo en la depresión experimental cuando ese periodo se extiende por varios meses. Otra alternativa terapéutica para tratar la depresión en la perimenopausia y posmenopausia es la terapia combinada de agentes hormonales y fármacos antidepresivos. En dos estudios con un reducido número de pacientes se determinó que la adición de estrógenos favorece el efecto de los fármacos antidepresivos en mujeres con depresión refractaria a dichos tratamientos. La investigación básica aporta resultados consistentes al respecto, ya que, por un lado, se ha determinado que diferentes estrógenos inducen un efecto tipo antidepresivo en ratas ovariectomizadas, y por otro, que la administración de dosis subefectivas de dichos estrógenos facilita el efecto antidepresivo, o incluso acorta la latencia de aparición del efecto antidepresivo de fármacos como la fluoxetina, la desipramina y la venlafaxina. Los resultados sugieren que los estrógenos pueden interactuar con diferentes sistemas de neurotransmisión para mejorar las acciones de los fármacos antidepresivos. Más aún, ha sido demostrado que el sistema serotonérgico participa en buena medida en las acciones antidepresivas de algunos estrógenos, lo cual aporta más evidencia sobre las fallas en la neurotransmisión serotonérgica en etapas de privación hormonal. La evidencia de los estudios básicos y clínicos apoya la idea de que la mujer tiene periodos de vulnerabilidad afectiva que se relacionan con cambios endocrinos importantes. Los tratamientos para la depresión en la mujer deben ser elegidos con base en las condiciones endocrinas de la paciente, así como en las características propias de los tratamientos.
ABSTRACT
Background. Among its behavioral action, progesterone reduces anxiety in several species including humans; however, any antidepressant-like properties remain to be explored. Methods. In the present study, Wistar rats received injections (i.p.) of progesterone (0.20-3.0 mg/kg) 24 and 2 h before being submitted to the forced swim, a test in which antidespressants regulary reduce immobility and exert few or on action on locomotor activity. In order to discard the cumulative effects of progesterone and a possible effect from the repetition of the swimming test, all animals received one of several progesterone doses in a different sequence following a completely randomized experimental intrasubjects design. Results. Ovariectomy did not modify immobility in the forced swin test as compared to control test practiced before surgery- A dose of 0.80 mg/kg strongly reduced the total time of immobility in forced swin test (p< 0.001), but did not modify locomotor activity. In a drug-free control test applied 1 week after the injection of progesterone, immobility returned to the higher values observed in the control tests. Conclusions. From these results, it is concluded that progesterone may possess some antidepressant-like activity