Perimenopausia y trastornos afectivos: aspectos básicos y clínicos

SUMMARY 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 ovariectomy 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 postmenopausal state. Aging rats in persistent diestrous, as well as ovariectomized 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 steroidal 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 antidepressant-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 ER 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.