Consumption of soy isoflavones during the prepubertal phase delays puberty and causes hypergonadotropic hypogonadism with disruption of hypothalamic-pituitary gonadotropins regulation in male rats.

Isoflavones are phytoestrogens with recognized estrogenic activity but may also affect testosterone, corticosterone and thyroid hormone levels in experimental models. However, the molecular mechanisms involved in these alterations are still unclear. Isoflavones are present in soy-based infant formula, in breast milk after the consumption of soy by the mother and are widely used for the preparation of beverages consumed by toddlers and teenagers. In this sense, we proposed to investigate the effects of soy isoflavone exposure during the prepubertal period, a recognized window of sensitivity for endocrine disruption, over the hypothalamic-pituitary-testicular (HPT) axis. For this, 42 3-week-old male Wistar rats were exposed to 0.5, 5 or 50 mg of soy isoflavones/kg from postnatal day (PND) 23 to PND60. We evaluated body growth, age at puberty, serum concentrations of LH, FSH, testosterone and estradiol, and the expression of the transcripts (mRNA) of genes encoding key genes controlling the hypothalamic-pituitary-testicular (HPT) axis. In the hypothalamus, we observed an increase in Esr1 mRNA expression (0.5 and 5 mg). In the pituitary, we observed an increase in Gnrhr mRNA expression (50 mg), a reduction in Lhb mRNA expression (0.5 mg), and a reduction in Ar mRNA expression. In the testis, we observed an increase in Lhcgr mRNA expression (50 mg) and a reduction in Star mRNA expression (0.5 and 5 mg). The serum levels of LH (5 and 50 mg) and FSH (0.5 mg) were increased, while testosterone and estradiol were reduced. Puberty was delayed in all groups. Taken together, these results suggest that prepubertal consumption of relevant levels of soy isoflavones disrupts the HPT axis, causing hypergonadotropic hypogonadism and altered expression levels of key genes regulating the axis.

Isoflavones alter male and female fertility in different development windows.

Isoflavones are a group of secondary metabolites found in plants belonging to the class of phytoestrogens. These, because they have a chemical structure similar to the endogenous hormone 17ß-estradiol, act as endocrine disruptors over the different development window periods. This study aimed to evaluate male and female reproductive systems' responses when exposed to isoflavones during the development window. It is characterized as a bibliographic review, built after analyzing clinical and preclinical articles indexed in English, Portuguese, and Spanish published in the last ten years. The isoflavones, aglycone or glucosides, have essential therapeutic properties in the relief of postmenopausal symptoms in women, reduce the proliferation of cancers, in addition to being antioxidants. On the other hand, they can still behave in a similar way to 17ß-estradiol, binding to hormone receptors and acting as endocrine disruptors over the gestational period until pre-puberty, negatively affecting the development of the reproductive system. The effects on reproduction are not dose-response but are influenced by the type of isoflavone and period. There are variations in the serum concentration of hormones and action on their negative feedback on the hypothalamic-pituitary-testicular axis in males. Reproductive functions are also affected by spermatogenesis, such as decreased sperm count, lower reproductive performance, reduced litter size, low sperm production, and reduced seminal vesicle size. In females, puberty is reached later, irregular estrous cycle, reduced weight of the ovary, uterus, lower serum levels of estradiol and progesterone, reduced fertility, or interrupted fertility. At the end of the analysis of the selected publications, it can be concluded that despite the beneficial therapeutic effects in the face of pathologies, the unknown consumption of doses and types of isoflavones in food can damage the development and reproduction of individuals. Therefore, further studies must be carried out to elucidate the usual safe doses of the analyzed phytoestrogen. Greater control over insertion in foods targeted at pediatric consumers should be implemented until we have adequate safety.