**3. Conclusion**

238 Sex Steroids

Fig. 3. Interactions of the GnRH system with the hypothalamo–pituitary–gonadal axis and immune system. Abbreviations: GnRH, gonadotropin releasing hormone-producing neurons; LH, luteinizing hormone; FSH, follicle stimulating hormone; LC, locus coeruleus; A1, A2, and A15, catecholamine-producing (tyrosine hydroxylase-immunoreactive) cell

Acidophilic and basophilic pituitary cells in the mutants are smaller than normal, and the synthesis of the growth hormone, prolactin, FSH, and luteinizing hormone is reduced (Goya et al, 2004). Thymic peptides, thymulin in particular, correct these disturbances (García et al., 2005). Neonatal thymulin gene therapy in nude mice results in normalization of blood thymulin and gonadotropin levels at maturity (Goya et al., 2007). Thus, the hormonal hypofunction of the thymus during early ontogeny entails long-term or irreversible disturbances in the structure and functions of both immune and reproductive systems. The sum of available data suggests the following scheme of interactions between the hypothalamo-pituitary reproductive system and the thymus (Fig. 3). Hypothalamic GnRH

groups in the brain.

The data considered in this review demonstrate that interactions of the hypothalamo– pituitary–gonadal and immune systems are a lifelong phenomenon that begins during embryonic development. The pattern of establishment and development of their interactions during early ontogeny is a major factor in programming the health of an individual. Changes in these systems upon perinatal exposure to various adverse factors upset the normal homeostatic balance of the body, causing disturbances in their functioning throughout the subsequent life span. The plasticity of physiological systems during early ontogeny provides for effective adaptation of the developing organism to variable ambient conditions; on the other hand, it is responsible for long-term or even permanent alteration of general response to environmental factors. Thus, thymic peptide deficiency in neonatally thymectomized or nude mice or increased levels of proinflammatory cytokines resulting from bacterial infection in a pregnant female cause disturbances in the formation of various brain systems, thereby affecting differentiation of GnRH neurons and, therefore, the establishment of the reproductive function. Since high concentrations of sex steroids can significantly intrude on the formation of the neuroendocrine–immune axis, caution should be taken in prescribing sex steroids and their synthetic analogs. In particular, this concerns prenatal treatment with estriol recommended by some specialists. Special attention should also be given to the children whose mothers suffered an infectious disease during pregnancy. On the other hand, experimental and clinical data accumulated to date provide evidence for a favorable effect of estrogens on patients with autoimmune diseases, e.g., multiple sclerosis.

The patterning of sexual behavior of sex steroids takes place not only during early development: these hormones can alter the prenatal programming of relevant systems at later stages of ontogeny, with adolescence being most responsive to their influence. The effects of GnRH and sex hormones on the immune system during adult life are apparently nonspecific and serve to maintain its homeostasis in response to changes in ambient conditions or to stress-induced immunosuppression. Indeed, thymocyte deficiency resulting from age-related thymus involution or stress can be reversed by treatment with hormones, including GnRH and its agonists.
