**1. Introduction**

220 Sex Steroids

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Watson C. S.; Goldblum R. M. & Midoro-Horiuti T. (2007). Estradiol activates mast cells via a non-genomic estrogen receptor-alpha and calcium influx. Molecular Reproduction is an essential function of every animal species, and its realization depends on a complex of interrelated neural, endocrine, immune, and behavioral reactions. It is now accepted that the neuroendocrine system (including its reproductive component) and the immune system have a reciprocal regulatory influence development and functioning during pre- and postnatal ontogeny (Watanobe & Hayakawa, 2003; Zakharova et al., 2005; Carreras et al., 2008; Li et al., 2007; Chapman et al., 2009; Wu et al., 2011). The functions of these systems change during ontogeny. In the perinatal period, they are involved not only in regulatory but also in morphogenetic processes, unlike in the postnatal period. The tight bilateral connection between these systems is of special significance during the early, critical period of ontogeny, when the functions necessary for postnatal life of newborns are being established. The key role in the interaction of the reproductive and immune systems is played by the hypothalamic neuropeptide gonadotropin-releasing hormone (GnRH) and sex hormones. During the perinatal period, they regulate the growth and differentiation of various fetal tissues, including the lymphoid tissue. In postnatal life, the dynamics of endocrine processes related to reproduction are regulated by the level of GnRH secretion into the hypothalamo-pituitary portal circulation. GnRH regulates secretion of pituitary gonadotropins, which regulate secretion of sex hormones. GnRH is also involved in regulation of sexual behavior, transmission of olfactory signals, and control of humoral and cell-mediated immunity. Sex hormones, in turn, regulate GnRH production in the hypothalamus (and, therefore, secretion of pituitary gonadotropins) and also its production in the thymus and spleen (Azad et al, 1998; Hrabovszky et al., 2000). On the other hand, immune system mediators such as thymic peptides and proinflammatory cytokines have a role in controlling the development and functioning of the reproductive system.

Interactions of the reproductive and immune systems during early ontogeny are prerequisite to their normal functioning in adult life. Changes in the normal levels of GnRH and sex steroids in the developing fetus or newborn and their exposure to adverse environmental factors cause disturbances in long-term programming of the regulatory mechanisms of both reproductive and immune systems (Jacobson et al., 2000; Razia et al., 2006; Cameron et al., 2008; Champagne & Curley, 2008). The brain is especially sensitive to perinatal programming by sex steroids, which not only contribute to the patterning of brain

Interactions Between Reproductive and Immune Systems

normalization of thymocyte count (Dixit et al., 2003).

**of ontogeny** 

During Ontogeny: Roles of GnRH, Sex Steroids, and Immunomediators 223

**2.1 Role of GnRH in immune system development and functioning at different stages** 

The involvement of GnRH in the differentiation of lymphocytes and regulation of immune response is lifelong. Its neonatal administration in normal mice accelerates the development of immune reactions (Marchetti et al., 1989). In rats and monkeys, central or peripheral blockade of the GnRH receptor antagonists in the neonatal period leads to reduction of mature T- and B-lymphocyte counts in the thymus, spleen, and circulating blood and suppression of antibody production and mitogen-induced proliferative response of T cells, with the immune reactions returning to the norm only by the age of 3 months in rats and 5 years in monkeys (Morale et al., 1991). Thymic and splenic lymphocytes differ in sensitivity to GnRH. Neonatal administration of a GnRH antagonist in rats results in complete block of the mitogen-induced proliferative response of thymocytes, whereas this response of splenocytes is blocked only partially. GnRH and its agonists prevent age-related involution of the thymus and normalize the suppressed functional activity of thymocytes (Marchetti et al., 1989). In pregnancy, the functional activity of GnRH in controlling the numbers of thymocytes is suppressed due to the intensified synthesis of prohibitin, an antiproliferative protein; as a consequence, the maternal thymus undergoes involution. The suppression of T-lymphocyte development in pregnancy is an adaptation against allogeneic fetal rejection. Administration of an GnRH agonist results in

There is evidence that GnRH exacerbates progression of autoimmune diseases. In particular, this follows (by contradiction) from the data by Jacobson et al. (2000) that administration of an GnRH antagonist to New Zealand mice with systemic lupus erythematosus leads to a drop in the levels of both total IgG and anti-DNA antibodies, relief of disease symptoms, and extension of life span, with these effects being observed in both intact and castrated animals of both sexes. It should be noted that the diseases progresses more severely in females than males, which the authors attribute to sex-related differences in the expression of GnRH receptors or G protein (Jacobson et al., 2000). Although the available data on the involvement of GnRH in immune response modulation and exacerbation of autoimmune diseases in adults are fairly abundant, its role in these processes is not yet completely clear. However, since the functions of many hormones in postnatal life are aimed at the maintenance of immune system homeostasis in response to changes in ambient conditions

According to our data (Zakharova et al., 2000), GnRH becomes involved in the regulation of T-cell immunity as early as during prenatal ontogeny. Surgical ablation of the hypothalamus (encephalectomy) *in utero* in 18-day rat fetuses results in 30–40% suppression of concanavalin A (Con A)-induced response in thymocytes isolated on day 22, but intraperitoneal injection of GnRH (0.2 μg per fetus) immediately after surgery restores this response to the norm. No such effect has been observed in experiments with sham-operated fetuses. Moreover, GnRH (10–9 and 10–7 M) added to a culture of thymocytes from encephalectomized fetuses has proved to enhance their Con A-induced proliferative response in a dose-dependent manner. The involvement of GnRH at early stages of immune system development is also confirmed by the results of experiments on central or peripheral blockade of the synthesis of GnRH or its receptors in rat fetuses (Zakharova et al., 2005). On day 20 of pregnancy, fetuses in one uterine horn were intraperitoneally injected with either the selective GnRH antagonist D-pGlu-D-Phe-D-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2 or anti-GnRH antibodies, and fetuses in the other horn, with 0.9% NaCl solution or nonimmune rabbit serum. The GnRH antagonist (2 μg per fetus) caused 40–50%

(Dorshkind & Horseman, 2000), such a function cannot be excluded for GnRH.

structures during early ontogeny but also activate sexual behavior in prepubertal and pubertal males and females. Thus, the brain retains its plasticity for programming at later stages of ontogeny, being most responsive to sex steroids in adolescence as well as in the perinatal period (Shulz et al., 2009). The formation of individual structural–functional elements of the reproductive and immune systems and the establishment of relationships between them are not strictly genetically controlled. These processes are characterized by high functional lability and sensitivity to various regulatory factors, which provides the possibility of correcting disturbances in the reproductive process.
