Different aspects of the reciprocal regulatory influence on the development of gonadotropin-releasing hormone (GnRH)-producing- and immune systems in the perinatal ontogenesis and their functioning in adults in normal and pathological conditions are discussed. The influence of GnRH on the development of the immune system, on the one hand, and the influence of proinflammatory cytokines on the development of the hypothalamic-pituitary-gonadal system, on the other hand, and their functioning in adult offspring are analyzed. We have focused on the effects of GnRH on the formation and functional activity of the thymus, as the central organ of the immune system, in the perinatal period. The main mechanisms of reciprocal regulation of these systems are discussed. The reproductive health of an individual is programmed by the establishment and development of physiological systems during critical periods. Regulatory epigenetic mechanisms of development are not strictly genetically controlled. These processes are characterized by a high sensitivity to various regulatory factors, which provides possible corrections for disorders.

Various stress factors during critical periods of fetal development modulate the epigenetic mechanisms controlling specific genes, which can affect the structure and function of physiological systems. Maternal immune stress by bacterial infection simulated by lipopolysaccharide (LPS) in an experiment is considered to be a powerful programming factor of fetal development. Studies of the molecular mechanisms controlling the formation and functioning of physiological systems are in the pilot stage. LPSs are the most potent natural inflammation factors. LPS-induced increases in fetal levels of pro- and anti-inflammatory cytokines can affect brain development and have long-term effects on behavior and neuroendocrine functions. The degradation of serotonergic neurons induced by LPS in the fetus is attributed to the increased levels of interleukin (IL)-6 and tumor necrosis factor (TNFα) as well as to anxiety and depression in children. Dopamine deficiency causes dysthymia, learning disability, and Parkinson’s disease. According to our data, an LPS-induced increase in the levels of IL-6, leukemia inhibitory factor (LIF), and monocyte chemotactic protein (MCP-1) in maternal and fetal rats during early pregnancy disturbs the development and functioning of gonadotropin-releasing hormone production and reproductive systems. It is important to note the high responsiveness of epigenetic developmental mechanisms to many regulatory factors, which offers opportunities to correct the defects.

The development of the neuroendocrine system, including the hypothalamic–pituitary–gonadal (HPG) axis, is sensitive to environmental impacts during critical developmental periods. Maternal immune system activation by bacterial or viral infection may be one of the negative impacts. This study focused on the effect of systemic inflammation induced by lipopolysaccharides (LPS E. coli) on the HPG axis development in male rat offspring, corrected by the anti-inflammatory action of polyclonal IgG and monoclonal anti-interleukin (IL)-6 receptor antibodies (IL-6RmAbs). A single LPS exposure on the 12th embryonic day (ED) led to a decrease in the number of afferent synaptic inputs on gonadotropin-releasing, hormone-producing neurons in adult male offspring. LPS exposure on ED18 did not lead to such disruptions. Moreover, after the LPS injections on ED12, circulating follicle-stimulating hormone and sex steroid levels were reduced, and the gonadal structure was disrupted. A prenatal IL-6R blockade with IL-6RmAbs and polyclonal IgG reduced the negative effects of inflammation on fetal HPG axis development. Overall, the data obtained confirm the morphogenetic effect of inflammation on fetal HPG development and IL-6 involvement in these processes.

Stress signals during fetal or early postnatal periods may disorganize reproductive axis development at different levels. This study was aimed to test the hypothesis that prenatal immunological stress induced by bacterial endotoxin, lipopolysaccharide (LPS), has impact on structure and function of the reproductive system in female offspring. Adult female Wistar rats were divided into two groups, a control group (n = 5) and a LPS group (n = 12). Rats were injected with LPS 50 μg/kg body or 0.9% saline intraperitoneally on the 12th day of pregnancy. After birth the female pups (n = 20 in each group) were divided into four groups: (group 1) 0.9% saline prenatally, sesame oil (vehicle) postnatally; (group 2) LPS prenatally, sesame oil postnatally; (group 3) LPS prenatally, fulvestrant postnatally; (group 4) LPS prenatally, flutamide postnatally. Pups were injected subcutaneously into the neck with fulvestrant (estrogen receptor antagonist), 1.5 mg/kg in sesame oil, from postnatal day (PND) 5 to PND14; or flutamide (androgen receptor antagonist), 20 mg/kg in sesame oil, from PND14 to PND30. Rats of the control group were injected with sesame oil during the same time period. Parameters were evaluated by ELISA (serum estradiol and testosterone) and ovarian histology. The main findings were: (1) prenatal stress during the critical period resulted in delayed vaginal opening, decreased body weight and serum concentrations of sex steroids, and significant disorders in ovarian development; (2) postnatal estradiol and testosterone antagonist treatments decreased follicular atresia through increasing the number of healthy follicles and restored endogenous steroid production. Lay summaryImmunological stress, caused by simulating infection through exposure to a bacterial toxin (LPS), during a critical period of fetal development in laboratory rats results in delayed reproductive maturity, decreased body weight and decreased secretion of sex steroids in female offspring, and abnormalities in the ovaries like those in polycystic ovarian syndrome. These prenatally toxin-induced sexual disorders in females could be corrected by estradiol/testosterone antagonists during the postnatal period.

This review analyzes data on the effect of cytokines on the development of the hypothalamic–pituitary–gonadal (HPG) axis at all levels during pre- and postnatal ontogenesis under physiological and pathological conditions in humans and other mammals. Changes in cytokine physiological balance, associated with stress, inflammation, aging, and metabolic syndromes, affect the secretion of gonadotropin-releasing hormone, a key regulator of the HPG axis, as well as the secretion of pituitary gonadotropins, gonadal steroidogenesis, and gametogenesis in both males and females. Special attention is given to proinflammatory cytokines, the levels of which increase under the influence of infectious agents. Their impact on the development of the fetal brain and HPG axis is examined, as are the ensuing long-term consequences for HPG axis function. The study of cytokine contribution to the development and function of the HPG axis opens up broad prospects for reproductive disorder prevention during early ontogenesis.