Cytokines, Hormones and Cellular Regulatory Mechanisms Favoring Successful Reproduction.

Its semi-allogeneic nature renders the conceptus vulnerable to attack by the maternal immune system. Several protective mechanisms operate during gestation to correct the harmful effects of anti-fetal immunity and to support a healthy pregnancy outcome. Pregnancy is characterized by gross alterations in endocrine functions. Progesterone is indispensable for pregnancy and humans, and it affects immune functions both directly and via mediators. The progesterone-induced mediator - PIBF - acts in favor of Th2-type immunity, by increasing Th2 type cytokines production. Except for implantation and parturition, pregnancy is characterized by a Th2-dominant cytokine pattern. Progesterone and the orally-administered progestogen dydrogesterone upregulate the production of Th2-type cytokines and suppress the production of Th1 and Th17 cytokine production in vitro. This is particularly relevant to the fact that the Th1-type cytokines TNF-α and IFN-γ and the Th17 cytokine IL-17 have embryotoxic and anti-trophoblast activities. These cytokine-modulating effects and the PIBF-inducing capabilities of dydrogesterone may contribute to the demonstrated beneficial effects of dydrogesterone in recurrent spontaneous miscarriage and threatened miscarriage. IL-17 and IL-22 produced by T helper cells are involved in allograft rejection, and therefore could account for the rejection of paternal HLA-C-expressing trophoblast. Th17 cells (producing IL-17 and IL-22) and Th22 cells (producing IL-22) exhibit plasticity and could produce IL-22 and IL-17 in association with Th2-type cytokines or with Th1-type cytokines. IL-17 and IL-22 producing Th cells are not harmful for the conceptus, if they also produce IL-4. Another important protective mechanism is connected with the expansion and action of regulatory T cells, which play a major role in the induction of tolerance both in pregnant women and in tumour-bearing patients. Clonally-expanded Treg cells increase at the feto-maternal interface and in tumour-infiltrating regions. While in cancer patients, clonally-expanded Treg cells are present in peripheral blood, they are scarce in pregnancy blood, suggesting that fetal antigen-specific tolerance is restricted to the foeto-maternal interface. The significance of Treg cells in maintaining a normal materno-foetal interaction is underlined by the fact that miscarriage is characterized by a decreased number of total effector Treg cells, and the number of clonally-expanded effector Treg cells is markedly reduced in preeclampsia. In this review we present an overview of the above mechanisms, attempt to show how they are connected, how they operate during normal gestation and how their failure might lead to pregnancy pathologies.

Effect of dietary n-3 polyunsaturated fatty acid supplementation on the expression of genes involved in progesterone biosynthesis in the corpus luteum of goat (Capra hircus).

Emerging evidence indicates that dietary n-3 polyunsaturated fatty acids (PUFA) alter the fatty acid composition of corpus luteum (CL) and directly affect the luteal function in the cow, which is independent of the inhibitory effect on the endometrial PGF2α production. The present study, thus, investigated the effects of n-3 PUFA rich fish oil (FO) supplementation on the transcriptional modulation of genes involved in the biosynthesis of progesterone (P4 ) in the CL collected during the luteolytic phase of oestrous cycle in the goat. On the day of synchronized oestrus, goats (n = 6/group) were fed an isocaloric diet supplemented with either FO or palm oil (PO). The dose of oil supplementation was 0.6 mlkg-1 body weight, and the duration was 55-57 days. The FO provided 156 mgkg-1 body weight of n-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The CL was collected by laparotomy on day 16 post-oestrus, and the relative abundance of P450 side-chain cleaving enzyme, steroid acute regulatory protein (StAR) and 3ß-hydroxy steroid dehydrogenase (3ß-HSD) genes was quantitated by real-time PCR. The results indicated that the dietary FO significantly upregulated the expression of 3ß-HSD by 1.13-fold and downregulated StAR by ~2-fold as compared to PO group (p < .05). It is concluded that dietary FO differently affected the expression of genes involved in P4 synthesis in the CL during the luteolytic window of the oestrous cycle in the goat.

Nutrient restriction induces failure of reproductive function and molecular changes in hypothalamus-pituitary-gonadal axis in postpubertal gilts.

People on a diet to lose weight may be at risk of reproductive failure. To investigate the effects of nutrient restriction on reproductive function and the underlying mechanism, changes of reproductive traits, hormone secretions and gene expressions in hypothalamus-pituitary-gonadal axis were examined in postpubertal gilts at anestrus induced by nutrient restriction. Gilts having experienced two estrus cycles were fed a normal (CON, 2.86 kg/d) or nutrient restricted (NR, 1 kg/d) food regimens to expect anestrus. NR gilts experienced another three estrus cycles, but did not express estrus symptoms at the anticipated fourth estrus. Blood samples were collected at 5 days' interval for consecutive three times for measurement of hormone concentrations at the 23th day of the fourth estrus cycle. Individual progesterone concentrations of NR gilts from three consecutive blood samples were below 1.0 ng/mL versus 2.0 ng/mL in CON gilts, which was considered anestrus. NR gilts had impaired development of reproductive tract characterized by absence of large follicles (diameter ≥ 6 mm), decreased number of corepus lutea and atrophy of uterus and ovary tissues. Circulating concentrations of IGF-I, kisspeptin, estradiol, progesterone and leptin were significantly lower in NR gilts than that in CON gilts. Nutrient restriction down-regulated gene expressions of kiss-1, G-protein coupled protein 54, gonadotropin-releasing hormone, estrogen receptor α, progesterone receptor, leptin receptor, follicle-stimulating hormone and luteinizing hormone and insulin-like growth factor I in hypothalamus-pituitary-gonadal axis of gilts. Collectively, nutrient restriction resulted in impairment of reproductive function and changes of hormone secretions and gene expressions in hypothalamus-pituitary-gonadal axis, which shed light on the underlying mechanism by which nutrient restriction influenced reproductive function.

Dydrogesterone supplementation in women with threatened preterm delivery--the impact on cytokine profile, hormone profile, and progesterone-induced blocking factor.

Progesterone is indispensable in creating a suitable endometrial environment for implantation, and also for the maintenance of pregnancy. Successful pregnancy depends on an appropriate maternal immune response to the fetus. A protein called progesterone-induced blocking factor (PIBF) acts by inducing Th2-dominant cytokine production to mediate the immunological effects of progesterone. The aim of this prospective study was to compare serum concentrations of progesterone (P), estradiol (E2), anti-inflammatory (IL-10) and pro-inflammatory (IL-6, TNFα, IFNγ) cytokines, and serum PIBF concentrations in women with threatened preterm delivery who were given progesterone supplementation (study group) with those of women with threatened preterm delivery who were not given progesterone supplementation (control group). After dydrogesterone treatment of patients in the study group, serum PIBF as well as progesterone concentrations significantly increased. Women in this group had significantly higher serum levels of IL-10 than controls. The length of gestation was significantly higher in the group of women who were given progesterone supplementation. Our data suggest that dydrogesterone treatment of women at risk of preterm delivery results in increased PIBF production and IL-10 concentrations, and lower concentrations of IFNγ.

[Observation on the protective effect of preventive acupuncture and moxibustion on uterus in ovariectomized rats].

OBJECTIVE: To observe the effect of preventive acupuncture and moxibustion of "Guanyuan" (CV 4) on uterus in ovariectomized (OVX) rats. METHODS: A total of 80 female SD rats were randomly divided into 5 groups: normal control, sham-operation (sham), model, preventive acupuncture (PA) and preventive moxibustion (PM) groups, with 16 cases in each. PA (with the needle retained for 20 min after insertion) and PM (one moxa-cone/rat) were applied to "Guanyuan" (CV 4) separately before ovariectomy, two times a week, 4 weeks altogether. Then, ovariectomy was performed on rats of model, PA and PM groups. Uterus tissue was taken under anesthesia for homogenate (10 rats/group) or sectioning (5-6 microm, 6 rats/group). Uterus estradiol (E2), progestone (P) were detected with radioimmunoassay; superoxide dismutase (SOD), nitric oxide synthase (NOS), and malondialdehyde (MDA) were assayed with immunoturdidimetry. Partial uterus slices were stained with H & E method for observing morphological changes, or stained with immunohistochemical method or with in situ hybridization method for displaying estrogen receptor (ER)-alpha and ER-alpha mRNA expression separately. RESULTS: After ovariectomy, the rat's uterus presented obvious squamous metaplasia, hyperplasy, and thickening of the endomembrane, decrease in glands and blood vessels and increase in fibrous connective tissue, etc; while the situation was evidently better in PA and PM groups. In comparison with normal control group, E2, P contents and SOD, NOS activities of uterus tissue in model group decreased significantly (P < 0.01), while MDA in model group increased evidently (P < 0.01). Compared with model group, uterus P content in PA and PM groups increased obviously (P < 0.05), while uterus MDA decreased apparently (P < 0.01). Compared with normal control group, the expression of ER-alpha and ER-alpha mRNA in model group was downregulated markedly (P < 0.01); after PA and PM, both ER-alpha and ER-alpha mRNA expression increased obviously (P < 0.01). No significant differences were found between PA and PM groups in the above mentioned 7 indexes (P > 0.05). CONCLUSION: Preventive acupuncture and moxibustion of CV4 can postpone the structural degeneration of uterus in OVX rats, which may be related to their effects in modulating the secretion of uterus E2 and P, upregulating the expression of ER-a and ER-alpha mRNA, and improving the anti-oxidative ability.