Unconjugated Estrogens in the Perinatal Period

Fm, Kenny; Angsusingha, K; Stinson, Dora A.; Hotchkiss, J.

doi:10.1203/00006450-197310000-00006

Cited by 76 publications

(32 citation statements)

References 16 publications

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“…Finally, estradiol and progesterone inhibited the NF-B pathway, which plays a seminal role in the control of inflammatory and innate immune responses. Blood levels of estradiol and progesterone are particularly elevated at birth and decrease 10-to 100-fold within 48 h (12,17,43). Considering that most of the newborns developing sepsis become symptomatic within the first 24 h of life (5), the potent anti-inflammatory effect of estradiol on cord blood monocytes may have clinically relevant implications in early-onset neonatal sepsis.…”

Section: Discussionmentioning

confidence: 99%

Estradiol and Progesterone Strongly Inhibit the Innate Immune Response of Mononuclear Cells in Newborns

et al. 2011

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Newborns are particularly susceptible to bacterial infections due to qualitative and quantitative deficiencies of the neonatal innate immune system. However, the mechanisms underlying these deficiencies are poorly understood. Given that fetuses are exposed to high concentrations of estradiol and progesterone during gestation and at time of delivery, we analyzed the effects of these hormones on the response of neonatal innate immune cells to endotoxin, bacterial lipopeptide, and Escherichia coli and group B Streptococcus, the two most common causes of early-onset neonatal sepsis. Here we show that at concentrations present in umbilical cord blood, estradiol and progesterone are as powerful as hydrocortisone for inhibition of cytokine production by cord blood mononuclear cells (CBMCs) and newborn monocytes. Interestingly, CBMCs and newborn monocytes are more sensitive to the effects of estradiol and progesterone than adult peripheral blood mononuclear cells and monocytes. This increased sensitivity is associated with higher expression levels of estrogen and membrane progesterone receptors but is independent of a downregulation of Toll-like receptor 2 (TLR2), TLR4, and myeloid differentiation primary response gene 88 in newborn cells. Estradiol and progesterone mediate their anti-inflammatory activity through inhibition of the NF-B pathway but not the mitogenactivated protein kinase pathway in CBMCs. Altogether, these results suggest that elevated umbilical cord blood concentrations of estradiol and progesterone acting on mononuclear cells expressing high levels of steroid receptors contribute to impair innate immune responses in newborns. Therefore, intrauterine exposure to estradiol and progesterone may participate in increasing susceptibility to infection during the neonatal period.Newborns are at high risk of severe bacterial infections. Early-onset neonatal sepsis occurs during the first week of life in 1 to 5 per 1,000 births (14,24,25). Group B Streptococcus (GBS) and Escherichia coli are involved in more than 50% of episodes of early-onset neonatal sepsis. Despite antimicrobial therapy and improvements in neonatal intensive care, the mortality due to neonatal sepsis remains high (5 to 15%) and survivors are at risk of permanent neurologic damage (14,24,25). The particularly high susceptibility to infection during the neonatal period has been associated with quantitative and qualitative deficiencies of innate immunity (such as reduced levels of opsonins, decreased cytokine production, and impaired function of phagocytes) and adaptive immunity (such as impaired function of antigen-presenting cells and T cells and decreased production of immunoglobulins) (1,19,36). Although the differences between the neonatal and adult immune responses are relatively well described, the underlying mechanisms that account for the decreased ability of newborns to mount efficient immune responses remain largely unknown.Fetuses are chronically exposed to high levels of steroid hormones due to placental production. Concentrations ...

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Section: Discussionmentioning

confidence: 99%

Estradiol and Progesterone Strongly Inhibit the Innate Immune Response of Mononuclear Cells in Newborns

et al. 2011

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“…Potential physiologic applications include an improved understanding of estrogen secretion during infancy (9-11), childhood ( 12,13,37), and menopause (38)(39)(40), including the diurnal variation in secretion and the potential cyclicity associated with premenarcheal follicular maturation and atresia (43). Pathologic applications include the pathophysiology of premature thelarche (44), the differential diagnosis and monitoring of treatment for precocious puberty (45), and optimization of treatment for estrogendependent neoplasms such as breast cancer (46).…”

Section: Discussionmentioning

confidence: 99%

Estrogen levels in childhood determined by an ultrasensitive recombinant cell bioassay.

Klein¹,

Baron²,

Colli³

et al. 1994

J. Clin. Invest.

352

225

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We hypothesized that estradiol levels are higher in prepubertal girls than in prepubertal boys and that this greater secretion of estradiol might drive the more rapid epiphyseal development and earlier puberty in girls. Since previous estradiol assays have lacked adequate sensitivity to test the hypothesis of higher estradiol levels in girls, we developed a new ultrasensitive assay to measure estrogen levels. The assay uses a strain of Saccharomyces cerevisiae genetically engineered for extreme sensitivity to estrogen. Yeast were transformed with plasmids encoding the human estrogen receptor and an estrogen-responsive promoter fused to the structural gene for f-galactosidase. Ether extracts of 0.8 ml of serum were incubated with yeast for 8 h and the 38-galactosidase response was used to determine estrogen bioactivity relative to estradiol standards prepared in charcoalstripped plasma. The assay was highly specific for estradiol with < 3 % cross-reactivity with estrone, estriol, or estradiol metabolites. The detection limit was < 0.02 pg/ml estradiol equivalents (100-fold lower than existing assays). Using this assay, we measured estrogen levels in 23 prepubertal boys (9.4±2.0 yr) and 21 prepubertal girls (7.7+1.9 [SD] yr). The estrogen level in girls, 0.6+0.6 pg/ml estradiol equivalents, was significantly greater than the level in boys, 0.08+0.2 pg/ml estradiol equivalents (P < 0.05). We conclude that the ultrasensitive recombinant cell bioassay for estrogen is approximately 100-fold more sensitive than previous estradiol assays, that estrogen levels are much lower prepubertally, in both sexes, than reported previously, and that prepubertal girls have 8-fold higher estrogen levels than prepubertal boys. (J. Clin. Invest. 1994Invest. . 94:2475Invest. -2480

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“…Despite difficulties about the sensitivity of the radioimmunoassay of plasma oestrogens and the relatively large volumes of blood that are required (8-10 ml plasma), some results have been obtained (Bidlingmaier et al, 1974;Kenny et al, 1973). Umbilical cord blood oestrone and oestradiol levels are one thousand times higher than those of the adult.…”

Section: G O Nmentioning

confidence: 99%

Hypothalamic‐pituitary‐gonadal Relationships in Man From Birth to Puberty

Forest

Peretti

Bertrand

1976

Clinical Endocrinology

134

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Gonadal function depends upon activities at various levels. Thus there is: (a) a central level (extra-hypothalamic, hypothalamic, and anterior pituitary); (b) an intermediate level (gonadal and plasma), and (c) a peripheral level consisting of the target organs to which the hormonal message is directed. These determine both the expression of gonadal function (physical, physiological, or psychological) and the feedback regulation of the secretion of gonadotrophins.(a) Central level (i) Extra-hypothalamic centres. The production of LH releasing hormone (LHRH) is affected in the rat, and probably in primates as well, by extra-hypothalamic stimuli coming, in particular, from the amygdala and the hippocampus. Adrenergic regulation exists at this level, noradrenaline having a stimulatory and dopamine an inhibitory effect (Bliss et al., 1972).(ii) Hypothalamic centres. These are localized in particular in the pre-optic area. Immunochemical techniques have demonstrated that LHRH is secreted by neurones of the arcuate nucleus, and released into the capillary plexus proximal to the hypophyseal portal system at the level of the median eminence, thereby reaching the anterior pituitary (Barry & Dubois, 1974;Setalo et al., 1975).(iii) Gonadotrophin secreting cells of the anterior pituitary. These synthesize and secrete the gonadotrophins, LH and FSH, under the influence of LHRH (Schally et al., 1972). The pituitary gonadotrophins stimulate the synthesis and the secretion of the gonadal

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Unconjugated Estrogens in the Perinatal Period

Cited by 76 publications

References 16 publications

Estradiol and Progesterone Strongly Inhibit the Innate Immune Response of Mononuclear Cells in Newborns

Estradiol and Progesterone Strongly Inhibit the Innate Immune Response of Mononuclear Cells in Newborns

Estrogen levels in childhood determined by an ultrasensitive recombinant cell bioassay.

Hypothalamic‐pituitary‐gonadal Relationships in Man From Birth to Puberty

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