Reduced levels of maternal progesterone during pregnancy increase the risk for allergic airway diseases in females only

Hartwig, Isabel; Bruenahl, Christian A.; Ramisch, Katherina; Keil, Thomas; Inman, Mark D.; Arck, Petra C.; Pincus, Maike

doi:10.1007/s00109-014-1167-9

Cited by 19 publications

(12 citation statements)

References 57 publications

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“…Despite sex-specificity in immune responses is frequently reported, 33 Surprisingly, similar effects of steroid hormones were observed in T cells isolated from non-pregnant and pregnant mice early (gd 7.5) and late (gd 18.5) of gestation. We used 10 −6 M of progesterone for in vitro cultures, which represents approximately three times the serum concentration in pregnant mice at gd 16.5-the peak of progesterone concentrations in the serum.…”

Section: Discussionmentioning

confidence: 71%

“…Since sex-specific immune responses are well-known, [32][33][34][35] we next assessed whether cells derived from male and female animals are differentially affected by steroid hormones. We isolated spleen cells from male and female C57BL/6 wild-type mice and cultured them with hormones as described before.…”

Section: Progesterone-mediated T-cell Death Induction Is Also Obsermentioning

confidence: 99%

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Progesterone modulates the T‐cell response via glucocorticoid receptor‐dependent pathways

Hierweger

Engler

Friese

et al. 2019

American J Rep Immunol

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Problem Steroid hormones such as progesterone and glucocorticoids rise during pregnancy and are accountable for the adaptation of the maternal immune system to pregnancy. How steroid hormones induce fetal tolerance is not fully understood. We hypothesized that steroid hormones selectively regulate the T‐cell response by promoting T‐cell death. Method of study We incubated murine spleen cells isolated from non‐pregnant and pregnant mice with physiological concentrations of steroid hormones in vitro and analyzed T‐cell subsets after 48 h of incubation. ResultsWe found that progesterone and the synthetic glucocorticoid dexamethasone induce T‐cell death. CD4+ regulatory T (Treg) cells were refractory toward progesterone‐induced cell death, in contrast to conventional CD4+ T cells, which resulted in a preferential enrichment of CD4+ Tregcells in culture. T cells isolated from pregnant mice at early and late gestation showed comparable sensitivity to steroid‐induced cell death. The target receptor for progesterone in immune cells is controversially discussed. We provide here support of progesterone binding to the glucocorticoid receptor as only T cells lacking the glucocorticoid but not the progesterone receptor showed resistance against progesterone‐induced death. ConclusionsOur results indicate that high levels of progesterone during pregnancy can induce selective T‐cell death by binding the glucocorticoid receptor. Although physiological hormone concentrations were used, due to different bioavailability of steroid hormones in vivo these results have to be validated in an in vivo model. This mechanism might ensure immunological tolerance at the feto‐maternal interface at gestation.

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Section: Discussionmentioning

confidence: 71%

Section: Progesterone-mediated T-cell Death Induction Is Also Obsermentioning

confidence: 99%

Progesterone modulates the T‐cell response via glucocorticoid receptor‐dependent pathways

Hierweger

Engler

Friese

et al. 2019

American J Rep Immunol

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“…Bidirectional interactions between the HPA and the hypothalamic-pituitary-gonadal (HPG) axes during development may also contribute to sex differences in early life stress exposures(70, 71). Notably, a recent study in a pregnancy cohort (n=409) found a relationship between lower prenatal maternal progesterone levels early in pregnancy and increased cumulative incidence of asthma and allergic rhinitis at 3–5 years of age among girls but not among boys(72). The authors conceptualized reduced progesterone as a surrogate marker of stress, given known interactions between the HPA and HPG axes.…”

Section: Discussionmentioning

confidence: 99%

Prenatal and postnatal stress and asthma in children: Temporal- and sex-specific associations

Lee

Chiu

Rosa

et al. 2016

Journal of Allergy and Clinical Immunology

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BACKGROUND Temporal- and sex-specific effects of perinatal stress have not been examined for childhood asthma. OBJECTIVES We examined associations between pre- and/or postnatal stress and children's asthma (n=765) and effect modification by sex in a prospective cohort study. METHODS Maternal negative life events (NLEs) were ascertained prenatally and postpartum. NLEs scores were categorized as 0, 1-2, 3-4, or ≥5 to assess exposure-response relationships. We examined effects of pre- and postnatal stress on children's asthma by age 6 years modeling each as independent predictors; mutually adjusting for prenatal and postnatal stress; and finally considering interactions between pre- and postnatal stress. Effect modification by sex was examined in stratified analyses and by fitting interaction terms. RESULTS When considering stress in each period independently, among boys a dose-response relationship was evident for each level increase on the ordinal scale prenatally (OR=1.38, 95% CI 1.06, 1.79; p-for-trend=0.03) and postnatally (OR=1.53, 95% CI 1.16, 2.01; p-for-trend=0.001); among girls only the postnatal trend was significant (OR=1.60, 95% CI 1.14, 2.22; p-for-trend=0.005). Higher stress in both the pre- and postnatal periods was associated with increased odds of being diagnosed with asthma in girls [OR=1.37, 95% CI 0.98, 1.91 (pinteraction=0.07)] but not boys [OR=1.08, 95% CI 0.82, 1.42 (pinteraction=0.61)]. CONCLUSIONS While boys were more vulnerable to stress during the prenatal period, girls were more impacted by postnatal stress and cumulative stress across both periods in relation to asthma. Understanding sex and temporal differences in response to early life stress may provide unique insight into asthma etiology and natural history.

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“…Indeed, sex differences in the placental response to stress has been well-documented by others, and these differences are proposed to play an important role in sexually dimorphic programming of development (6,43). The sex-differences in the placental response to stress are thought to contribute the increased risk for adverse neurodevelopmental programming in males (45), and others have proposed that sex-differences in the placental response to progesterone levels might affect programming of asthma in offspring (46). The interaction of sexually dimorphic organ development with sex differences in placental functions will likely need to be considered in future studies in order to define the mechanisms underlying sex-specific developmental programming.…”

Section: Discussionmentioning

confidence: 97%

Chronic, Elevated Maternal Corticosterone During Pregnancy in the Mouse Increases Allergic Airway Inflammation in Offspring

et al. 2020

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Allergic asthma is a chronic pulmonary disorder fundamentally linked to immune dysfunction. Since the immune system begins developing in utero, prenatal exposures can affect immune programming and increase risk for diseases such as allergic asthma. Chronic psychosocial stress during pregnancy is one such risk factor, having been associated with increased risk for atopic diseases including allergic asthma in children. To begin to define the underlying causes of the association between maternal stress and allergic airway inflammation in offspring, we developed a mouse model of chronic heightened stress hormone during pregnancy. Continuous oral administration of corticosterone (CORT) to pregnant mice throughout the second half of pregnancy resulted in an ∼2-fold increase in circulating hormone in dams with no concomitant increase in fetal circulation, similar to the human condition. To determine how prolonged heightened stress hormone affected allergic immunity in offspring, we induced allergic asthma with house dust mite (HDM) and examined the airway immune response to allergen. Female mice responded to HDM more frequently and had a more robust immune cell response compared to their male counterparts, irrespective of maternal treatment. Male offspring from CORT-treated dams had a greater number of inflammatory cells in the lung in response to HDM compared to males from control dams, while maternal treatment did not affect immune cell numbers in females. Alternatively, maternal CORT caused enhanced goblet cell hyperplasia in female offspring following HDM, an effect that was not observed in male offspring. In summary, prenatal exposure to mild, prolonged heightened stress hormone had sexually dimorphic effects on allergic inflammation in airways of adult offspring.

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Reduced levels of maternal progesterone during pregnancy increase the risk for allergic airway diseases in females only

Cited by 19 publications

References 57 publications

Progesterone modulates the T‐cell response via glucocorticoid receptor‐dependent pathways

Progesterone modulates the T‐cell response via glucocorticoid receptor‐dependent pathways

Prenatal and postnatal stress and asthma in children: Temporal- and sex-specific associations

Chronic, Elevated Maternal Corticosterone During Pregnancy in the Mouse Increases Allergic Airway Inflammation in Offspring

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