Limits...
Loss of cannabinoid receptor CB1 induces preterm birth.

Wang H, Xie H, Dey SK - PLoS ONE (2008)

Bottom Line: Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition.In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation.Moreover, CB1 inactivation resulted in aberrant corticotrophin-releasing hormone and corticosterone activities prior to parturition, suggesting that CB1 regulates labor by interacting with the corticotrophin-releasing hormone-driven endocrine axis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

ABSTRACT

Background: Preterm birth accounting approximate 10% of pregnancies in women is a tremendous social, clinical and economic burden. However, its underlying causes remain largely unknown. Emerging evidence suggests that endocannabinoid signaling via cannabinoid receptor CB1 play critical roles in multiple early pregnancy events in both animals and humans. Since our previous studies demonstrated that loss of CB1 defers the normal implantation window in mice, we surmised that CB1 deficiency would influence parturition events.

Methods and findings: Exploiting mouse models with targeted deletion of Cnr1, Cnr2 and Ptgs1 encoding CB1, CB2 and cyclooxygenase-1, respectively, we examined consequences of CB1 or CB2 silencing on the onset of parturition. We observed that genetic or pharmacological inactivation of CB1, but not CB2, induced preterm labor in mice. Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition. More strikingly, the phenotypic defects of prolonged pregnancy length and parturition failure in mice missing Ptgs1 were corrected by introducing CB1 deficiency into Ptgs1 mice. In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation. The pathophysiological significance of this altered corticotrophin-releasing hormone-driven endocrine activity in the absence of CB1 was evident from our subsequent findings that a selective corticotrophin-releasing hormone antagonist was able to restore the normal parturition timing in Cnr1 deficient mice. In contrast, wild-type females receiving excessive levels of corticosterone induced preterm birth.

Conclusions: CB1 deficiency altering normal progesterone and estrogen levels induces preterm birth in mice. This defect is independent of prostaglandins produced by cyclooxygenase-1. Moreover, CB1 inactivation resulted in aberrant corticotrophin-releasing hormone and corticosterone activities prior to parturition, suggesting that CB1 regulates labor by interacting with the corticotrophin-releasing hormone-driven endocrine axis.

Show MeSH

Related in: MedlinePlus

CB1 deficiency alters normal progesterone (P4) and estradiol-17β (E2) levels prior to parturition in mice.Serum P4 and E2 levels were analyzed by radioimmunoassay. While CB1 deficiency induced an early drop in serum P4 levels on day 19 (A), circulating E2 levels were elevated on days 16–18 (B), resulting in a remarkable decrease in P4/E2 ratio prior to labor in Cnr1−/− females (C) (n = 6–10, *P<0.05).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2553193&req=5

pone-0003320-g003: CB1 deficiency alters normal progesterone (P4) and estradiol-17β (E2) levels prior to parturition in mice.Serum P4 and E2 levels were analyzed by radioimmunoassay. While CB1 deficiency induced an early drop in serum P4 levels on day 19 (A), circulating E2 levels were elevated on days 16–18 (B), resulting in a remarkable decrease in P4/E2 ratio prior to labor in Cnr1−/− females (C) (n = 6–10, *P<0.05).

Mentions: Recent evidence suggests the involvement of endocannabinoid signaling via central CB1 in neuroendocrine regulation of reproduction. For example, both exogenous cannabinoids and endocannabinoids have been shown to modulate the secretion of hypothalamic and pituitary hormones including luteinizing hormone and prolactin in rodents [32]–[36]. To reveal potential causes of preterm birth in the absence of CB1 in mice, we first examined the expression of CB1 in the hypothalamus and ovary. As illustrated in Figure 2A & B, we observed a wide distribution of CB1 in these tissues on day 18 of pregnancy, suggesting the contention that endocannabinoids would impact the hypothalamic-ovarian axis at multiple levels during late gestation. Since functional progesterone (P4) withdrawal either due to fall in circulating P4 levels or attenuation of P4 action together with heightened estrogen action determines the parturition timing in most viviparous species including humans [37], we measured serum levels of P4 and 17β-estradiol (E2) in Cnr1−/− females during late gestation to assess potential causes of preterm labor in the absence of CB1. As shown in Figure 3A, CB1 deficiency induced an early drop in serum P4 levels on day 19 of pregnancy. In contrast, circulating E2 levels substantially increased on days 16–18 with the loss of CB1 (Figure 3B). This inverse relationship between P4 and E2 levels in the absence of CB1 creates a significant decrease in P4/E2 ratio (Figure 3C), leading to preterm birth in Cnr1−/− females.


Loss of cannabinoid receptor CB1 induces preterm birth.

Wang H, Xie H, Dey SK - PLoS ONE (2008)

CB1 deficiency alters normal progesterone (P4) and estradiol-17β (E2) levels prior to parturition in mice.Serum P4 and E2 levels were analyzed by radioimmunoassay. While CB1 deficiency induced an early drop in serum P4 levels on day 19 (A), circulating E2 levels were elevated on days 16–18 (B), resulting in a remarkable decrease in P4/E2 ratio prior to labor in Cnr1−/− females (C) (n = 6–10, *P<0.05).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2553193&req=5

pone-0003320-g003: CB1 deficiency alters normal progesterone (P4) and estradiol-17β (E2) levels prior to parturition in mice.Serum P4 and E2 levels were analyzed by radioimmunoassay. While CB1 deficiency induced an early drop in serum P4 levels on day 19 (A), circulating E2 levels were elevated on days 16–18 (B), resulting in a remarkable decrease in P4/E2 ratio prior to labor in Cnr1−/− females (C) (n = 6–10, *P<0.05).
Mentions: Recent evidence suggests the involvement of endocannabinoid signaling via central CB1 in neuroendocrine regulation of reproduction. For example, both exogenous cannabinoids and endocannabinoids have been shown to modulate the secretion of hypothalamic and pituitary hormones including luteinizing hormone and prolactin in rodents [32]–[36]. To reveal potential causes of preterm birth in the absence of CB1 in mice, we first examined the expression of CB1 in the hypothalamus and ovary. As illustrated in Figure 2A & B, we observed a wide distribution of CB1 in these tissues on day 18 of pregnancy, suggesting the contention that endocannabinoids would impact the hypothalamic-ovarian axis at multiple levels during late gestation. Since functional progesterone (P4) withdrawal either due to fall in circulating P4 levels or attenuation of P4 action together with heightened estrogen action determines the parturition timing in most viviparous species including humans [37], we measured serum levels of P4 and 17β-estradiol (E2) in Cnr1−/− females during late gestation to assess potential causes of preterm labor in the absence of CB1. As shown in Figure 3A, CB1 deficiency induced an early drop in serum P4 levels on day 19 of pregnancy. In contrast, circulating E2 levels substantially increased on days 16–18 with the loss of CB1 (Figure 3B). This inverse relationship between P4 and E2 levels in the absence of CB1 creates a significant decrease in P4/E2 ratio (Figure 3C), leading to preterm birth in Cnr1−/− females.

Bottom Line: Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition.In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation.Moreover, CB1 inactivation resulted in aberrant corticotrophin-releasing hormone and corticosterone activities prior to parturition, suggesting that CB1 regulates labor by interacting with the corticotrophin-releasing hormone-driven endocrine axis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

ABSTRACT

Background: Preterm birth accounting approximate 10% of pregnancies in women is a tremendous social, clinical and economic burden. However, its underlying causes remain largely unknown. Emerging evidence suggests that endocannabinoid signaling via cannabinoid receptor CB1 play critical roles in multiple early pregnancy events in both animals and humans. Since our previous studies demonstrated that loss of CB1 defers the normal implantation window in mice, we surmised that CB1 deficiency would influence parturition events.

Methods and findings: Exploiting mouse models with targeted deletion of Cnr1, Cnr2 and Ptgs1 encoding CB1, CB2 and cyclooxygenase-1, respectively, we examined consequences of CB1 or CB2 silencing on the onset of parturition. We observed that genetic or pharmacological inactivation of CB1, but not CB2, induced preterm labor in mice. Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition. More strikingly, the phenotypic defects of prolonged pregnancy length and parturition failure in mice missing Ptgs1 were corrected by introducing CB1 deficiency into Ptgs1 mice. In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation. The pathophysiological significance of this altered corticotrophin-releasing hormone-driven endocrine activity in the absence of CB1 was evident from our subsequent findings that a selective corticotrophin-releasing hormone antagonist was able to restore the normal parturition timing in Cnr1 deficient mice. In contrast, wild-type females receiving excessive levels of corticosterone induced preterm birth.

Conclusions: CB1 deficiency altering normal progesterone and estrogen levels induces preterm birth in mice. This defect is independent of prostaglandins produced by cyclooxygenase-1. Moreover, CB1 inactivation resulted in aberrant corticotrophin-releasing hormone and corticosterone activities prior to parturition, suggesting that CB1 regulates labor by interacting with the corticotrophin-releasing hormone-driven endocrine axis.

Show MeSH
Related in: MedlinePlus