Peptídeo natriurético tipo C (CNP): relação com o crescimento folicular e a maturação oocitária em humanos

Abstract

Introduction: C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family that binds to the cell membrane receptor NPR2 and signals through the second messenger cGMP. Previous studies in mice suggested that CNP stimulates preantral and antral follicle growth but inhibits meiotic resumption of oocytes. Preliminary data in humans have suggested that ovarian CNP levels may decrease after the preovulatory LH surge. Despite the evidence from animals studies that CNP is a key paracrine regulator of oocyte maturation, its correlation with ovulation induction in humans is unknown. Methods: Following IRB approval and written informed consent, follicular fluid samples were collected prospectively from 46 women during oocyte retrieval for in vitro fertilization. CNP levels were measured by enzyme immunoassay. The granulosalutein cells were also collected and the reverse-transcription polymerase chain reaction analysis for CNP precursor gene, NPPC, and its receptor, NPR2, was performed. Results: CNP was detectable in all follicular fluid samples, at concentrations ranging from 0.07 to 0.47 ng/ml. Patients with endometriosis or unexplained infertility presented significantly lower levels of intrafollicular CNP when compared to the other groups, as well as those using the short protocol of ovarian induction. CNP levels correlated directly with the number of antral follicles (r = 0,454, p = 0,002), preovulatory follicles (r = 0.361, p = 0.016) and the number of oocytes retrieved (r = 0.371, p = 0.013) and inversely with the proportion of mature oocytes at metaphase II (r = 0.386, p = 0.035). No correlation was found between NPPC mRNA and CNP concentration in follicular fluid. However, in the analysis of the NPR2 expression, an inverse correlation was found between the intrafollicular CNP and the NPR2 mRNA in the granulosa cells (r = -0.385, p = 0.020). Conclusions: The present results indicate that intra-follicular CNP could turn in a novel biomarker of ovarian response to gonadotropin stimulation and oocyte maturation in humans. Moreover, these findings corroborate the experimental evidence for a critical role of CNP in the paracrine stimulation of follicle growth, while protecting oocytes from early meiotic resumption.