The relationship between H19 and parameters of ovarian reserve

Abstract

Context: The H19 long noncoding RNA (lncRNA) belongs to a highly conserved, imprinted gene cluster involved in embryonic development and growth control. We previously described a novel mechanism whereby the Anti-mullerian hormone (Amh) appears to be regulated by H19. However, the relationship between circulating H19 and markers of ovarian reserve including AMH not been investigated.

Objective: To determine whether H19 expression is altered in women with decreased ovarian reserve.

Design: Experimental study.

Setting: Yale School of Medicine (New Haven, USA) and Gazi University School of Medicine (Ankara, Turkey).

Patients or other participants: A total of 141 women undergoing infertility evaluation and treatment.

Intervention: Collection of discarded blood samples and cumulus cells at the time of baseline infertility evaluation and transvaginal oocyte retrieval, respectively.

Main outcome measure: Serum and cumulus cell H19 expression.

Results: Women with diminished ovarian reserve (as determined by AMH) had significantly lower serum H19 expression levels as compared to controls (p < 0.01). Serum H19 was moderately positively correlated with serum AMH. H19 expression was increased 3.7-fold in cumulus cells of IVF patients who demonstrated a high response to gonadotropins, compared to low responders (p < 0.05).

Conclusion: In this study, we show that downregulation of H19 in serum and cumulus cells is closely associated with decreased ovarian reserve, as measured by decreased AMH levels and reduced oocyte yield at oocyte retrieval. Further study with expanded sample sizes is necessary to determine whether H19 may be of use as a novel biomarker for diminished ovarian reserve.

Keywords: AMH; H19; Noncoding RNA; Ovarian reserve; ncRNA.

Fig. 1

Serum H19 expression in decreased in women with DOR. a) Expression level of H19 in women with DOR is presented as fold change relative to women without DOR (i.e. unexplained infertility and male/tubal factor). Relative H19 expression was decreased by half in women with DOR compared to women with male/tubal factor infertility, and by nearly 60% as compared to women with unexplained infertility (p < 0.05). B) A moderate positive correlation between H19 expression and serum AMH levels (r = 0.35) was observed; p < 0.05

Fig. 2

Serum H19 expression in women who are poor responders to IVF treatment. Expression level of H19 in women who were high and low responders to gonadotropins is presented as fold change relative to controls (women who had a normal / midrange gonadotropin response). Relative H19 expression was significantly decreased in “low responder” women (p < 0.05)

Fig. 3

H19 acts as a molecular “sponge” for let-7. (a) The microRNA let-7 functions as a negative regulator of target genes [36]. (b) We have shown that H19 acts as a molecular “sponge” for let-7, binding and modulating its availability [36]. The Amh mRNA contains putative binding sites for let-7 [14], and let-7 transfection leads to decreased Amh expression in GCs [14], supporting Amh as a novel let-7 target and representing a novel ncRNA mediated mechanism by which the bioavailability of Amh can be regulated by H19