Serum Concentrations of Oocyte-Secreted Factors BMP15 and GDF9 During IVF and in Women With Reproductive Pathologies

Abstract

Oocyte-secreted factors bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) are critical for folliculogenesis and fertility. This study developed ELISAs for the measurement of BMP15 and GDF9 in serum and investigated their usefulness as biomarkers of female reproductive function. Serum samples were obtained from women undergoing infertility treatments (n = 154) and from perimenopausal and postmenopausal women (n = 28). Serum concentrations of BMP15 and GDF9 were analyzed in women relative to age, anti-Müllerian hormone, number of oocytes retrieved, and polycystic ovary syndrome (PCOS) after superovulation for in vitro fertilization. BMP15 and GDF9 immunoassays were validated for specificity, sensitivity (24 and 26 pg/mL, respectively), and reproducibility. BMP15 and GDF9 were detectable in 61% and 29% of women, respectively. BMP15 and GDF9 varied 64-fold and 15-fold, respectively, between women, but they did not change within subjects following ovarian stimulation with gonadotropins. Serum GDF9 concentration, but not BMP15 concentration, was associated with oocyte number retrieved in patients without PCOS (P = 0.018). GDF9 and BMP15 associations with oocyte number differed significantly (P < 0.05) with PCOS status. GDF9 concentrations were lower in poor responders (women with fewer than four oocytes retrieved or with cancelled cycles; P = 0.020). Serum BMP15, but not GDF9, was lower in women >55 years of age, compared with women of reproductive age (P < 0.01). This study develops and validates immunoassays to quantitate BMP15 and GDF9 in human serum and to correlate concentrations with female reproductive potential. Although assay sensitivities require improvement, this study demonstrates the diagnostic potential of oocyte-secreted BMP15 and GDF9 as serum biomarkers in reproductive medicine.

On measurement and classification; the clinical utility of biomarkers of female reproductive health

“…Prior work by the investigators (4) evaluated serum concentrations of BMP15 and GDF9 in a cohort including 154 women undergoing infertility treatment. Within this cohort, serum concentrations of BMP15 and GDF9 were similar in women with (n ¼ 18) and without (n ¼ 52) polycystic ovary syndrome, although relationships with oocytes retrieved differed by polycystic ovary syndrome status (4). As in the current study (1), there was no relationship between the biomarkers and age (4).…”

Intrafollicular Concentrations of the Oocyte-secreted Factors GDF9 and BMP15 Vary Inversely in Polycystic Ovaries

“…Because of assay limitations protein concentrations of GDF9 and BMP15 in oocytes, follicle fluids (FFs), and serum are less well characterized. Recent studies by Riepsamen and colleagues found low but relative uniform serum concentrations of GDF9 and BMP15 throughout the menstrual cycle in both healthy ovulatory women and infertile women undergoing in vitro fertilization, possibly reflecting the total population of oocytes within a woman’s ovaries, similar to anti-Mullerian hormone (AMH) ( 34 , 35 ). However, no correlations between serum AMH and either GDF9 or BMP15 serum concentrations were found, nor with concentrations of FSH ( 34 ).…”

“…Intrafollicular concentrations of GDF9 and BMP15 are expected to be higher than in serum. The study by Riepsamen and colleagues showed higher detection rates of GDF9 and BMP15 in FF from preovulatory follicles compared with serum ( 34 ), and with a new highly sensitive commercially available ELISA assay our group recently reported high concentrations of GDF9 in human small antral follicles collected in the natural menstrual cycle ( 36 ). We also found that women with PCO had significantly reduced intrafollicular concentrations of inhibins and an aberrant regulation of the inhibin-activin-follistatin axis, as well as AMH, which may reflect underlying mechanisms characterizing aberrant follicle growth in PCOS ( 36 ).…”

Regulatory Role and Potential Importance of GDF-8 in Ovarian Reproductive Activity

“…Indeed, activin A, BMP15 and GDF9 concentrations are very low in serum (in the pg/mL range), leading to the quantitation in serum being difficult. A recent study showed that BMP15 and GDF9 were detectable in 61% and 29% of women ( 120 ). Serum AMH levels are significantly higher in women with PCOS than in normal ovulatory women ( 121 , 122 ).…”