Measurement of Inhibin and Activin in Early Human Pregnancy: Demonstration of Fetoplacental Origin and Role in Prediction of Early-Pregnancy Outcome1

Abstract

To determine the source of the dimeric glycoproteins inhibin A (alpha-betaA) and activin A (betaA-betaA) in early pregnancy, we analyzed serial blood samples from women who became pregnant following in vitro fertilization (IVF) with fresh embryo transfer (ET; n = 52) and from women who achieved pregnancy with frozen-thawed embryos (n = 8). Elevated serum levels of inhibin A were detected in ongoing pregnancies from 4 wk gestation (13 days following ET) and increased to an initial peak at 9-10 wk gestation. Significantly higher levels (p < 0.05) were found in the multiple pregnancies, and nonviable clinical pregnancies had very low levels of inhibin A. Total activin A was detectable 14 days after ET (positive pregnancy test), and higher levels were associated with multiple gestations while rapidly falling levels heralded embryonic demise. The fetoplacental unit is thus confirmed as the major source of these glycoproteins. Inhibin pro-alphaC, which circulates in great excess as a functionally inactive monomer and as part of high molecular weight functional dimers, was detectable at levels above normal late-luteal values in singleton and multiple IVF arising from fresh ETs. With frozen-thawed embryo pregnancies, the levels of pro-alphaC-containing inhibins were extremely low, confirming that the corpus luteum of pregnancy is the major source of the alpha monomer. The initially low levels and very rapid decline in inhibin A in pregnancies with embryonic failure suggest a role for this glycoprotein as a monitor of early-pregnancy viability.

Increased Day 15–17 Serum Pro-αC Inhibin Levels Specific to Successful Pregnancy

“…Although the relative contributions of the corpus luteum and the fetoplacental unit to circulating serum levels of inhibin A in early pregnancy remain uncertain (6,7,13), it is generally accepted that the predominant source of pro-␣C inhibin is the corpus luteum (13,14). Our data would support this.…”

“…These observations are more in keeping with a luteal than a placental origin. Furthermore, that we observed that the levels of pro-␣C inhibin in women with a frozenthawed embryo pregnancy are significantly higher than levels previously reported (13,14) reflects that the women in this current study were treated with protocols where there is often luteal function present, whereas in previous reports (13,14), women receiving frozen-thawed ETs underwent a protocol of complete ovarian suppression and therefore had a total absence of luteal tissue. Because there is an obvious discrimination in pro-␣C inhibin levels between successful and unsuccessful cycles and because it has been previously shown that administration of exogenous hCG rescues luteal production of pro-␣C inhibin (7), it is likely that hCG is the physiological stimulus for the higher luteal pro-␣C inhibin production observed in the successful pregnancies.…”

Serum biomarkers for predicting pregnancy outcome in women undergoing IVF: human chorionic gonadotropin, progesterone, and inhibin A level at 11 days post-ET

“…Initially low levels and a rapid decline of serum inhibin A concentrations during the first trimester have been shown to be related to non-viable pregnancies [16]. However, in a subsequent study, no significant difference was found between serum inhibin A levels at day 16 post-OPU in those with ongoing pregnancies and those that spontaneously aborted [8].…”

Does measurement of inhibin have a clinical role?

“…Eldar-Geva et al K2 found that serum inhibin 8 concentrations measured during the early stages (days 4-6) after administration of fixed-dose recombinant human FSH treatment provided an early predictor of the number of recruited follicles. Lindheim et al have shown that the measurement of inhibin A may be used to identify the women undergoing natural-cycle in vitro fertilization-embryo transfer (IVF-ET) who should be prepared for e~~retrieval.V Lockwood et al 84 found initially nsmg levels and then a rapid decline of maternal serum inhibin A in pregnancies with embryonic failure, indicating a possible clinical a~plication in the diagnosis of failed pregnancies, There are possible advantages here over existing markers: progesterone and hCG conntr~tions might both be expected to remain high in the continued presence of a functioning o~~s luteum and placental sac, whereas IUhlbm A is made by the foeto-placental unit.~~t her studies are required to confirm the Imbal observation and demonstrate clinical ut~lity. Since assisted pregnancies have a higher f~dure rate than spontaneous pregnancies and Since a successful outcome is so keenly awaited, this potential application of inhibin assay is Worth exploring.…”