Assisted reproduction technologies impair placental steroid metabolism

Abstract

The placenta plays a vital role in pregnancy by facilitating steroid passage from maternal to fetal circulation and/or direct production of hormones. Using a murine model, we demonstrated the differences in placental steroid metabolism between pregnancies conceived naturally and with assisted reproduction technologies (ART): in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). While the ovarian steroid production was similar (estrone, 17beta-estradiol) or higher (estriol) in ART pregnancies compared to mating, the levels of placental estriol were significantly lower in ART group. Placentas from ART had significantly higher activities of the steroid metabolizing enzymes UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT), which in ICSI were also coupled with decreased activity of the steroid regenerating enzymes beta-glucuronidase (beta-G) and aryl sulfatase (AS). Levels of steroid metabolites androstane-3alpha-17beta-diol glucuronide and dehydroepiandrosterone sulfate were higher in fetal compared to maternal blood in ART, but not in mating. This study demonstrates that in murine ART pregnancies, higher metabolism and clearance of steroids by the placenta may seriously affect the passage of essential hormones to the fetus. If a similar phenomenon exists in humans, this could provide a plausible explanation for obstetric and neonatal complications associated with ART, including the higher incidence of low birth weight babies.

Figure 1. Placental weights in mice impregnated using mating, IVF and ICSI

Each bar represents a mean of 30 placentas ± SD. Statistical significance: a vs. b, a vs. c = P < 0.001.

Figure 2. Glucuronidation Activity

A: UGT in placenta; B: β-G in placenta. Each bar represents a mean of n = 30 placentas ± SD. Statistical significance: A vs. C, B vs. C, A vs. a, B vs. b, C vs. c, a vs. c, b vs. c = P < 0.001; A vs. B = P < 0.05. For explanation of abbreviations see Table 1.

Figure 3. Sulfonation Activity

SULT and AS in placenta. Each bar represents a mean of n = 30 placentas ± SD; Statistical significance: A vs. C = P < 0.001; C vs. c = P < 0.01; A vs. B, B vs. C = P < 0.05. For explanation of abbreviations see Table 1.

Figure 4. Levels of steroid metabolites in blood plasma from dams and fetuses

A: 3αdiolG; B: DHEAS. Each bar represents a mean of n = 3 samples ± SD, except for IVF pups, n = 2 ± SD). Statistical significance: d vs. f, E vs. e, F vs. f = P < 0.05. For explanation of abbreviations see Table 1.

Figure 5. Estriol levels in placentas from mice impregnated by mating, IVF and ICSI

Each bar represents a mean of n = 3 pools (range: 7-15 placentas per pool) ± SD. Statistical significance: a vs. b P < 0.05, a vs. c = P 0.09.

Figure 6. Estrogenic steroid levels in ovaries from mice impregnated by mating, IVF or ICSI

Each bar represents a mean of n = 3 ovaries, ± SD. Statistical significance: a = P < 0.05 vs. Mated, b = P < 0.001 vs. Mated.